Unilateral Isolated Paucisymptomatic Optic Disc Edema

Unilateral isolated optic disc edema (UIODE) represents a challenging clinical presentation that frequently precipitates an extensive diagnostic work-up. Patients without an apparent diagnosis despite appropriate investigations are often categorized as having "papillophlebitis," an entity that is poorly defined in the existing literature. Our aim was to describe the characteristics of a series of patients with paucisymptomatic UIODE, determine the optimal diagnostic approach to such cases, and clarify the clinical features of presumed papillophlebitis

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Unilateral Isolated Paucisymptomatic Optic Disc Edema Eman Hawy, MD, Rahul A. Sharma, MD, MPH, Jason H. Peragallo, MD, Michael Dattilo, MD, PhD, Nancy J. Newman, MD, Valérie Biousse, MD Background: Unilateral isolated optic disc edema (UIODE) represents a challenging clinical presentation that frequently precipitates an extensive diagnostic work-up. Patients without an apparent diagnosis despite appropriate investigations are often categorized as having “papillophlebitis,” an entity that is poorly defined in the existing literature. Our aim was to describe the characteristics of a series of patients with paucisymptomatic UIODE, determine the optimal diagnostic approach to such cases, and clarify the clinical features of presumed papillophlebitis. Methods: We retrospectively identified 29 patients with UIODE who were seen by neuro-ophthalmologists at a single center between 2005 and 2019. Each patient presented with isolated, unilateral disc edema that was either entirely asymptomatic or associated with minimal visual symptoms. Patients underwent a comprehensive neuro-ophthalmic evaluation and several ophthalmic and systemic investigations. Data from the initial visit and all subsequent clinical visits were collected, including patient demographics, examination findings, and details of the diagnostic work-up. Results: Our 29 patients with UIODE were found to have a variety of underlying diagnoses including unilateral papilledema due to idiopathic intracranial hypertension (10 patients), optic nerve sheath meningioma (5), incipient nonarteritic anterior ischemic neuropathy (4), vitreopapillary traction (3), orbital masses (2), a peripapillary choroidal neovascular membrane (1), and presumed papillophlebitis (4). The duration of disc edema varied considerably based Departments of Ophthalmology (EH, RAS, JHP, MD, NJN, VB), Pediatrics (JHP), Neurology (NJN, VB), and Neurological Surgery (NJN), Emory University School of Medicine, Atlanta, Georgia. Supported in part by a departmental grant (Department of Ophthalmology) by NIH/NEI core grant P30-EY06360 (Department of Ophthalmology, Emory University School of Medicine), and by NIH/ NINDS (RO1NSO89694). Previously presented as an abstract presentation at the North American Neuro-Ophthalmology Society (NANOS) Annual Meeting (2019), Las Vegas, NV. V. Biousse and N. J. Newman are consultants for GenSight Biologics. N. J. Newman is a consultant for Santhera Pharmaceuticals and Stealth BioTherapeutics. The remaining authors report no conflicts of interest. E. Hawy and R. A. Sharma denotes equal contributions as first authors. Address correspondence to Valérie Biousse, MD, NeuroOphthalmology Unit, Emory Eye Center, The Emory Clinic, 1365-B Clifton Road NE, Atlanta, GA 30322; E-mail: [e-mail] Hawy et al: J Neuro-Ophthalmol 2021; 41: e523-e534 on the etiology, but most patients had favorable visual outcomes. Conclusions: A systematic approach to the evaluation of UIODE, combined with long-term follow-up, led to a definite diagnosis in a majority of patients, with only 4 patients presumed to have papillophlebitis, a diagnosis the actual existence of which remains controversial. Journal of Neuro-Ophthalmology 2021;41:e523–e534 doi: 10.1097/WNO.0000000000001136 © 2020 by North American Neuro-Ophthalmology Society U nilateral isolated optic disc edema (UIODE) with preserved visual function is uncommon and may result from various pathophysiological mechanisms, including optic nerve compression (1), impaired axonal transport secondary to intracranial hypertension (2,3), optic nerve head drusen (4), incipient anterior ischemic optic neuropathy (5), mild anterior inflammatory optic neuritis or perineuritis (6), vitreopapillary traction (VPT) (7), ocular hypotony (8), central retinal venous occlusion (9), and so-called “papillophlebitis” (10–17). The evaluation of patients with UIODE is frequently challenging, but a systematic approach should allow for accurate diagnosis and the early identification of patients that may require treatment to mitigate their risk of vision loss. A negative workup for UIODE may lead to