Antiphospholipid Antibody Syndrome: Raised Intracranial Pressure Without Cerebral Venous Sinus Thrombosis

The primary role of brain imaging in idiopathic intracranial hypertension (IIH) is to exclude other pathologies causing intracranial hypertension. However, subtle radiologic findings suggestive of IIH have emerged with modern neuroimaging. This review provides a detailed description of the imaging findings reported in IIH and discusses their possible roles in the pathophysiology and the diagnosis of IIH.; ; References were identified by searches of PubMed from 1955 to January 2015, with the terms "idiopathic intracranial hypertension," "pseudotumor cerebri," "intracranial hypertension," "benign intracranial hypertension," "magnetic resonance imaging," "magnetic resonance venography," "computed tomography (CT)," "CT venography," "imaging," and "cerebrospinal fluid (CSF) leak." Additional references were identified by hand search of relevant articles. When possible, we extracted the number of patients and control subjects from each study for each radiological finding. When at least 2 studies used the same criteria to define a radiological finding, all patients from these studies were pooled to obtain a mean sensitivity and specificity with 95% confidence interval.; ; Specific neuroimaging findings may suggest long-standing IIH, including empty sella, flattening of the posterior globes, optic nerve head protrusion, distention of the optic nerve sheaths, tortuosity of the optic nerve, cerebellar tonsillar herniation, meningoceles, CSF leaks, and transverse venous sinus stenosis.; ; Although IIH remains a diagnosis of exclusion, the most recently proposed diagnostic criteria have included neuroimaging findings to suggest IIH when major diagnostic criteria are not fulfilled. However, these findings are not diagnostic of IIH, and their presence is not required for the diagnosis of definite IIH. Their incidental discovery on brain imaging should not prompt invasive procedures, unless other signs of IIH, such as papilledema, are present.

Clinical Observation Antiphospholipid Antibody Syndrome: Raised Intracranial Pressure Without Cerebral Venous Sinus Thrombosis Danielle S. Rudich, MD, Samuel H. Yun, MD, Anne Liebling, MD, Jonathan E. Silbert, MD, Gilbert W. Moeckel, MD, PhD, FASN, Robert L. Lesser, MD Abstract: Antiphospholipid antibody syndrome (APS) has been reported to cause elevated intracranial pressure, but usually this is due to cerebral venous sinus thrombosis (CVST). We present a 36-year old man with APS with elevated intracranial pressure with neuro-ophthalmic, renal and hematological involvement without identifiable CVST. Journal of Neuro-Ophthalmology 2015;35:396-399 doi: 10.1097/WNO.0000000000000277 © 2015 by North American Neuro-Ophthalmology Society A ntiphospholipid antibody syndrome (APS) is characterized by thromboembolic events, including deep venous thrombosis, cerebral venous sinus thrombosis (CVST), and glomerular microthrombi (1). Patients with antiphospholipid antibodies who develop vascular thrombosis in 3 or more organs in 1 week are diagnosed with catastrophic antiphospholipid antibody syndrome (CAPS) (2). We report of a patient with neuro-ophthalmic, hematological and renal complications which occurred over several weeks, which we designate as "almost" CAPS. CASE REPORT A 36-year-old man reported a 1 month history of headache, blurry vision, and intermittent diplopia at distance. His medical history was unremarkable. Visual acuity was 20/40 in the right eye and 20/25 in the left eye. Automated perimetry showed enlarged blind spots bilaterally and funduscopic examination revealed bilateral optic disc edema with disc hemorrhages. The Eye Care Group (DSR, JES, RLL), New Haven, Connecticut; Departments of Ophthalmology & Visual Sciences (DSR, SY, JES, RLL), Pathology and Nephrology (GWM), and Neurology (RLL), Yale University, New Haven, Connecticut; New Haven Rheumatology (AL), New Haven, Connecticut. The authors report no conflicts of interest. Address correspondence to Danielle S. Rudich, MD, The Eye Care Group, New Haven, CT 06510; E-mail: [e-mail] 396 On