1226 Cerebral Venous Thrombosis in Systemic Lupus Erythematosus Marie Vidailhet, MD, Jean-Charles Piette, MD, Bertrand Wechsler, MD, Marie-Germaine Bousser, MD, and Pascal Brunei, MD We describe six cases of cerebral venous thrombosis in patients with systemic lupus erythematosus. In one patient, cerebral venous thrombosis was the initial manifestation of lupus; in the five others, it occurred 1-33 years after the diagnosis of lupus. The main clinical features of cerebral venous thrombosis were persistent headache in all six patients, focal symptoms in four, and seizures in three; papilledema was present in only one patient. Cerebral venous thrombosis was diagnosed based on angiography or magnetic resonance imaging. Both the transverse (in five patients) and the superior sagittal (in three) sinuses were involved. Extracranial arterial and/or venous thrombosis were present in three patients, abortion in two, thrombocytopenia in four, and lupus anticoagulant in three. The neurologic symptoms resolved rapidly in five patients treated with steroids and heparin. Cerebral venous thrombosis should be suspected in patients with lupus who complain of persistent headache, especially in the presence of neurologic symptoms. (Stroke 1990;21:1226-1231) Downloaded from http://ahajournals.org by on April 11, 2024 mong the numerous causes1 of cerebral venous thrombosis, systemic lupus erythematosus L (SLE) has been rarely mentioned, with only five cases published2-5; lupus anticoagulant was present in two of these cases.5 We retrospectively studied six patients fulfilling the classical criteria for SLE6 who developed cerebral venous thrombosis documented angiographically or anatomically. A Case Reports Between 1973 and 1987, cerebral venous thrombosis was diagnosed in six of 400 patients with SLE. The main features of the two disorders are summarized in Tables 1 and 2, respectively. Case 4 has been reported.7 All six patients fulfilled the classical criteria for SLE.6 There were five women and one man, the usual sex ratio of SLE. The age at onset of SLE ranged from 10 to 30 (mean 20) years. The age at diagnosis of cerebral venous thrombosis ranged from 24 to 52 (mean 35) years. In one patient it was the initial manifestation of SLE, but in the other five the interval between the diagnoses of SLE and cerebral venous thrombosis ranged from 1 to 33 years. From the Service de Medecine Interne (M.V., J-C.P., B.W.) and the Service de Neurologie (M.V., M-G.B., P.B.), Groupe Hospitalier Pitid-Salpetriere, Paris, France. Presented at the 52nd Annual Meeting, American Rheumatism Association, Houston, Tex., 1988. Address for correspondence: Marie Vidailhet, Service de Neurologie et Neuropsychologie, Groupe Hospitalier Piti6-Salpetriere, 47 Boulevard de l'Hdpital, 75651 Paris, Cedex 13, France. Received January 3, 1990; accepted April 3, 1990. Table 1 shows the manifestations of SLE. Five patients had arthritis, and five had cutaneous manifestations (malar rash, discoid rash, or photosensitivity). Five had lupus nephritis, but the nephrotic syndrome was present in only one patient. Five had neurologic manifestations unrelated to cerebral venous thrombosis (seizures in three patients and psychiatric symptoms in two). Thrombocytopenia occurred in four. Antinuclear and anti-deoxyribonucleic acid (DNA). antibodies were present in four patients; both antibodies were lacking in the other two (cases 1 and 4) despite follow-ups of 9 and 29 years, respectively. The presence of lupus anticoagulant diagnosed on the basis of a partial thromboplastin time (PTT) >6 seconds longer than the upper normal limit and failure of the prolonged PTT to correct upon 1 : 1 dilution of the patient's plasma with control plasma was present in three patients. Other assays such as the Russell's viper venom time were not routinely performed. Anticardiolipin antibodies were looked for in two patients and were found in one (case 6). A false-positive test for syphilis (VDRL) was not found in any patient. Three patients had other vascular events (upper- or lower-limb thrombophlebitis and middle cerebral, renal, or tibial artery thrombosis). Two patients had histories of spontaneous abortions, and two developed vascular complications while pregnant (one developed cerebral venous thrombosis and the other developed middle cerebral artery occlusion). Of the four patients with vascular events and/or abortion three Vidailhet et al Lupus Erythematosus and Sinus Thrombosis TABLE 1. Main Features of SLE in Six Patients With Cerebral Venous