the diagnosis of “papillophlebitis,” a clinical entity that is poorly defined in the literature (Table 1). Lyle and Wybar’s 1961 report (10) of 5 patients younger than 50 years old with unilateral optic disc edema, generalized dilatation of the retinal veins, little or no involvement of the retinal arterioles, and minimal visual symptoms is generally credited as the first published series of papillophlebitis patients. However, 4 of these 5 cases had additional features that are more commonly attributed to central retinal vein occlusion (CRVO), including peripheral retinal hemorrhages. The authors termed the cases “retinal vasculitis” and proposed an underlying inflammatory etiology. Lonn and Hoyt first used the term “papillophlebitis” in 1966 (11) to describe 5 e523 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Hawy et al: J Neuro-Ophthalmol 2021; 41: e523-e534 Author Year n Age/Sex Lonn and Hoyt11 1966 5 25–65/3M, 2F Cogan12 1969 11 22–40/5M, 6F 13 1972 4 30–35/2M, 2F Laibovitz17 1979 1 20F Bienfait et al.19 1986 6 32–45/3M, 3F Hrabovsky et al.27 2012 5 29–51/3M, 2F Associated Medical History Visual Symptoms Examination Findings Systemic Work-up Ophthalmic Investigations Mildly blurred Unilateral disc edema, “Routine serologic, — vision, peripapillary hematologic and urologic photopsias hemorrhages, venous studies”, carotid congestion arteriogram, lumbar puncture, pneumoencephalogram IVFA Variable serological workMildly blurred Unilateral disc edema, Lupus (1), up; patients underwent cerebral vision venous neurological and general congestion, minimal vasculitis (1), medical examination skin vasculitis retinal hemorrhages, and exudate (1) Sinusitis (1), Mildly blurred Unilateral optic disc Unspecified IVFA childhood vision edema, mild venous tuberculosis congestion, minimal (1), pregnancy retinal hemorrhages, (1) white exudates None Mildly blurred Mild disc edema, “Complete medical and — vision venous dilation laboratory evaluation” Sinusitis, Mildly blurred Disc edema, retinal Unspecified serological IVFA, VEP tobaccovision venous congestions, work-up; patients alcohol abuse, few retinal underwent neurological platelet hemorrhages and general medical aggregation examination dysfunction None Mildly blurred Unilateral disc edema, Included inflammatory, IVFA, ERG, vision peripapillary infective and VEP hemorrhages, cotton autoimmune serologies; wool spots, venous MRI brain/orbits; lumbar tortuosity puncture None Treatment Visual Outcome (BCVA) “Steroid and anticoagulant therapy” 20/20 Oral steroids Not specified; “no residuum” Oral steroids 20/20 — 20/20 Oral steroids 20/32 or better Oral and intravenous steroids in 1 case Normal vision Age, patient age at the time of presentation; BCVA, best-corrected Snellen visual acuity; ERG, electroretinogram; F, female; IVFA, intravenous fluorescein angiography; M, male; n, number of patients with presumed papillophlebitis; VEP, visual evoked potential; Year, year of publication. Original Contribution e524 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 1. Published cases of so-called “papillophlebitis” in the English literature Original Contribution patients with chronic, benign, unilateral, paucisymptomatic optic disc edema. All but 1 patient lacked the peripheral retinal findings noted by Lyle and Wybar (10), but the authors likewise proposed a pathogenesis involving local phlebitis causing occlusion of the central retinal vein and suggested that it was the optic disc counterpart of Eales’ disease. In 1969, Cogan (12) described 11 patients with similar clinical presentations who had “minimal symptoms, unilateral isolated disc swelling, congestions of the veins, and a few hemorrhages.” He diagnosed these patients with “mild papillary vasculitis” with resulting “partial venous occlusion.” He emphasized that this condition had a good prognosis and that the disc edema could persist for months or years and tended to not recur. Despite using the term “vasculitis,” he stated that the inflammatory etiology remained hypothetical. Eight similar cases were subsequently described by Hayreh in 1972 (13). Others, including Hart et al in 1971 (9 cases) (14), Sogg in 1974 (1 case) (15), and Ellenberger and Messner in 1978 (3 cases) (16), reported cases of presumed papillophlebitis with retinal findings suggesting CRVO or retinal vasculitis. Subsequent publications have described the diagnosis of papillophlebitis in a highly inconsistent manner (17–19). Most authors agree that nearly all patients are asymptomatic or paucisymptomatic and have a benign and protracted course. Several articles (17–20) support the initial theories that papillophlebitis has an inflammatory basis, although to our knowledge there is no published report of pathology. Other studies