Retinal and Optic Nerve Deformations Due to Orbital Versus Intracranial Venous Hypertension.

INTRODUCTION: Abnormal forces around the optic nerve head (ONH) due to orbital diseases, intracranial hypertension (IH), glaucoma, and space travel, are associated with alterations of the ONH shape. Elevated cerebral and ophthalmic venous pressure can contribute to stress and strain on the ONH and peripapillary retina. We hypothesize that IH and elevated ophthalmic venous pressure without IH cause different ONH and retinal changes. METHODS: We compared MRI and spectral domain optical coherence tomography (SDOCT) findings in patients with cavernous sinus arteriovenous shunts (CSAVSs), where orbital venous pressure is known to be elevated, with patients with intracranial dural venous sinus thrombosis and secondary IH. We also compared the results to those obtained in the Idiopathic IH (IIH) Treatment Trial. RESULTS: Among 18 patients with dural venous sinus thrombosis, the MRI/magnetic resonance venography displayed partial empty sella (61%) and optic nerve sheath distension (67%). None exhibited ophthalmic vein dilation or signs of orbital congestion. SDOCT of these eyes and IIH eyes showed a similar frequency of abnormal thickening of the mean retinal nerve fiber layer, anterior displacement of the basement membrane opening, peripapillary wrinkles, retinal folds (RF), and choroidal folds (CF). Among 21 patients with CSAVSs, MRI showed ipsilateral dilated superior ophthalmic vein (76%) and orbital congestion (52%) without distension of the optic nerve sheath or globe distortion. SDOCT showed CF (19%), one with overlying RF, and no ONH deformations. CONCLUSIONS: SDOCT findings for dural venous sinus thrombosis are similar to those seen with IIH but distinct from changes due to local ophthalmic venous hypertension. These data support the concept that IH even if due to a vascular cause and local orbital venous hypertension cause different stresses and strains on the ONH.

Peripapillary Hyper-reflective Ovoid Mass-like Structure (PHOMS): An Optical Coherence Tomography Marker of Axoplasmic Stasis in the Optic Nerve Head.

BACKGROUND: With the development and widespread adoption of spectral-domain optical coherence tomography (OCT), peripapillary hyper-reflective ovoid mass-like structures (PHOMS) have become a frequent OCT finding in neuro-ophthalmic practice. Although originally assumed to represent a form of buried optic disc drusen (ODD), PHOMS differ from ODD in many important ways. The histopathological underpinnings of PHOMS are now becoming more clearly understood. EVIDENCE ACQUISITION: Review of literature. RESULTS: PHOMS can be broadly classified as disk edema-associated PHOMS, ODD-associated PHOMS, or anomalous disk-associated PHOMS. PHOMS are seen in many conditions, including papilledema, nonarteritic anterior ischemic optic neuropathy, central retinal vein occlusion, acute demyelinating optic neuritis, ODD, and tilted disks (myopic obliquely inserted disks) and in many cases resolve along with the underlying condition. The histopathological study of these diverse entities reveals the common feature of a bulge of optic nerve fibers herniating centrifugally over Bruch membrane opening into the peripapillary space, correlating exactly with the location, shape, and space-occupying nature of PHOMS on OCT. Because of the radial symmetry of these herniating optic nerve fibers, PHOMS are best thought of as a complete or partial torus (i.e., donut) in 3 dimensions. CONCLUSIONS: PHOMS are a common but nonspecific OCT marker of axoplasmic stasis in the optic nerve head. They are not themselves ODD or ODD precursors, although they can be seen in association with ODD and a wide spectrum of other conditions. They do not exclude papilledema and often accompany it. The circumferential extent and characteristic 3D toroidal nature of a PHOMS are best appreciated by scrolling through consecutive OCT images.

Optical Coherence Tomography Neuro-Toolbox for the Diagnosis and Management of Papilledema, Optic Disc Edema, and Pseudopapilledema.

BACKGROUND: Distinguishing optic disc edema from pseudopapilledema is a common, sometimes challenging clinical problem. Advances in spectral-domain optical coherence tomography (SD-OCT) of the optic nerve head (ONH) has proven to be a cost effective, noninvasive, outpatient procedure that may help. At its core are tools that quantify the thickness of the retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GC-IPL). The SD-OCT also provides a set of tools that may be qualitatively interpreted in the same way that we read an MRI. They include the transverse axial, en face, and circular tomogram. Our goal is to describe a practical office-based set of tools using SD-OCT in the diagnosis and monitoring of papilledema, optic disc edema, and pseudopapilledema. EVIDENCE ACQUISITION: Searches on PubMed were performed using combinations of the following key words: OCT, papilledema, pseudopapilledema, optic disc drusen, retinal folds (RF), and choroidal folds (CF). RESULTS: The principal elements of SD-OCT analysis of the ONH are the RNFL and GC-IPL thickness; however, these metrics have limitations when swelling is severe. Qualitative interpretation of the transverse axial SD-OCT aids in assessing peripapillary shape that may help distinguish papilledema from pseudopapilledema, evaluate atypical optic neuropathies, diagnose shunt failures, and identify outer RF and CF. There is a consensus that the SD-OCT is the most sensitive way of identifying buried optic disc drusen. En face SD-OCT is especially effective at detecting peripapillary wrinkles and outer retinal creases, both of which are common and distinctive signs of optic disc edema that rule out pseudopapilledema. Mechanically stressing the ONH in the adducted eye position, in patients with papilledema, may expose folds and peripapillary deformations that may not be evident in primary position. We also discuss how to optimize the acquisition and registration of SD-OCT images. CONCLUSIONS: The SD-OCT is not a substitute for a complete history and a careful examination. It is, however, a convenient ancillary test that aids in the diagnosis and management of papilledema, optic disc edema, and pseudopapilledema. It is particularly helpful in monitoring changes over the course of time and distinguishing low-grade papilledema from buried drusen. The application of the SD-OCT toolbox depends on optimizing the acquisition of images, understanding its limitations, recognizing common artifacts, and accurately interpreting images in the context of both history and clinical findings.