Thrombosis 1 F 29 Feature Downloaded from http://ahajournals.org by on April 11, 2024 Sex Age at onset of SLE (yr) Criteria for diagnosing SLE Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis Serositis Renal disorder Neurologic disorder (not cerebral venous thrombosis) Hematologic disorder Hemolytic anemia Leukopenia Lymphopenia Thrombocytopenia Immunologic disorder Lupus erythematosus cell Anti-DNA antibody Anti-Sm antibody False-positive VDRL Antinuclear antibody Other features of SLE Lupus anticoagulant Spontaneous abortion Thrombosis Arterial Patient 3 F 30 2 F 14 4 F 23 5 M 10 6 F 17 + + Middle cerebral Renal, limb Venous (extracranial) Limb Limb SLE, systemic lupus erythematosus; DNA, deoxyribonucleic acid; VDRL, test for syphilis; F, female; M, male. TABLE 2. Main Features of Cerebral Venous Thrombosis in Six Patients With Systemic Lupus Erythematosus Feature Age at first symptom of thrombosis (yr) Headache Focal symptoms Seizures Papilledema Diagnostic tests Computed tomography Angiography Treatment Course Patient 4 5 6 31 + Aphasia, agraphia + - 52 26 24 + - + + Left monoplegia + - - Left hemiplegia + - Frontal hypodensity Old arterial cerebral infarction Normal SSS, TS S+A Resolved TS, JV S+A Resolved TS S+A Resolved 1 2 3 29 47 + - + Alternate hemiparesis - + * * None Optic atrophy SSS, TS S+A Resolved Parietal hypodensity and hyperdensity SSS S+A Resolved L, left; SSS, superior sagittal sinus; TS, transverse sinus; JV, jugular vein; S+A, steroids and anticoagulants. •Diagnosis was made during surgical decompression in 1973. 1227 1228 Stroke Vol 21, No 8, August 1990 F I G U R E 1. Right carotid angiogram of 24-year-old woman with systemic lupus erythematosus and cerebral venous thrombosis. Note absence of filling of superior sagittal sinus and of parietal cortical veins (arrows). Downloaded from http://ahajournals.org by on April 11, 2024 had thrombocytopenia and lupus anticoagulant was present in two. The neurologic manifestations of cerebral venous thrombosis are listed in Table 2. The mode of onset was acute (<48 hours) in five patients and progressive (a few weeks) in the other. Focal deficits (left hemiparesis and hypesthesia, alternate hemiplegia, aphasia and agraphia, and left lower limb paresis) were present in four patients. Three had seizures (grand mal seizures in one and partial motor seizures in two). No patient had an altered level of consciousness. Persistent headache was a constant feature; however, isolated intracranial hypertension with headache and papilledema was the initial presentation of cerebral venous thrombosis in one patient. Lumbar puncture was performed in four patients, and the cerebrospinal fluid composition was found to be abnormal (55 mg protein/dl and 55 lymphocytes/ mm3) in one. Unenhanced cerebral computed tomography (CT scan), performed in four patients, was normal in one and abnormal (hypodensity of the left frontal lobe, hyperdensity surrounded by hypodensity of the right parietal lobe suggestive of a hemorrhagic infarction of venous origin, and hypodensity as sequelae of a past left middle cerebral artery occlusion) in three. Cerebral angiography was performed in five patients and showed a partial or total lack of filling of one or several sinuses (the superior sagittal sinus and/or the transverse sinus) on at least two projections. Cortical vein involvement associated with sinus occlusion was seen in one case. In the earliest patient (case 1, 1973), left transverse sinus occlusion was diagnosed during surgery for intracra- nial hypertension. Magnetic resonance imaging (MRI) was performed in only one patient (case 6). Due to delayed diagnosis, one patient (case 1) was not treated and developed optic atrophy secondary to papilledema. The other five patients received heparin associated with steroids (1 mg/kg prednisone daily); neurologic improvement occurred within 1 week and recovery within 1 month. Heparin was given without any complications, even when a hemorrhagic infarct was present (case 6). Oral anticoagulant therapy was started after 4 weeks of heparin and has not been discontinued until the time of the study in two patients (3 and 12 months). The other two patients received oral anticoagulant therapy during at least 3 months and were subsequently lost to follow-up. Warfarin was given to one patient during 5 months until she died of an extraneurologic lupus flare. After initial tapering, corticosteroids had been maintained in all patients. Case 6 This 24-year-old white woman had been treated with hydroxychloroquine