have favored a mechanism involving increased retinal venous pressure, similar to CRVO (14–16). The inclusion of patients with retinal hemorrhages, venous sheathing, and cotton wool spots is confusing and has lead several authors to use the term papillophlebitis simply to refer to findings of CRVO with disc edema, especially in young patients (14,16,21–23). Hayreh (13) attempted to account for these inconsistencies by proposing a classification of 2 subgroups of papillophlebitis patients, one with and one without marked retinal features of venous occlusion in addition to disc edema. Walsh and Hoyt in 1969 (24) described papillophlebitis as “isolated disc edema with venous engorgement.” The aim of our study was to report a series of patients with paucisymptomatic UIODE to determine the optimal diagnostic approach to such cases, further elaborate the differential diagnosis of this clinical presentation, and describe patients ultimately diagnosed with presumed papillophlebitis as a diagnosis of exclusion. METHODS This study received institutional review board approval. We conducted a retrospective chart review to identify all patients with unilateral, isolated, paucisymptomatic optic disc edema assessed at our institution between January 2005 and February 2019. We included only patients aged 18 years and older with chronic disc edema in one eye. Patients Hawy et al: J Neuro-Ophthalmol 2021; 41: e523-e534 had normal best corrected visual acuity and color vision, no relative afferent pupillary defect, and had either normal visual fields or findings of very mild field depression. Patients with decreased visual function in the affected eye (either from the assessment of visual acuity, visual fields, or color vision) were excluded. Patients with highly asymmetric but bilateral disc edema were excluded, as were those with abnormal ocular examination findings other than disc edema with or without very proximate peripapillary hemorrhages or exudates and retinal venous congestion. Specifically, patients with optic nerve head drusen, ocular hypotony, uveitis, posterior scleritis, and definite CRVO were excluded. Examination All patients received a standardized, detailed neuro-ophthalmic evaluation, including Snellen visual acuity measurement, color vision assessment using Ishihara pseudo-isochromatic plates, pupil examination, slit-lamp examination, assessment of intraocular pressure, dilated fundus examination, and 24-2 Humphrey visual field (HVF) analysis. Depending on the results of the clinical assessment, patients also underwent ocular fundus photography, optical coherence tomography (OCT) of the retinal nerve fiber layer, intravenous fluorescein angiography (IVFA), fundus autofluorescence (FAF), and b-scan ocular echography. Patients also had systemic investigations at the discretion of the treating physician, including serological tests, brain and orbital MRI and magnetic resonance venography (MRV) with contrast, and a lumbar puncture (LP) for cerebrospinal fluid (CSF) analysis and opening pressure when intracranial hypertension was suspected (Table 2). Patient Data All medical records were reviewed to collect data regarding patient age at the discovery of disc edema; body mass index (BMI); race; gender; pertinent past medical and ocular histories; medications; best-corrected visual acuity (BCVA) at initial examination; intraocular pressure; optic nerve appearance of both eyes; and results of any investigations obtained (fundus photographs, HVF, OCT, IVFA, FAF). Clinical records for each patient throughout the follow-up period were then reviewed to determine: final diagnosis; follow-up duration since discovery of disc edema (in weeks); the duration of the interval before visual loss (in weeks) or the interval before the resolution of disc edema (in weeks) if no visual loss occurred; final visual outcome (BCVA and VF); and all investigations obtained as part of the patient’s clinical work-up. Patients lost to follow-up were specifically identified, as were those with incidentally found disc edema, as the true duration of disc edema in these patients could not be estimated. Review of Literature To identify prior cases of papillophlebitis, we searched PubMed from 1960 to 2020 with the terms e525 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. # Age 1 20 2 59 3 Race Gender BMI Past Medical/Ocular Incidental History Diagnosis? Final Diagnosis W F W F 27 None 36 42 AA F 4 24 5 No Eye Follow-up Duration (wks) Hawy et al: J Neuro-Ophthalmol 2021; 41: e523-e534 IIH OS 96* Diabetes, Yes hypertension, obesity IIH OS 44* 46 Diabetes, No hypertension, dyslipidemia IIH OD 44 W F 30 Hypertension No IIH OD 37* 44 AA F 34 None Yes IIH OS 65 6 39 29 None Yes IIH OS 142* 7 42 49 Hypertension Yes IIH OS 146 8 45 W M