further evaluation, the patient denied transient visual obscurations, tinnitus, and the use of steroids, vitamin A, antibiotics, or isotretinoin. His body mass index was 34.7 kg/m2. Brain magnetic resonance imaging (MRI) revealed a partially empty sella turcica and magnetic resonance venography (MRV) showed no evidence of CVST. Lumbar puncture opening pressure was 40 cm of water with a normal cerebrospinal fluid (CSF) profile. The patient was prescribed acetazolamide, 500 mg twice daily, for presumed idiopathic intracranial hypertension (IIH). Several weeks later, his papilledema worsened, and he was referred for neuro-opthalmic assessment. Visual acuity was 20/40 in the right eye and 20/30 in the left eye. There was no relative afferent pupillary defect, and he was orthophoric with full ocular motility. Color vision was slightly reduced in each eye, and automated visual field testing showed enlarged blind spots and inferonasal field loss in each eye (Fig. 1). Both optic discs were swollen with hemorrhages and exudates extending into both maculae (Fig. 2). Acetazolamide was increased to 1,000 mg twice daily, and prednisone 100 mg daily was prescribed. Optic nerve sheath fenestration of the left eye was scheduled. Because preoperative testing revealed microcytic anemia and thrombocytopenia (hemoglobin 7.1 gm/dL [normal: 14.0-18.0 gm/dL]; hematocrit 23.4 [normal: 40-52]; platelet count 45,000/mL platelet count [normal: 150,000-350,000/mL]), surgery was postponed. Additional testing revealed that the patient had anticardiolipin antibody/IgG 54 gm/L (normal: ,15 gm/L), glycoprotein 1 IgG 4,099 gm/L (normal: ,10 gm/L), and lupus anticoagulant (Russell viper venom) 1.72 (normal ,1.21). The presence of these 3 markers confirmed the diagnosis of APS. The patient developed obstructive nephrolithiasis treated with a renal stent, and acetazolamide was discontinued. Several days later, he was found to have a rapidly rising blood urea nitrogen of 53 mg/dL (normal: 7-20 mg/dL) Rudich et al: J Neuro-Ophthalmol 2015; 35: 396-399 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 1. Visual fields demonstrate enlarged blind spots and nasal field loss bilaterally. and creatinine of 2.4 mg/dL (normal: 0.5-1.2 mg/dL). Urinalysis showed 2+ protein with many red blood cells and white blood cells. A kidney biopsy showed glomerular microthrombi (Fig. 3). An MRV showed no evidence of CVST (Fig. 4). Our patient was treated with intravenous immunoglobulin (IVIg), plasmapheresis, corticosteroids, and anticoagulation. His visual acuity returned to 20/20 bilaterally with improvement in visual field (Fig. 5). His symptoms improved, and he did not develop other systemic complications of APS. DISCUSSION Approximately 1% of patients with APS develop CAPS, which is defined as venous and arterial thrombosis in 3 or more organs within 1 week (2). Because our patient had renal and hematological involvement developing over more than 1 week, we have termed this "almost" CAPS. Intracranial hypertension associated with APS in the absence of CVST is rare (3). Although the mechanism is unknown, it has been hypothesized that intracranial FIG. 3. Kidney biopsy. Low (A), medium (B), and high (C) power view of thrombotic microangiography with a microthrombus (arrow) within a blood vessel (hematoxylin & eosin, ·40, ·100, and ·400, respectively). hypertension is caused by damage to the endothelial cells and arachnoid villi capillaries from the antiphospholipid antibodies impairing CSF flow (3,4). Antiphospholipid antibodies may activate platelets, increase adhesion FIG. 2. There is marked bilateral optic disc edema with exudates extending into the macula of each eye. Rudich et al: J Neuro-Ophthalmol 2015; 35: 396-399 397 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 4. (A-C) Autotriggered elliptic centric-ordered magnetic resonance venography shows no evidence of cerebral venous sinus thrombosis. molecules, inhibit antithrombin and activated protein C, thereby promoting coagulation (5). Pendse et al (2) reported a patient who initially presented as IIH with no evidence of CVST on MRV. One year later, he developed CVST