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Show ORIGINAL CONTRIBUTION Optic Disc Edema, Cystoid Macular Edema, and Elevated Vascular Endothelial Growth Factor in a Patient With POEMS Syndrome Deborah Y. Chong, MD, Grant M. Comer, MD, and Jonathan D. Trobe, MD Abstract: A 48- year- old man with polyneuropathy, organomegaly, endocrinopathy, monoclonal gamm-opathy, and skin changes ( POEMS) syndrome had bilateral optic disc edema ( ODE), bilateral cystoid macular edema ( CME), anasarca, and elevated serum vascular endothelial growth factor ( VEGF). This is the first reported example of ophthalmoscopic, angiographic, and optical coherence tomographic evidence of the combination of ODE and CME in this syndrome. This combination of features suggests that the ODE in this condition may be due to increased vascular permeability. (/ Neuro- Ophthalmol 2007; 27: 180- 183) Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes ( POEMS) syndrome is rare multisystem disorder of obscure etiology ( 1,2). In addition to the features for which it is named, there are also manifestations of increased vascular permeability such as extremity edema ( 24%- 100%), ascites ( 7%- 62%), pleural effusion ( 3%- 70%), and optic disc edema ( ODE) ( 29%- 73%) ( 2- 7). The pathogenesis of ODE in POEMS remains uncertain. We report a patient with POEMS syndrome who had ODE as well as cystoid macular edema ( CME), anasarca, and increased serum levels of vascular endothelial growth factor ( VEGF) as evidence that increased vascular permeability may explain the ODE in this syndrome. CASE REPORT A 48- year- old man complained of blurred vision for 3 months and predominantly right eye metamorphopsia for 1 week. He also had increasing abdominal distension and Department of Ophthalmology ( DYC, GMC, JDT), W. K. Kellogg Eye Center, Department of Neurology ( JDT), University of Michigan, Ann Arbor, Michigan. No authors have any proprietary interests. Address correspondence to Jonathan D. Trobe, MD, Kellogg Eye Center, 1000 Wall Street, Ann Arbor, MI 48105; E- mail: jdtrobe@ umich. edu pain, early satiety, shortness of breath, and severe lower extremity pitting edema that elicited a hospital admission. POEMS syndrome was diagnosed in 1999 on the basis of chronic sensorimotor demyelinating and axonal polyneuropathy, generalized lymphadenopathy, monoclonal gammopathy, and hypogonadism. A sural nerve biopsy had demonstrated axonal loss without evidence of amyloid deposition or vasculitis. Axillary lymph node biopsy had demonstrated angiofollicular lymph node hyperplasia. Later, he developed splenomegaly and hypothyroidism. He did not have diabetes. The peripheral neuropathy had initially been treated with intravenous immunoglobulin and high- dose intravenous dexamethasone without benefit, but chronic prednisone treatment eventually produced sustained improvement. Mycophenolate mofetil was later added to prednisone, a regimen he continued until the time of his admission. The ophthalmic history was remarkable only for high myopia and presbyopia. Best- corrected visual acuity was 20/ 80 in the right eye and 20/ 50 in the left eye. Ishihara color plates were normal bilaterally. He described central metamorphopsia in the right eye on Amsler grid testing. A 24- 2 Humphrey visual field demonstrated enlargement of the blind spot in the right eye and an inferior nerve fiber bundle defect in the left eye ( Fig. 1). Pupils were of normal size and reactivity without a relative afferent pupillary defect. Intraocular pressures were 10 mm Hg in the right eye and 8 mm Hg in the left eye. Ophthalmoscopy revealed bilateral ODE ( Fig. 2A) and CME ( Fig. 2B). Fluorescein angiography ( FA) disclosed bilateral late leakage from the optic discs and late petalloid leakage in the macula consistent with CME ( Fig. 2C). The retinal and choroidal vascular perfusions appeared normal. Optical coherence tomography ( OCT) revealed bilateral increased macular thickness with peri-foveal intraretinal hypoechoic cavitations consistent with CME ( Fig. 2D). There was no vitreous traction or epiretinal membrane. Brain and orbit MRI, not shown because of poor resolution owing to patient motion, demonstrated symmetric normal- diameter optic nerves of normal signal intensity 180 J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 Optic Disc Edema in POEMS JNeuro- Ophthalmol, Vol. 27, No. 3, 2007 Pattern d £ B & J eviati ft * tt Dn ft • ft ft ft • • £ - • £ • • • • ft • & £ • • £ • ft &. • • • • £ :: " £ ft • • • - • • • : • • • " • ft FIG. 1. 