W M W M 24 None No IIH OD 253* 9 33 Iraqi M 35 None No IIH OS 154 10 48 37 None Yes IIH OS 144 11 38 W F W M 29 Colloid cyst third Yes ventricle (resected) ONSM OD 186† 12 46 W M 34 None ONSM OD 144† No Visual Outcome (BCVA and VF) Interval Before Resolution of Disc Edema Interval Before Visual Loss (wks) (wks) VA: 20/15 OU N/A HVF: full OU VA: 20/20 OU At presentation HVF: full OD; enlarged blind spot, inferonasal depression OS VA: 20/25 OD, N/A 20/20 OS (baseline) HVF: enlarged blind spot OD, full OS VA: 20/20 OU N/A HVF: enlarged blind spot OD, full OS VA: 20/20 OU N/A HVF: full OD, enlarged blind spot OS VA: 20/20 OU N/A HVF: full OU VA: 20/15 OU N/A HVF: full OU VA: 20/15 OU N/A HVF: inferonasal depression OD, full OS VA: 20/20 OU N/A HVF: non-specific depressed points OU VA: 20/20 OU N/A HVF: full OU VA: 20/250 OD, At presentation 20/20 OS Superior island of vision OD, HVF full OS VA: 20/20 OU N/A HVF: full OU 22 Persistent mild disc edema Work-up Ophthalmic Investigations MRI brain/orbits, B-scan, OCT MRV, LP MRI brain/orbits, B-scan, IVFA, LP OCT 44 MRI brain/orbits, IVFA, OCT MRV, LP Persistent mild disc edema MRI brain/orbits, OCT MRV, LP 65 MRI brain/orbits, None MRV, LP Persistent mild disc edema 103 MRI brain/orbits, B-scan, IVFA, MRV, LP OCT MRI brain/orbits, B-scan, FAF, OCT MRV, LP MRI brain/orbits, B-scan, OCT MRV, MRA, LP Persistent mild disc edema 102 MRI brain/orbits, B-scan, OCT MRV, LP Persistent mild disc edema 520 MRI brain/orbits, B-scan, OCT MRV, LP MRI brain/orbits, B-scan, OCT MRV, LP Persistent disc edema MRI brain/orbits B-scan, OCT Original Contribution e526 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 2. Clinical characteristics of 29 patients presenting with unilateral isolated paucisymptomatic optic disc edema Hawy et al: J Neuro-Ophthalmol 2021; 41: e523-e534 Race Gender BMI Past Medical/Ocular Incidental History Diagnosis? Final Diagnosis # Age 13 33 W F 33 None No ONSM OD 431† 14 65 22 Hypertension Yes ONSM OD 82* 15 28 26 None No ONSM OD 41* 16 70 W F Indian F W F 29 Dyslipidemia No Incipient NAION OD 87 17 54 W F 20 None No Incipient NAION OS 59 18 61 W M 35 Incipient NAION OD 24 19 66 W F 27 Yes Diabetes, hypertension, dyslipidemia None No Incipient NAION OS 93 20 58 W F 59 VPT OD Single visit 21 78 W F 26 VPT OS Single visit 22 41 28 None Yes VPT OD 23 42 AA M AA M 28 None No Orbital vascular OS malformation Single visit Single visit No Diabetes (with DME OD), hypertension, uterine cancer Atrial fibrillation, No CAD, hypertension Eye Follow-up Duration (wks) Visual Outcome (BCVA and VF) Interval Before Resolution of Interval Before Disc Edema Visual Loss (wks) (wks) Work-up Ophthalmic Investigations At presentation 177 MRI brain/orbits OCT At presentation MRI brain/orbits OCT 8 Persistent disc edema Persistent disc edema 12 6 8 MRI brain/orbits, FAF, OCT MRV N/A 24 MRI brain/orbits, OCT MRV VA: 20/25 OU HVF: full OU N/A 56 VA: 20/40 OD, 20/20 OS HVF: enlarged blind spot OD, full OS VA 20/20 OD, 20/20 OS HVF: Full OD, enlarged blind spot OS VA: 20/20 OU HVF: full OU VA: 20/20 OD, 20/25 OS HVF: full OD, subtle inferior arcuate OS At presentation Single visit MRI brain/orbits, B-scan, OCT MRV, CBC, CRP, ESR MRI brain/orbits OCT At presentation Persistent disc edema MRI brain/orbits OCT N/A Single visit None At presentation Single visit MRI brain/orbits IVFA VA: 20/20 OU HVF: inferior depression OD, full OS VA: 20/20 OU HVF: full OU VA: 20/20 OU HVF: full OU VA: 20/20 OU HVF: inferior depression OD, full OS VA: 20/20 OU HVF: full OD, superior arcuate OS VA: 20/20 OU HVF: full OU N/A MRI brain/orbits None MRI brain/orbits, OCT CBC, CRP, ESR OCT Original Contribution e527 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. (Continued ) Race Gender # Age BMI 24 56 W M 36 25 52 Asian M 26 38 27 17 28 29 Past Medical/Ocular Incidental History Diagnosis? Final Diagnosis Eye Follow-up Duration (wks) Visual Outcome (BCVA and VF) Interval Before Resolution of Interval Before Disc Edema Visual Loss (wks) (wks) Work-up Ophthalmic Investigations No Optic canal mass OS 311† N/A VA: 20/20 OU HVF: OD full, nonspecific changes OS Persistent disc edema MRI brain/orbits, B-scan, OCT LP 26 Coronary artery disease, myocardial infarction Myopia Yes CNVM OS 176* Persistent disc edema MRI brain/orbits B-scan, FAF, IVFA OCT AA F W F 21 None Yes Papillophlebitis OD 479† 21 None Yes Papillophlebitis OS 111* VA: 20/20 OU N/A HVF: full OD; enlarged blind spot OS VA: 20/20 OU N/A HVF: full OU VA: 20/20 OU N/A HVF: full OU MRI brain/orbits, B-scan, FAF, MRV IVFA, OCT MRI brain/orbits IVFA, OCT 35 Hispanic M 32 None No Papillophlebitis OD 40* VA: 20/20 OU N/A HVF: enlarged blind spot OD; full OS 28 W M 35 None No Papillophlebitis OD 185 VA: 20/20 OU HVF: full OU Persistent