Chorea, Eosinophilia, and Lupus Anticoagulant Associated with Acute Lympho astic Leukemia Deborah E. Schiff, MD and Jorge A. Ortega, MD

Contrary to its name, the lupus anticoagulant is an antiphospholipid antibody that has been found in patients with a variety of diseases, including cancer 15,61. The lupus anticoagulant-antiphospholipid antibody syndrome is associated with a n u m b e r of different clinical features. Although the most c o m m o n feature of this s y n d r o m e is thrombosis, an association with chorea has also been reported [5-8]. L u b b e and Walker reported a patient with chorea gravidarum associated with a lupus anticoagulant in the absence of SLE [9]. Bouchez et al. reported the association of the lupus anticoagulant and chorea in 3 patients [10]. Asherson et al. reported that 9 of 12 patients with chorea and SLE or "lupus-like" disease had antiphospholipid antibodies; 5 of 6 samples obtained at the time of presentation with chorea had antiphospholipid antibodies [6]. We report a child with A L L who had the associated triad of chorea, eosinophilia, and a lupus anticoagulant.

Case Report A child is reported with chorea as the initial presentation of acute lymphoblastic leukemia. Subsequent laboratory studies revealed marked eosinophilia and a lupus anticoagulant. No peripheral or central nervous system lymphoblasts were observed. The chorea, eosinophilia, and lupus anticoagulant all resolved once remission of the acute lymphoblastic leukemia was induced. It is suggested that acute lymphoblastic leukemia be included in the differential diagnosis of chorea and eosinophilia in childhood. Schiff DE, Ortega JA. Chorea, eosinophilia, and lupus a n t i c o a g u l a n t associated with acute lymphoblastic leukemia. Pediatr Neurol 1992;8:466-8.

Introduction Several paraneoplastic syndromes, such as the hypereosinophilia syndrome, have b e e n reported in association with childhood ALL. We present a previously undescribed syndrome: childhood A L L associated with the triad of chorea, eosinophilia, and a lupus anticoagulant. Eosinophilia is a rare but reported finding in patients with ALL, occurring in less than 1% of these patients [1]. Similarly, eosinophilia m a y be found in patients with systemic lupus erythematosus (SLE) and a lupus anticoagulant. Eosinophilia occurs in as m a n y as 30% o f patients with SLE [2]. Eosinophilia associated with a lupus antic o a g u l a n t in the absence of SLE has also been reported [3]. U p to 20% eosinophilia has been reported in patients with S y d e n h a m chorea [4].

From the Division of Hematology/Oncology; Children's Hospital Los Angeles; Los Angeles, California.


This 5-year-old girl, who was previously well, presented with fever, sore throat, and myalgia. Throat culture and rapid streptococcus screen were negative. During the following week, she continued to have intermittent fevers, abdominal pain, and myalgia. Approximately 2 weeks after the onset of illness, she developed difficulty with balance and an abnormal gait with in-turning of the left foot. She began having nonrhythmic, involuntary jerking movements of the extremities, occasional facial twitching, increased slurred speech, and difficulty chewing. She was examined by a pediatric neurologist and confirmed to have chorea. Cranial magnetic resonance imaging (MRI) perlbrmed at that time was normal. A complete peripheral blood count revealed a leukocyte count of 54,000/p_1with 18% neutrophils, 7% bands; 15% lymphocytes, and 59% eosinophils. Hemoglobin concentration was 9.9 gm/dl, hematocrit 29%, platelet count 342,000/Ial, and erythrocyte sedimentation rate (ESR) 64 ram/hr. Cerebrospinal fluid (CSF) cell count revealed no leukocyte cells. CSF protein was 23 mg/dl and glucose 61 mg/dl; CSF culture was negative. The patient was transferred to Children's Hospital Los Angeles for evaluation of progressive chorea and eosinophilia. Admission examination revealed a well-nourisbed and well-developed child who was alert and cooperative. Her skin had no lesions or rash. The oropharynx had no erythema or exudate. No lymphadenopathy or hepatosplenomegaly was present. Upon neurologic examination, she followed commands well, had a mild lisp while speaking, and had some difficulty performing repetitive lingual sounds. Continuous choreiform movements of the arms and legs were observed with occasional choreic movements of the head and neck. Otherwise, her neurologic examination was unremarkable. Admission laboratory findings disclosed a leukocyte count of 59,200/lal with 28% neutrophils, 3% bands, 14% lymphocytes, 3% monocytes, and 52% eosinophils. Hemoglobin concentration was 10.1 gm/dl, hematocrit 31%, platelet count 193,000/~d, reticulocyte count 4.3%, and ESR 80 mtrghr. Bone marrow aspirate was hypercellular with 48% lymphoblasts (LI FAB morphology), 21% eosinophils, and decreased megakaryocytes. Immunophenotyping revealed that the leukemic cells had a mixed B-lymphoid/myeloid phenotype. Cytogenetic studies revealed no clonal abnormality. Prothrombin time (PT) was

