Papilledema and Extensive Dural Sinus Thrombosis Due to JAK2 Mutation

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Gour Wang, MD Papilledema and Extensive Dural Sinus Thrombosis Due to JAK2 Mutation Eli Kisilevsky, MD, Eugene Yu, MD, Edward Margolin, MD W e present a case of papilledema due to extensive dural sinus thrombosis (DST) that was not seen on unenhanced brain MRI. Hypercoagulability work-up demonstrated the presence of JAK2 mutation, alerting neuroophthalmologists that testing for this mutation should be performed in all patients with suspected hypercoagulable state. A previously healthy 64-year-old man was referred for neuro-ophthalmological evaluation because of bilateral optic nerve head edema that was noticed during a routine optometric examination and subsequently confirmed by an ophthalmologist. Computer tomography of the brain without contrast was unremarkable. MRI of the brain and orbits without contrast demonstrated only indirect signs of increased intracranial pressure including empty sella and posterior flattening of the globes and widened optic nerve sheaths (Fig. 1A). The patient denied having any symptoms of increased intracranial pressure including headaches, pulsatile tinnitus, or transient visual obscurations. On examination, central vision was 20/20 on the right and 20/25 on the left. There was no relative afferent pupillary defect. Color vision testing with Ishihara isochromatic plates was normal in each eye (17/17 plates identified). Dilated ophthalmoscopic examination revealed severe optic nerve head edema bilaterally with normalappearing macula and retinal vasculature (Fig. 1B). Visual fields (Humphrey 24-2 algorithm) were normal in each eye with exception of mildly enlarged blind spots. Ocular coherence tomography of the peripapillary retinal nerve fiber layer (RNFL) demonstrated increased RNFL thickness bilaterally with average thickness of 246 mm on the right and 252 mm on the left. Fundus autofluorescence did not demonstrate optic nerve head autofluorescence. As the visual function was normal, it was felt that bilateral optic nerve head edema was secondary to papilledema and because the patient was outside of the typical demographic group for idiopathic intracranial hypertension, urgent MR Department of Ophthalmology and Vision Science (EK, EM), and Medical Imaging (EY), University of Toronto, Toronto, Canada; and Division of Neurology (EM), Department of Medicine, Toronto, Canada. The authors report no conflicts of interest. Address correspondence to Edward Margolin, MD, Department of Ophthalmology and Vision Sciences, University of Toronto, 801 Eglinton Ave West, Suite 301, Toronto, Canada M5N1E3; E-mail: [e-mail] Kisilevsky et al: J Neuro-Ophthalmol 2021; 41: e307-e308 venography was performed. It demonstrated extensive DST involving the superior sagittal sinus, and bilateral transverse sinuses (Fig. 2) along with signs of brain dural arteriovenous fistula (bdAVF) in the area of thrombosis. Digital subtraction angiography confirmed the presence of high flow bdAVF causing reflux into cerebral veins, which was embolized during the procedure. When the original noncontrast MRI of the brain was examined retrospectively, no signs of DST were visible despite the presence of extensive thrombus on MR venography. Testing for the underlying cause of hypercoagulable state was performed and revealed the presence of V617F JAK2 mutation confirming a diagnosis of polycythemia rubra vera (PCV). The association of DST with oral contraceptive use, peripartum, thrombophilias, neoplasms, inflammatory disease, and infections is well known (1). The recommended FIG. 1. A. Axial T2W image showing flattening of the posterior margin of the globes at the insertion point of the optic nerves (arrowhead) and dilatation of the subarachnoid space along the optic nerve sheaths (arrow), signs of elevated intracranial pressure. These findings are symmetrical between the 2 eyes. B. Fundus photograph demonstrating Grade 3–4 optic nerve edema of the left eye; the visualized retinal vessels and retina are normal. The right eye had a similar appearance. e307 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 2. Postgadolinium T1W sagittal MRI shows thrombosis of a large segment of the superior sagittal sinus as demonstrated by the filling defect following the curvature of the sagittal sinus (area between arrows). work-up for patients with suspected hypercoagulable state includes measuring the levels of Protein C and S, homocysteine, and presence of prothrombin, factor V Leiden mutations, and titers of lupus anticoagulant and anticardiolipin antibodies (2). However, DST can also be associated with myeloproliferative disorders (MPDs) including essential thrombocythemia (ET) and PCV, and this association should be explored in patients with DST. A novel JAK2 mutation has been described in 2005 and is present in 96% of patients with PCV and up to 65% of those with ET (3). JAK2 encodes Janus Activated Kinase, a tyrosine kinase involved in cellular regulation and proliferation (4). The V617F JAK2 mutation is a gain-of-function mutation resulting in constitutive expression and is associated with venous thrombosis both in patients with or without overt MPD (5,6). DST can be the first presenting sign of MPD in up to half of patients, and patients with DST and MPD have an increased risk of recurrent thrombosis compared to those with thrombosis in other sites, necessitating the need for continued anticoagulation and cytoreductive treatment (6). The JAK2 mutation is one of the WHO major criteria for diagnosis of ET and PCV supporting the need for its testing in patients with DST (3). Another important lesson from this case is that noncontrasted MRI did not demonstrate any features suspicious for DST despite a very extensive thrombus e308 identified on MR venography. Normally, a low signal/ black flow void is present in patent dural sinuses and a loss of a flow void can signify thrombosis; however, turbulent flow unrelated to thrombosis can also give rise to an apparent loss of the normal black signal. Radiographic features of dural sinus thrombosis on unenhanced MRI can be subtle because acute and chronic thrombi seem isointense to the normal brain. A subacute thrombus, although, will characteristically show a high intrinsic T1 signal in the affected vessel due to presence of methemoglobin. Adding gradient echo and susceptibility weighted sequences can thus be useful in demonstrating the thrombus where it will appear as low signal within the affected vein or sinus (7). In summary, this case underscores the need for cerebral venography study or at least adding gradient echo and susceptibility-weighted sequences to the MRI in all patients with papilledema who do not fit the demographic for IIH because even in the presence of a large thrombus, unenhanced MRI might not demonstrate any signs of DST. It also emphasizes the importance of testing for presence of JAK2 mutation in patients with DST because it has been specifically associated with increased risk of thrombosis even in the absence of overt features of MPD. REFERENCES 1. Ferro JM, Aguiar de Sousa D. Cerebral venous thrombosis: an update. Curr Neurol Neurosci Rep. 2019;19:74. 2. Nakashima MO, Rogers HJ. Hypercoagulable states: an algorithmic approach to laboratory testing and update on monitoring of direct oral anticoagulants. Blood Res. 2014;49:85–94. 3. Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management. 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Imaging of cerebral venous thrombosis. Diagn Interv Imaging. 2014;95:1145–1150. Kisilevsky et al: J Neuro-Ophthalmol 2021; 41: e307-e308 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.