disc edema Persistent disc edema with optociliary shunt vessel Persistent disc edema with peripapillary folds 68 N/A MRI brain/orbits, B-scan, OCT MRV, LP (normal pressure) MRI brain/orbits B-scan, OCT Hawy et al: J Neuro-Ophthalmol 2021; 41: e523-e534 AA, African American; Age, patient age at the time of presentation; BCVA, best-corrected Snellen visual acuity; BMI, body mass index, rounded to nearest whole value; b-scan, b-scan ocular ultrasonography; CAD, coronary artery disease; CBC, complete blood count; CNVM, choroidal neovascular membrane; CRP, c-reactive protein; ESR, erythrocyte sedimentation rate; F, female; FAF, fundus autofluorescence; IIH, idiopathic intracranial hypertension; IVFA, intravenous fluorescein angiography; LP, lumbar puncture with CSF analysis and opening pressure; M, male; MRV, magnetic resonance venography; NAION, nonarteritic anterior ischemic optic neuropathy; OCT, optical coherence tomography; ONSM, optic nerve sheath meningioma; OU, both eyes; PMH, past medical history; VF, 24-2 humphrey visual field analysis; VPT, vitreopapillary traction; W, white. *Indicates no further follow-up. † Indicates that follow-up is ongoing. Original Contribution e528 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. (Continued ) Original Contribution FIG. 1. Diagnostic algorithm for our assessment of 29 patients with unilateral, isolated, paucisymptomatic optic disc edema. Included is the clinical work-up and final diagnoses, with the number of patients with each diagnosis indicated in parentheses. By definition, cases with optic nerve head drusen and central retinal vein occlusion were not included in our series of patients. However, these entities should be included when evaluating patients with paucisymptomatic unilateral disc edema. Diabetic papillopathy is similar to incipient nonarteritic anterior ischemic optic neuropathy, and although we had no patient with diabetic papillopathy in our series, we combined these 2 entities in our figure. B-scan, b-scan ocular echography; CNVM, choroidal neovascular membrane; CRVO, central retinal vein occlusion; CSF, cerebrospinal fluid; FAF, fundus autofluorescence; ICP, intracranial pressure; IIH, idiopathic intracranial hypertension; IVFA, intravenous fluorescein angiogram; LP, lumbar puncture; MRV, magnetic resonance venography; NAION, nonarteritic anterior ischemic optic neuropathy; OCT, optical coherence tomography; RNFL, retinal nerve fiber layer. “papillophlebitis,” “isolated disc edema,” “central retinal vein occlusion,” and “CRVO.” We only included patients that had asymptomatic or paucisymptomatic isolated disc edema and were identified by the authors as having papillophlebitis (Table 1). Patients were permitted to have retinal venous congestion and retinal hemorrhages or exudates in the very proximate peripapillary region, but those with classical features of a CRVO, including peripheral retinal hemorrhages, cotton wool spots, and macular edema, were excluded. Additional references were found through a review of the references from identified articles. RESULTS We included 29 patients with UIODE. Figure 1 outlines our diagnostic algorithm of patients with unilateral, isolated, paucisymptomatic disc edema. Table 2 provides the clinical data for each patient included in our study. Idiopathic Intracranial Hypertension (10 Patients; Case #s 1–10) Ten of our 29 patients (34% of cases; 6 women, 4 men) had unilateral papilledema and were eventually diagnosed with idiopathic intracranial hypertension (IIH) (Fig. 2). All our IIH patients were obese (BMI .25); all had radiographic Hawy et al: J Neuro-Ophthalmol 2021; 41: e523-e534 findings consistent with intracranial hypertension on MRI and MRV of the brain (25,26); and all had elevated opening pressures with normal CSF contents on LP. The diagnosis of IIH was made 1–32 months after discovery of UIODE based on the modified Dandy criteria (26). Optic Nerve Sheath Meningioma (5 Patients; Case #s 11–15) Five of our 29 patients (17% of cases; 3 women, 2 men) had evidence of an optic nerve sheath meningioma (ONSM) on postcontrast MRI of the orbits (Fig. 3). Four of these patients endorsed mild visual blurring on initial presentation but no appreciable change in visual acuity, color vision, and visual fields were detectable on examination of the affected eye; whereas 4 patients retained normal visual acuity throughout the follow-up period (20/20 OU in 4 patients) and one patient (Case # 11) suffered loss of vision to 20/250 4 months later (before the correct diagnosis). The diagnosis of ONSM was made 1 week to 5 months after discovery of UIODE. Incipient Nonarteritic Anterior Ischemic Optic Neuropathy (4 Patients; Case #s 16–19) All 4 patients (14% of cases; 3 women, 1 man) with presumed incipient