from the age of 12 years to the age of 22 years for discoid lupus. At age 23 years she had a spontaneous abortion after 30 weeks of pregnancy. Pathologic examination of the placenta revealed multiple infarcts. One year later, she was admitted to the hospital at 28 weeks of her second pregnancy. Laboratory investigations showed a platelet count of 60,000/mm3, an erythrocyte sedimentation rate of 27 mm/hr, a PTT of 60 seconds, a prothrombin time of 10 seconds, a positive anticardiolipin antibody assay, and a nega- Vidailhet et al Lupus Erythematosus and Sinus Thrombosis 1229 F I G U R E 2. Magnetic resonance image taken 1 day after angiogram in Figure 1. T2weighted image. Note superior sagittal sinus (arrow); parietal hemorrhagic infarction. Downloaded from http://ahajournals.org by on April 11, 2024 tive VDRL. Her antinuclear antibody titer was 1/20, and an anti-DNA radioimmunoassay was positive. At 30 weeks she had placental abruption with disseminated intravascular coagulation, and a cesarian section was performed. The baby was hypotrophic. The woman's disseminated intravascular coagulation improved in 48 hours with symptomatic management. Steroid therapy was started (55 mg prednisone daily), and the patient was discharged. During the postpartum period she complained of increasing headaches. She denied any photophobia, nausea, or diplopia. Fifteen days after delivery, she was readmitted for left partial motor seizures, with secondary generalization and subsequent left hemiplegia. Examination on admission revealed a nonconfused woman with moderate left hemiplegia and sensory disturbance. Funduscopy was normal. General examination was normal. Laboratory investigations showed a platelet count of 135,000/mm3, an erythrocyte sedimentation rate of 44 mm/hr, a PTT of 35 (normal 22-36) seconds, and a thrombin time of 10 (normal 9.5-11.5) seconds. Lupus anticoagulant was absent. Her antinuclear antibody titer was 1/1,000, and an anti-DNA antibody assay was slightly positive; an anticardiolipin antibody assay was positive. Urinalyses were normal. Unenhanced CT scan showed a right parietal hyperdensity surrounded by hypodensity, suggestive of hemorrhagic infarction. Angiography revealed the absence of filling of the superior sagittal sinus and of the parietal cortical veins (Figure 1). On MRI (1.5 T) the next day, the occluded sinus appeared isointense on Tl-weighted images (resonance time [TR] 400 msec and echo time [TE] 12 msec) and hyperintense on T2-weighted images (TR 1,800 msec and TE 60 msec). The hemorrhagic infarct was visible (Figure 2). The patient was treated with continuous heparin infusion (20,000 units/day) for 3 weeks and later with warfarin. The steroid dosage remained unchanged. The day after heparin was started she improved dramatically, and she recovered completely within 3 weeks. 1230 Stroke Vol 21, No 8, August 1990 TABLE 3. Previously Reported Cases of Cerebral Venous Thrombosis in Patients With SLE Reference Parnass et al4 Shiozawa et al3 Kaplan et al2 Feature Sex Age at first symptom of Thrombosis (yr) Headache Focal symptoms Seizures Papilledema Diagnostic tests Computed tomography Angiography Features of SLE Antinuclear antibodies Anti-DNA antibodies Lupus anticoagulant Treatment Course F 11 F 41 + + Jugular vein thrombosis F 27 Levine et al5 Levine et al5 F 21 M 32 Hyperdensity sinus rectus SSS Right hemiplegia Normal Parietal hypodensity Normal SSS SSS, TS TS + + S Resolved S+H S+H s Resolved Resolved Resolved SLE, systemic lupus erythematosus; DNA, deoxyribonucleic acid; F, female; M, male; SSS, superior sagittal sinus; TS, transverse sinus; S, steroids; H, heparin. s Resolved Downloaded from http://ahajournals.org by on April 11, 2024 One month after this patient's second admission, MRI demonstrated vascular recanalization with resumption of blood flow in the superior sagittal sinus and regression of the infarct. She was maintained on steroids, and heparin was changed to warfarin (international normalized ratio=3). One year later, the patient's condition remains satisfactory. Discussion Cerebral venous thrombosis is a rare complication of SLE. Only five such patients have been reported previously (Table 3). Three of the five2-4 fulfilled four or more criteria for SLE. Among the patients of Levine et al,5 one fulfilled three criteria (arthritis, nephritis, and thrombocytopenia) and can be considered as having probable SLE; the other patient had a history of spontaneous abortions, deep venous thrombosis, pulmonary embolism, and thrombocytopenia