24- 2 Humphrey visual fields show enlargement of the blind spot in the right eye and an inferior nerve fiber bundle defect in the left eye. without pathologic contrast enhancement. Optic nerve sheath dilation was present bilaterally. There was no pathologic contrast enhancement, mass, or mass effect within the orbits or the brain. There was no ventriculomegaly, loss of sulcal markings, compromise of cisternal spaces, or periependymal signal changes to suggest elevated intracranial pressure ( ICP). Magnetic resonance venography was negative for venous sinus thrombosis. The patient was too ill to undergo a lumbar puncture for relieving pressure. Serum VEGF and interleukin- 6 ( IL- 6) levels were elevated at 432 pg/ mL ( normal 31- 86 pg/ mL) and 10 pg/ mL ( normal < 5 pg/ mL), respectively. The patient was treated with intravenous bevacizu-mab, an anti- VEGF monoclonal antibody, in combination with oral dexamethasone, and continued mycophenolate mofetil. One month after this regimen was started, the ophthalmic examination was unchanged. In the ensuing 4 weeks, the patient's systemic condition deteriorated with worsening ascites and shortness of breath. Bevacizumab and dexamethasone were discontinued and replaced with melphalan and prednisone. After 1 month of this therapy, the ophthalmic examination was still unchanged. The patient expired shortly thereafter, and thus repeat serum VEGF and IL- 6 levels could not be obtained. DISCUSSION The occurrence of ODE in POEMS syndrome, as found in our patient, has been well documented ( 2- 12). The presence of bilateral CME in POEMS syndrome has been reported only once ( 13). In that case, bilateral CME was present together with late fluorescein staining of the optic discs, but ophthalmoscopic evidence of ODE was not described. We believe our patient to be the first reported example of ophthalmoscopic, angiographic, and OCT evidence of the combination of ODE and CME in this syndrome. We propose that this combination, together with the presence of anasarca and increased serum VEGF, implies that increased vascular permeability is the mechanism of the ODE in POEMS syndrome. There is a lingering controversy as to whether the ODE of POEMS syndrome is a manifestation of increased ICP, nerve infiltration, ischemia, or vascular hyperperme-ability Some case series ( 6,8) and case reports ( 9,10) have documented elevated ICP in patients with POEMS syndrome with bilateral ODE. However, other studies have not found elevated ICP in such patients with bilateral ODE ( 3,4,7,11,12). We acknowledge that, given the absence of a lumbar puncture, we were unable to exclude elevated ICP in our patient. We would defend our proposition that the ODE is based on vascular leakage rather than papilledema by citing evidence that CME, defined as petalloid intraretinal fluid-filled cavitations, does not typically occur in papilledema. OCT analysis of 7 patients with papilledema secondary to idiopathic intracranial hypertension or metastatic cancer to the brain and ophthalmoscopic evidence of macular edema showed that the edema was entirely subretinal rather than intraretinal ( 14). We also cannot exclude infiltration of the optic nerve by abnormal proteins as the cause of ODE. Case reports have described orbital, choroidal, and/ or optic nerve infiltration in POEMS syndrome or Castleman disease, an angiofollicular lymph node hyperplasia that can be associated with POEMS syndrome ( 15- 18). However, we did not observe choroidal lesions on ophthalmoscopy, FA, or OCT. MRI did not show infiltrative lesions in the optic nerves or orbits. Vascular occlusion and ischemia are also potential causes of ODE. Venous and arterial thromboses have been loosely associated with POEMS syndrome ( 6). However, the ODE in POEMS syndrome is typically bilateral and would require two separate thrombotic events to occur. The simultaneous presence of bilateral CME, severe lower extremity edema, and ascites supports the idea that the ODE may result from capillary leakage similar to that happening elsewhere in the body. Elevated serum levels of VEGF, a potent angiogenic and vascular permeability factor, have been documented in POEMS syndrome ( 7,13,19- 21). In 10 patients with POEMS syndrome, Watanabe et al ( 7) found a mean serum VEGF level of 1,673.2 pg/ mL compared with < 131 pg/ mL in control 181 J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 Chong et al FIG. 2. A. Fundus photographs demonstrate bilateral optic disc edema and B. bilateral blunting of the foveal reflex. C. Late- phase fluorescein angiography demonstrates bilateral vascular leakage in the optic discs and petalloid leakage in the macular region. D. Optical coherence tomography demonstrates bilateral increased macular thickness and hypoechoic intraretinal cavitations consistent with cystoid macular edema. subjects. Additionally, serum VEGF levels appear to With regard to treatment of POEMS syndrome, correlate with disease activity- including the degree of Badros et al ( 19) described a patient with serum VEGF CME- in POEMS syndrome ( 13,19- 21). Macular edema levels > 2,300 pg/ mL who had persistent systemic in uveitis, diabetic retinopathy, central retinal vein symptoms after treatment with melphalan and dexameth-occlusion, and age- related macular degeneration has been asone, but who had a dramatic improvement in edema and associated with elevated intraocular VEGF levels ( 22). peripheral neuropathy after intravenous bevacizumab was 182 © 2007 Lippincott Williams & Wilkins Optic Disc Edema in POEMS J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 added to the regimen. Further investigation is needed to determine whether anti- VEGF agents, alone or in conjunction with other agents, may ameliorate the symptoms of POEMS syndrome. 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