NAION had normal visual function (by e529 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. Unilateral optic disc edema secondary to intracranial hypertension. A. Bilateral optic nerve photographs of case #9, a 33-year-old man with idiopathic intracranial hypertension, showing optic nerve edema of the left optic nerve only. B. Ocular coherence tomography results in the same patient. Neuroretinal rim thickness values are elevated beyond the normal range in the patient’s left eye only, indicating unilateral edema of the left optic nerve. RNFL = retinal nerve fiber layer; C/D = cup-todisc. C. Sagittal T1 MRI of the brain (left) shows a partially empty sella (arrow); MRV of the brain (right) shows a stenosis at the junction of the right transverse and sigmoid sinuses (arrow) and a hypoplastic left transverse venous sinus. Both features are suggestive of chronic intracranial hypertension. FIG. 3. Unilateral optic disc edema secondary to an optic nerve sheath meningioma. A. Bilateral optic nerve photographs of Case #14, a 65-year-old woman with a right optic nerve sheath meningioma (ONSM), showing optic nerve edema in the right eye only. The patient had disc edema, normal visual function, and no symptoms for at least one month before the ONSM was recognized. B. Coronal T1 postcontrast MRI of the orbits shows enhancement of the right intraorbital optic nerve sheath, consistent with an optic nerve sheath meningioma (arrow head). e530 Hawy et al: J Neuro-Ophthalmol 2021; 41: e523-e534 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution definition) on initial examination. Two patients (Case #s 16 and 17) developed visual field loss (at 8 and 6 weeks, respectively) consistent with NAION. In 2 additional patients (Case #s 18 and 19), the disc edema spontaneously resolved at 24 and 56 weeks, respectively, without any visual deficit. All 4 patients had contralateral cup-to-disc ratios of 0.2 or less, consistent with a “disc at risk”; 3 patients (Case #s 16– 18) had luxury perfusion of the swollen optic nerve at presentation; and 1 patient (Case # 19) had segmental disc swelling. None of the patients had dilated retinal veins. All 4 patients were more than 60 years old and 2 patients had known vascular risk factors including diabetes, dyslipidemia, and hypertension. Vitreopapillary Traction (3 Patients; Case #s 20–22) Three patients (10% of cases; 2 women, 1 man) had evidence of VPT on OCT of the optic nerve. Two of these patients were asymptomatic at presentation, and one (Case # 20) had only subtle visual blurring in the affected eye due to associated vitreomacular traction and secondary macular edema. Orbital Masses (2 Patients; Case #s 23 and 24) Two patients (7% of cases; both men) had disc edema for less than 1 month duration and were found to have orbital masses (one vascular malformation and one orbital extension of an intracranial mass). Peripapillary Choroidal Neovascular Membrane (1 Patient; Case # 25) One patient (3% of cases; a man) with high myopia had a peripapillary choroidal neovascular membrane, as diagnosed with OCT of the optic nerve and IVFA. The patient was not treated, because he retained normal visual function. The disc edema was ongoing after 40 months of follow-up. Presumed Papillophlebitis (4 Patients; Case #s 26–29) FIG. 4. Unilateral optic disc edema secondary to presumed papillophlebitis. Bilateral optic nerve photographs of Case #26, a 38-year-old woman with presumed papillophlebitis, showing optic nerve edema in the left eye only, with mildly dilated retinal veins (top panel). The left optic nerve edema persisted at 21-, 33-, 59-, and 68-month follow-up visits (subsequent panels). She developed an asymptomatic small flame peripapillary hemorrhage after 59 months of follow-up and another one at 68 months. Visual function remained normal. Hawy et al: J Neuro-Ophthalmol 2021; 41: e523-e534 Four patients (14% of cases; 2 women and 2 men) remained without a definite diagnosis after extensive investigations. All 4 patients had high resolution brain and orbital MRIs with contrast, which did not show any orbital lesion or signs of intracranial hypertension, including no stenosis of the cerebral venous sinuses. These cases were classified as presumed “papillophlebitis.” The patients ranged in age from 17 to 38 years at the time of diagnosis, and all were without any relevant medical history. Two of 4 patients underwent IVFA which showed retinal venous dilation and engorgement suggesting retinal venous congestion, but no other retinal findings. One patient (Case # 27) had an optociliary shunt vessel in association with chronic disc swelling (but no retinal hemorrhages), very suggestive of chronic venous occlusive disease. One patient (Case # 26) e531 