with lupus anticoagulant. Cerebral venous thrombosis was the presenting symptom of SLE in the patient of Shiozawa et al3 and in our case 1. Cerebral venous thrombosis occurred during pregnancy in the first patient of Levine et al5 and in our case 6. Assays for antinuclear and anti-DNA antibodies were negative in the patients of Levine et als and in our cases 1 and 4. Clinical and neuroimaging features of cerebral venous thrombosis in SLE patients were similar to those of patients with cerebral venous thrombosis of other origin.1*9 Focal signs were present in four of our six patients, whereas isolated intracranial hypertension was present in one. In the literature, signs of intracranial hypertension of progressive onset were isolated in four cases2"3-5 and were associated with a right hemiparesis in the patient reported by Parnass et al.4 Isolated intracranial hypertension has been described in association with SLE in other patients,10"12 and the pathogenesis is regarded as unknown. Since angiography was not systematically performed, cerebral venous thrombosis might have been overlooked in some of these cases. Diagnosis is based only rarely on CT alone, usually on angiography1-8 and more recently on MRI, which is now the study of choice if available.9 Manifestations of SLE are similar in our patients and in the five cases reported previously. There is an increased tendency to arterial and venous thrombosis, especially when lupus anticoagulant is present. Recent studies have clearly demonstrated the strong association between the presence of lupus anticoagulant and the occurrence of cerebral arterial, cerebral venous, and/or systemic arterial thrombosis,13-16 spontaneous abortions,1718 and thrombocytopenia.19 Lupus anticoagulant often coexists with other antiphospholipid antibodies (anticardiolipin antibodies and/or a false-positive VDRL).19-20 The mechanisms responsible for in vivo thrombosis involve complex interactions between endothelial cells and lupus anticoagulant, leading to an inhibition of the functions of protein C and protein S.21-23 However, other factors such as defective24fibrinolysis,altered antithrombin III function, hyperfibrinemia, or coagulation changes observed during pregnancy or nephritis, especially during nephrotic syndrome, may play a role. In this respect, the high frequency of renal involvement in patients with cerebral venous thrombosis (References 2-5, Table 1) should be emphasized. The use of anticoagulants in the treatment of cerebral venous thrombosis remains controversial. A recent controlled study comparing heparin and placebo suggested that heparin was both effective and Vidailhet et al Downloaded from http://ahajournals.org by on April 11, 2024 safe, even in patients with hemorrhagic infarcts.25 Our results favor the use of combined therapy with heparin and steroids in patients with cerebral venous thrombosis complicating SLE. Levine et al5 obtained similar good results with this therapy. Three patients reported in the literature received steroids without anticoagulation; two improved, but the third required lumboperitoneal shunt for persistent intracranial hypertension.2 Long-term treatment for cerebral venous thrombosis is not standardized. Lupus anticoagulant may persist despite treatment with corticosteroids, and recurrent cerebral arterial ischemic events are not uncommon, even with anticoagulant and antiplatelet therapy.14 Our report demonstrates that cerebral venous thrombosis is one possible mechanism of central nervous system involvement in patients with SLE.26 Since cerebral venous thrombosis can occasionally be the presenting symptom of the disease, SLE and lupus anticoagulant should be systematically looked for in women with cerebral venous thrombosis. On the other hand, despite the high prevalence of migraine in patients with documented SLE,27 cerebral venous thrombosis should be suspected in patients with persistent headache, especially those with neurologic symptoms. Patients with lupus anticoagulant, thrombocytopenia, and/or previous vascular events are notably prone to develop such a complication. In such patients, angiographic or MRI demonstration of cerebral venous thrombosis prompts combined therapy with steroids and heparin. Acknowledgments We are indebted to Professor Loi'c Guillevin for providing the observation of one patient and to Professor Pierre Godeau for his critical review and suggestions during the preparation of the article. References 1. Bousser MG, Chiras J, Bones J, Castaigne P: Cerebral venous