Communications should be addressed to: Dr. Schiff; Box 54; Children's Hospital Los Angeles; 4650 Sunset Boulevard; Los Angeles, CA 90027. Received March 4, 1992; accepted May 28, 1992.

prolonged at 14.1 s with a control of 10.%13.3 s. Partial thromboplastin time (FFF) was 31 s with a control of 24-36 s. Prolongation of the PT did not correct with the addition of normal pooled plasma, thus revealing the presence of an inhibitor. A lupus anticoagulant was demonstrated by a positive Russell's viper venom test. Tests for antinuclear antibodies, and serum antibodies to rheumatoid factor, antistreptolysinO, paragonimus, trichinella, coccidiomycosis, echinococcus, schistosomiasis, and toxicara all were negative. Quantitative immunoglobulins revealed elevated immunoglobulin G (IgG) of 2,020 mg/dl (normal: 633-1,280 mg/dl) and IgM of 304 mg/dl (normal: 48-207 mg/dl), but normal IgA and IgE. Chest radiography and echocardiography were normal. Repeat cranial MRI with gadolinium was normal. No lesions were identified within the basal nuclei or thalami. Electroencephalography also was normal. Haloperidol (0.5 mg/day) was administered to control chorea. In addition, four-drug induction chemotherapy consisting of prednisone, vincristine, L-asparaginase, and daunomycin was initiated. After 1 month of treatment, the patient's choreiform movements had resolved and haloperidol was discontinued. After 1 month, leukocyte count, differential, FIT, and PT all were within the normal range. Bone marrow aspirate on day 28 of chemotherapy revealed a remission marrow. Five months after diagnosis, the patient remained free of choreiform movements, a test for lupus anticoagulant by Russell's viper venom time was negative, and the bone marrow was normocellular with no evidence of leukemic infiltration.


Our patient had chorea as the initial presentation of ALL. Subsequently, eosinophilia and a lupus anticoagulant were discovered. No peripheral or central nervous system (CNS) blast forms were observed. The chorea, eosinophilia, and lupus anticoagulant all resolved once remission of the leukemia was induced. Patients with ALL occasionally present with eosinophilia which disappears with remission. Eosinophilia may be severe and associated with hypereosinophilia syndrome, such as fever, cough, pulmonary infiltrates, Loeffler endocarditis, and intravascular thrombi [11]. Both B-lineage and T-lineage ALL have been reported in a few patients with hypereosinophilia syndrome [11]. Our patient had leukemic cells that expressed a mixed B-lymphoid/myeloid phenotype. A distinct subtype of ALL exists, characterized by B-lineage phenotype, associated eosinophilia, and a t(5;14)(q31 ;q32) chromosomal translocation [ 1]; however, bone marrow cytogenetic studies of our patient failed to demonstrate any chromosomal abnormalities. Eosinophil production is normally regulated by several hematopoietic growth factors, including interleukin-3 (IL-3) and interleukin-5 (IL-5) [12,13]. Grimaldi and Meeker [1] and Meeker et al. [14] demonstrated in 2 patients that the promoter of the IL-3 gene and the immunoglobulin heavy chain gene are joined by t(5;14). In 1 patient with t(5;14), serum IL-3 was measured and correlated to the degree of eosinophilia [14]. Circulating lupus anticoagulants are immunoglobulins, predominantly IgG and IgM, with antiphospholipid activity. Our patient had a mild hypergammaglobulinemia. The lupus anticoagulant is often initially suspected when a coagulation profile reveals a prolonged PTT. In general, the lupus anticoagulant prolongs all phospholipid-dependent coagulation tests, occasionally including the PT. The