with CAPS. The authors hypothesized that the initial presentation of IIH without thrombosis resulted from 1 or more of 3 possible mechanisms: 1) progressive evolution of CVST that was missed on multiple MRVs, 2) diagnostic procedure (lumbar puncture) precipitating thrombosis, and 3) diuretic (acetazolamide) producing hyperviscosity-induced thrombosis. In our patient, CVST was not documented on 2 MRVs including one with autotriggered elliptic centric-ordered technique. We agree with others (6) that the probable mechanism for increased intracranial pressure in our case was microvenous thrombosis of the arachnoid villi, which cannot be visualized with current imaging modalities. Treatment options for APS include antiplatelet therapy and anticoagulation with agents such as heparin or warfarin. In addition, some patients respond to prednisone or other immunosuppressive agents, including cyclophosphamide and rituximab (3,7,8). Plasma exchange also has been successful in some patients who failed steroid treatment (9). Studies have shown that use of IVIg and/or plasma exchange in conjunction with steroids and anticoagulation enables higher survival rates among patients with CAPS (10). STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: S. Yun, R. L. Lesser, J. E. Silbert, and A. Liebling; b. Acquisition of data: S. Yun, R. L. Lesser, J. E. Silbert, and A. Liebling; c. Analysis and interpretation of data: S. Yun, R. L. Lesser, J. E. Silbert, and A. Liebling. Category 2: a. Drafting the manuscript: S. Yun, R. L. Lesser, J. E. Silbert, and A. Liebling; b. Revising the manuscript for intellectual content: S. Yun, R. L. Lesser, J. E. Silbert, and A. Liebling. Category 3: a. Final approval of the completed manuscript: S. Yun, R. L. Lesser, J. E. Silbert, and A. Liebling. REFERENCES FIG. 5. Dramatic improvement in visual fields is seen 6 weeks after treatment of antiphospholipid antibody syndrome. 398 1. Kupfer JM, Ruan XM, Liu G, Matloff J, Forrester J, Chaux A. High-efficiency gene transfer to autologous rabbit jugular vein grafts using adenovirus-transferrin/polylysine-DNA complexes. Hum Gene Ther. 1994;5:1437-1443. 2. Pendse S, Bilyk JR, Olivia C, Biousse V. Now you see it. Surv Ophthalmol. 2008;53:177-182. 3. Joseph RE, Radhakrishnan J, Appel GB. Antiphospholipid antibody syndrome and renal disease. Curr Opin Nephrol Hypertens. 2001;10:175-181. Rudich et al: J Neuro-Ophthalmol 2015; 35: 396-399 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation 4. Wan T, Tsang P. Catastrophic antiphospholipid syndrome presenting with pulmonary hemorrhage: case report. J Thromb Thrombolysis. 2014;39:68-70. 5. Cervera R, Rodriguez-Ointo I, Colafrancesco S, Conti F, Valesini G, Rosario C, Agmon-Levin N, Shoenfeld Y, Ferrao C, Faria R, Vasconcelos C, Signorelli F, Espinosa G. 14th international congress on antiphospholipid antibodies task force report on catastrophic antiphospholipid syndrome. Autoimmun Rev. 2014;13:699-707. 6. Orefice G, De Joanna G, Coppola M, Brancaccio V, Ames PR. Benign intracranial hypertension: a non-thrombotic complication of the primary antiphospholipid syndrome? Lupus. 1995;4:324-326. 7. Pierangeli SS, Chen PP, Raschi E, Scurati S, Grossi C, Borghi MO, Palomo I, Harris EN, Meroni PL. Antiphospholipid Rudich et al: J Neuro-Ophthalmol 2015; 35: 396-399 antibodies and the antiphospholipid syndrome: pathogenic mechanisms. Semin Thromb Hemost. 2008;34:236-250. 8. Sussman J, Leach M, Greaves M, Malia R, Davies-Jones GA. Potentially prothrombotic abnormalities of coagulation in benign intracranial hypertension. J Neurol Neurosurg Psychiatry. 1997;62:229-233. 9. Jadhav AP, Aghaebrahim N, Jankowitz BT, Jovin TG. Cerebral microbleeds in lupus anticoagulant-hypoprothrombinemia syndrome. JAMA Neurol. 2013;70:1452-1453. 10. Bucciarelli S, Espinosa G, Cervera R, Erkan D, Gomez-Puerta J, Ramos-Casals M, Font J, Asherson R. European forum on antiphospholipid antibodies mortality in the catastrophic antiphospholipid syndrome: causes of death and prognostic factors in a series of 250 patients. Arthritis Rheum. 2006;54:2588-2576. 399 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.