thrombosis: A review of 38 cases. Stroke 1985;16:199-213 2. Kaplan RE, Springate JE, Feld LG, Cone ME: Pseudo tumor cerebri associated with cerebral venous sinus thrombosis, internal jugular vein thrombosis and SLE. / Pediatr 1985; 107:266-268 3. Shiozawa Z, Yoshida M, Kobayashi K, Tsunoda S, Mano T: Superior sagittal sinus thrombosis and systemic lupus erythematosus (letter). Ann Neurol 1986;20:272 4. Parnass SM, Goodwin JA, Patel DV, Levinson DJ, D'Arcy Reinhard J: Dural sinus thrombosis: A mechanism for pseudo tumor cerebri in systemic lupus erythematosus. J Rheumatol 1987;41:152-155 5. Levine SR, Kieran S, Puzio K, Feit H, Patel SC, Welch KMA: Cerebral venous thrombosis with lupus anticoagulants: Report of two cases. Stroke 1987;18:801-804 6. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ: The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271-1277 Lupus Erythematosus and Sinus Thrombosis 1231 7. Molle D, Guillevin L, Herreman G, Godeau P: Thrombophlebite du sinus longitudinal supdrieur et lupus eryth£mateux dissemine. Sent Hop Paris 1982;52:1215-1219 8. Thron A, Wessel K, Linden D, Schroth G, Dighgans J: Superior sagittal sinus thrombosis: Neuroradiological and clinical finding. Neurology 1986;233:283-288 9. Erdman WA, Weinreb JC, Cohen JM, Bujal M, Chaney C, Peschock RM: Venous thrombosis: Clinical and experimental MR imaging. Radiology 1986;161:233-238 10. Carlow J, Glaser JS: Pseudo tumor cerebri syndrome in systemic lupus erythematosus. JAMA 1974;222:197-200 11. Delgiudice GC, Scher CA, Athreya BH, Diamond GH: Pseudo tumor cerebri and childhood in disseminated lupus erythematosus. / Rheumatol 1986;13:748-752 12. Silberg DH, Laties AM: Increased pressure in disseminated lupus erythematosus. Arch Neurol 1973;29:88-90 13. Asherson RA, Khamashta M, Gil A, Vazquez JJ, Chan O, Baguley E, Hughes GRV: Cerebrovascular disease and antiphospholipid antibodies in systemic lupus erythematosus, lupus-like disease, and the primary antiphospholipid syndrome. Am J Med 1989;86:391-399 14. Levine SR, Welch KMA: Cerebrovascular ischemia associated with lupus anticoagulant. Stroke 1987;18:257-263 15. Kushner M, Simonian N: Lupus anticoagulants, anticardiolipin antibodies, and cerebral ischemia. Stroke 1989;20: 225-229 16. Elias M, Eldor A: Thromboembolism in patients with the "lupus"-type circulating anticoagulant. Arch Intern Med 1984; 144:510-515 17. Hughes GRV: Thrombosis, abortion, cerebral disease, and the lupus anticoagulant (letter). BrMedJ 1983;287:1089 18. Glueck HI, Kant KS, Weiss MA, Pollak VE, Miller MA, Coots M: Thrombosis in systemic lupus erythematosus: Relation to the presence of circulating anticoagulants. Arch Intern Med 1985;145:1389-1395 19. Hughes GRV, Harris NN, Gharavi AE: The anticardiolipin syndrome. / Rheumatol 1986;13:486-489 20. Meyer O, Piette JC, Bourgeois P, Fallas P, Bletry O, Jungers P, Kahn MF, Godeau P, Ryckewaert A: Antiphospholipid antibodies: A disease marker in 25 patients with antinuclear antibody negative systemic lupus erythematosus (SLE). Comparison with a group of 91 patients with antinuclear antibody positive SLE. / Rheumatol 1987;14:502-506 21. Cariou R, Tobelem G, Soria C, Caen J: Inhibition of protein C activation by endothelial cells in the presence of lupus anticoagulant. N EnglJ Med 1986;314:1193-1194 22. Lo SC, Salem HH, Howard MA, Oldmeadow MJ, Firkin BG: Inhibition of protein C and protein S function by plasma from patients with the lupus anticoagulant (abstract). Thromb Haemost 1989;62:1172 23. Hasselaar P, Derksen RHWM, Oosting JD, Blokzijl L, De Groot PG: Synergistic effect of low doses of tumor necrosis factor and serum from patients with systemic lupus erythematosus on the expression of procoagulant activity by cultured endothelial cells. Thromb Haemost 1989;62:654-660 24. Cosgriff TM, Martin BA: Low functional and high antigenic antithrombin III level in a patient with the lupus anticoagulant and recurrent thrombosis. Arthritis Rheum 1981;24:94-96 25. Villringer A, Garner C, Meister W, Haberl R, Pfister W, Einhaeupl KM: High-dose heparin treatment in cerebral sinus-venous thrombosis (abstract). Stroke 1988;19:135 26. Ellis SG, Verity MA: Central nervous system involvement in systemic lupus erythematosus: A review of neurologic findings in 57 cases, 1955-1977. Arthritis Rheum 1979;8:212-221 27. Isenberg DA, Meyrick-Thomas D, Snaith ML, McKeran RO, Royston JP: A study of migraine in systemic lupus erythematosus. Ann Rheum Dis 1982;41:30-32 KEY WORDS • anticoagulants, lupus • systemic • thrombosis lupus erythematosus,