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution had a recurrent small peripapillary flame hemorrhage over time but never developed a CRVO (Fig. 4). One patient (Case # 28) had peripapillary retinal folds in addition to chronic swelling with dilated retinal veins. This finding prompted us to obtain an LP which showed normal CSF opening pressure; the optic nerve appearance did not change after the LP. All 4 patients retained normal visual function throughout follow-up durations of 40–479 weeks. Three of the 4 patients had ongoing disc edema throughout the entirety of the follow-up period, lasting 40, 111, and 479 weeks, respectively; the remaining patient (Case # 29) experienced spontaneous resolution of disc edema after 68 weeks. DISCUSSION A systematic approach to the evaluation of UIODE, combined with long-term follow-up, led to a definite diagnosis in 86% of our patients, emphasizing the need to investigate these patients thoroughly (Fig. 1). Interestingly, the most common diagnosis was IIH with unilateral papilledema. These 10 cases all had radiographic signs suggesting intracranial hypertension (25,26), including bilateral transverse venous sinus stenosis on MRV, prompting LP with CSF opening pressure. In 4 cases (14%), a comprehensive work-up was unrevealing and no definite diagnosis could be made despite prolonged follow-up periods (40, 111, 185 and 479 weeks, respectively); these patients likely have so-called “papillophlebitis,” a diagnosis which remains uncommon, even in our tertiary neuro-ophthalmologic clinic. Indeed, the designation of UIODE as “papillophlebitis” is controversial and it is unclear whether this term should be used at all (27). Our review of the existing literature indicates that the term remains ill-defined and, as a result, this diagnosis is made with great inconsistency. For example, we found many cases in the literature with retinal findings entirely consistent with the diagnosis of CRVO who were labeled as papillophlebitis, usually because of young patient age, only mild symptoms, or even just because of the very presence of optic disc edema or its extent out of proportion to the associated typical vascular and retinal findings of CRVO. However, disc edema is a known feature of many patients with CRVO (9), and many patients with nonischemic CRVO will present with normal visual acuity and minimal visual field findings (28). Therefore, the finding of paucisymptomatic disc edema in addition to other classical retinal features of CRVO should not be considered a separate entity from CRVO. Instead, similar to earlier descriptions by Lonn and Hoyt (11), Cogan (12), and Hayreh (13), we agree that the diagnosis of papillophlebitis should only be made in patients with asymptomatic or paucisymptomatic isolated disc edema without the classic funduscopic features of a CRVO (peripheral retinal hemorrhages, cotton wool spots, and macular edema), albeit allowing for some element of retinal venous congestion. Using this e532 clinical definition, we found only 32 cases of papillophlebitis in the English literature (Table 1). Miller in 1977 (29) reported 8 patients with isolated unilateral disc edema that could be consistent with the description of so-called papillophlebitis. These cases all had negative detailed workups, including normal CSF pressure, and all had good outcomes. Miller termed this condition “the big blind spot syndrome” because all patients had an enlarged blind spot on visual field testing. Other similar cases are likely published in the literature but could not be identified by our search terms because they were not designated as possible papillophlebitis. The pathophysiology of papillophlebitis remains debatable. The term was first used based on the presumption that the underlying pathophysiology involved venous inflammation (phlebitis) (11); however, this theory has been largely abandoned for one that proposes a similar pathophysiological basis as that of classic CRVO. As previously suggested (27), the term “venous papillopathy” may be more appropriate. It has been postulated that certain patients with retinal venous outflow obstruction may present with predominantly papillary and peripapillary findings because of anatomic variability of the central retinal vein or because of the specific site of retinal venous occlusion; patients with papillophlebitis may have partial venous occlusion in the pre-laminar rather than the laminar or retrolaminar regions (13,14). As suggested by Lonn and Hoyt (11), it is possible that patients with isolated chronic disc edema and venous engorgement may have previously suffered a mild CRVO that was not diagnosed because of the lack of visual loss. Spontaneous partial recanalization of the occluded vein, or the development of collateral