PT was prolonged initially in our patient but the P T r w a s not. To diagnose the lupus anticoagulant, a prolongation of a phospholipid-dependent coagulation test must not be corrected by a 1:1 dilution of the patient's blood with normal plasma, as was the case with our patient. A lupus anticoagulant can be overcome by providing an extraneous source of phospholipid. The underlying pathophysiology of chorea associated with the lupus anticoagulant is unknown. It may be postulated that chorea is the result of thrombosis of small vessels supplying the basal ganglia. That thrombosis occurs in association with lupus anticoagulant is well-established but the proposed mechanism is manifold and may be related to any of the following alterations in the coagulation cascade; the lupus anticoagulant is associated with the following: (1) Inhibition of prothrombin to thrombin; (2) Prekallikrein inhibition; (3) Prostacyclin inhibition; (4) Antithrombin-III function alteration; (5) Interaction with platelet factor III; (6) Increased platelet adhesiveness; (7) Direct antigen-antibody interaction in the vascular wall; and, (8) Inhibition of protein C activation via thrombomodulin inhibition [3,6-8]. Conversely, CNS tissue contains large quantities of phospholipids; some have postulated that antiphospholipid antibodies cause chorea by binding phospholipid in the basal ganglia [6]. Normal findings on CT and MRI scans of patients with the lupus anticoagulant and chorea support this mechanism. Asherson et al. reported that cranial CT scans performed on 6 patients with SLE or "lupus-like" disease and active chorea were normal in 5 patients [6]; severe cortical atrophy was demonstrated in the sixth patient. One patient with chorea who underwent MRI scan also had a negative study [6]. Similarly, our patient had a negative cranial MRI on two occasions. Furthermore, the eosinophilia of this patient may have led to the disruption of the blood-brain barrier; therefore, it allowed antiphospholipid antibody to penetrate into the CNS. Based on our experience with this patient, we suggest including ALL in the differential diagnosis of chorea and eosinophilia, even in the absence of peripheral blasts. In addition, we suggest screening patients with ALL and eosinophilia for a lupus anticoagulant. The mechanism underlying the association of ALL with this unusual triad remains to be determined. References

[1] Grimaldi JC, Meeker TC. The t(5;14) chromosomal translocation in a case of acute lymphocytic leukemia joins the interleukin-3 gene to the immunoglobulin heavy chain gene. Blood 1989,73:2081-5. [2] Dubois EL, Wallace DJ. The clinical and laboratory manifestations of systemic lupus erythematosus. Philadelphia: Lea & Febiger, 1987;470-87. [3] Simon LS, Mark EJ. Case records of the Massachusetts General Hospital. N Engl J Med 1990;322:754-68.

Schiff and Ortega: Acute Lymphoblastic Leukemia 467

[4] Ford FR. Encephalopathies. In: Diseases of the nervous system in infancy, childhood and adolescence. Baltimore: Charles C. Thomas, 1973;702-7. [5] Sanunaritano LR, Gharavi AE, Lockshin MD. Antiphospholipid antibody syndrome: Immunologic and clinical aspects. Semin Arthritis Rheum 1990;20:81-96. [6] Asherson RA, Derk~n RHWM, Hartis EN, et al. Chorea in systemic lupus erythematosus and "lupus-like" disease: Association with antiphospholipid antibodies. Semin Arthritis Rheum 1987;16: 253-9. [7] Levine SR, Welch KMA. The spectrum of neurologic disea~ associated with antiphospholipid antibodies. Arch Neurol 1987;44: 876-83. [8] Roddy SM, Giang DW. Antiphospholipid antibodies and stroke in an infant. Pediatrics 1991;87:933-5. [9] Lubbe WF, Walker EB. Chorea gravidarum associated with circulating lupus anticoagulant: Successful outcome of pregnancy with prednisone and aspirin therapy. Br J Obstet Gynaecol 1983;90:487-90.



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[10] Bouchez B, Arnotl G, Hatmn PY. Chorcc cl iup~s ercthema teux dissemine avec anticoagulant circulanl: 'l'mi~ ~~, !~,ev Neuror 1985;141:571-7. [11] Behm FG. Morphologic and cytt~chemical v!l~trzi~zlcrtsli~.:xo{ childhood lymphoblastic leukemia. Hemat~l ()nc~l (?lh~ North A~ 1990;4:715-.41. [12] Clark SC, Kamen R. The human hcmat~poiehc ~:~,hmy ~tilnu lating factors. Science 1987;236:1229-37. [13] Warren DJ, Moore MAS. Synergism among interleukin I. interleukin 3, and interleukin 5 in the production of e~sinophils from primitive hemopoietic stem cells. J Immunol 1988:140:¢)4-9. [14] Meeker TC, Hardy D, Willman C, Hogan T, Abrams ,!. Activation of the interleukin-3 gene by chromosome translocation in acute lymphocytic leukemia with eosinophilia. Blo~xt 1990;76:285-'0.

Chorea, eosinophilia, and lupus anticoagulant associated with acute lymphoblastic leukemia.

A child is reported with chorea as the initial presentation of acute lymphoblastic leukemia. Subsequent laboratory studies revealed marked eosinophili...
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