circulation, could result in improvement of retinal findings but persistence of asymptomatic disc edema related to chronic mild impaired venous drainage. One of our patients (Case # 27) had an optociliary shunt vessel in addition to very prolonged disc edema, indeed very suggestive of a previous CRVO. Some authors have claimed that papillophlebitis is a disease exclusively of young, healthy patients. Each of our 4 patients were indeed without any significant past medical history, but many prior cases in the literature do include patients with additional diagnoses, including hypercoaguable states and inflammatory diseases (12,13,19). The suggestion that patients with papillophlebitis have good visual outcomes is supported by the literature and by our own cases, who all ultimately retained 20/20 visual acuity and normal visual function on visual field testing, despite very prolonged disc edema. Patients with papillophlebitis may be observed, as the natural history of this diagnosis most often involves spontaneous resolution of the disc edema; however, given the underlying pathophysiology, a minority of patients may develop a CRVO and must then be treated accordingly, although the risk is not known. Because of a presumed inflammatory mechanism, steroids have occasionally been prescribed to papillophlebitis patients (8–11), but there is no proven efficacy and no good rationale to support such treatment. Hawy et al: J Neuro-Ophthalmol 2021; 41: e523-e534 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Our study has several limitations. The extent of investigations obtained for each patient varied based on the clinical suspicion and the investigative process was stopped once a diagnosis was made. All patients except one (with definite VPT) received high resolution brain and orbital imaging. We did not systematically perform a LP on all patients; instead, we chose to only perform an LP in patients with signs of raised intracranial pressure on brain MRI, including bilateral transverse venous sinus stenosis, and in one of our patients with presumed papillophlebitis because of the presence of peripapillary folds. Blood tests looking for vascular risk factors, inflammatory and infectious disorders were often obtained and, except for the identification of vascular risk factors, were unrevealing. Figure 1 shows our diagnostic strategy, which resulted in definite diagnoses in most patients. In only 8 patients (4 with presumed incipient NAION and 4 with presumed papillophlebitis) was the work-up entirely normal. Similar to presumed papillophlebitis, the diagnosis of incipient NAION is difficult and often a diagnosis of exclusion (5,30). Subtle differences in optic disc and vascular appearance helped us classify patients as incipient NAION or papillophlebitis; however, the fact that these 2 entities result in chronic, asymptomatic, often reversible disc edema makes their distinction very challenging. All our patients with incipient NAION had a small cup-to-disc ratio in the contralateral eye, 3 had evidence of luxury perfusion associated with the disc edema at presentation and 1 had segmental disc edema. In these 4 patients, the initial optic nerve appearance was very suggestive of NAION. Two of these 4 patients developed visual loss from NAION after 8 and 6 weeks, and the disc edema spontaneously resolved in the other 2 patients after 24 and 56 weeks of follow-up. One of our 4 patients with presumed papillophlebitis (Case # 26) had marked retinal venous dilation at presentation and the other 3 cases had mild venous dilation; none had luxury perfusion and one had an optociliary shunt vessel. It is true that the differences between presumed NAION and presumed papillophlebitis are subtle, but careful examination of the swollen optic disc should allow for identification of arterial vs venous abnormalities. In conclusion, our case series highlights the need to systematically and thoroughly evaluate patients with UIODE. Brain and orbital imaging with contrast is essential to rule-out chronic compression of the optic nerve. The addition of brain MRV or CTV is very useful to detect bilateral transverse venous stenosis, the presence of which should strongly suggest intracranial hypertension as the cause of unilateral disc edema and prompt performance of an LP with measurement of the opening pressure. The diagnosis of so-called papillophlebitis should be made with caution and only in patients who have isolated, chronic disc edema with or without retinal venous congestion, but without evidence of retinal signs that would definitively indicate the diagnosis of CRVO. 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Hawy et al: J Neuro-Ophthalmol 2021; 41: e523-e534 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.