Multirater Validation of Peripapillary Hyperreflective Ovoid Mass-like Structures (PHOMS).

Peripapillary hyperreflective ovoid mass-like structures (PHOMS) are a new retinal optical coherence tomography (OCT) finding. The Optic Disc Drusen Studies Consortium had made recommendations to distinguish PHOMS from true optic disc drusen (ODD) in 2018. While publications on PHOMS have increased since then, the accuracy of the definition of PHOMS and reliability of detection is unknown. In this multi-rater study, we demonstrate that the 2018 definition of PHOMS resulted in a poor multi-rater kappa of 0.356. We performed a Delphi consensus process to develop a consistent and refined definition of PHOMS with clear principles around the nature of PHOMS and how they differ from normal anatomy. Fifty explanatory teaching slides, provided as supplementary material, allowed our expert group of raters to achieve a good level of agreement (kappa 0.701, 50 OCT scans, 21 raters). We recommend adopting the refined definition for PHOMS.

Gaze-Evoked Deformations in Optic Nerve Head Drusen: Repetitive Shearing as a Potential Factor in the Visual and Vascular Complications.

PURPOSE: To determine if ocular ductions deform intrapapillary and peripapillary tissues in optic nerve head drusen (ONHD) and to compare these deformations with healthy eyes and eyes with other optic neuropathies. DESIGN: Observational case series. PARTICIPANTS: Twenty patients with ONHD. METHODS: Axial rasters of the optic nerve from a spectral-domain OCT device (Cirrus 5000; Carl Zeiss Meditec, Inc, Dublin, CA) were used to analyze the shape of the peripapillary basement membrane (ppBM) layer in 20 confirmed cases of ONHD. We compared registered images obtained from 2 eye positions: 10° to 15° in adduction and 30° to 40° in abduction. Geometric morphometrics was used to analyze the shape of the ppBM layer defined by placing 10 equidistant landmarks extending 2500 µm on both sides of the basement membrane opening. We also adapted an image strain tracking technique to measure regional intrapapillary strains in 6 patients. Using manually placed nodes on the reference image (in adduction), an iterative, block-matching algorithm is used to determine local displacements between the reference and its paired image in abduction. Displacement vectors were used to calculate the mean shear and effective strain (percent change). MAIN OUTCOME MEASURES: Peripapillary shape deformations, intrapapillary shear strains, and effective strains. RESULTS: We found a statistically significant difference in the shape of the ppBM layer between abduction and adduction (P < 0.01). The deformation was characterized by a relative posterior displacement temporally in adduction that reversed in abduction. Strain tracking in all 6 patients showed substantial gaze-induced shearing and effective strains. Mean effective strains were 7.5% outside the drusen. Shear and effective strains were significantly larger outside versus within the drusen (P < 0.003 and P < 0.01, respectively). CONCLUSIONS: This study demonstrates that horizontal ocular ductions induce significant shearing deformations of the peripapillary retina and prelaminar intrapapillary tissues. We also found that the deformations in healthy persons are similar in magnitude to ONHD. Based on these findings, we speculate that patients with intrapapillary calcifications exposed to the long-term effects of repetitive shearing (induced by ocular ductions) may contribute to the progressive axonal loss and vascular complications associated with ONHD.

The Optic Disc Drusen Studies Consortium Recommendations for Diagnosis of Optic Disc Drusen Using Optical Coherence Tomography.

BACKGROUND: Making an accurate diagnosis of optic disc drusen (ODD) is important as part of the work-up for possible life-threatening optic disc edema. It also is important to follow the slowly progressive visual field defects many patients with ODD experience. The introduction of enhanced depth imaging optical coherence tomography (EDI-OCT) has improved the visualization of more deeply buried ODD. There is, however, no consensus regarding the diagnosis of ODD using OCT. The purpose of this study was to develop a consensus recommendation for diagnosing ODD using OCT. METHODS: The members of the Optic Disc Drusen Studies (ODDS) Consortium are either fellowship trained neuro-ophthalmologists with an interest in ODD, or researchers with an interest in ODD. Four standardization steps were performed by the consortium members with a focus on both image acquisition and diagnosis of ODD. RESULTS: Based on prior knowledge and experiences from the standardization steps, the ODDS Consortium reached a consensus regarding OCT acquisition and diagnosis of ODD. The recommendations from the ODDS Consortium include scanning protocol, data selection, data analysis, and nomenclature. CONCLUSIONS: The ODDS Consortium recommendations are important in the process of establishing a reliable and consistent diagnosis of ODD using OCT for both clinicians and researchers.

Optical Coherence Tomography in Neuroretinitis: Epipapillary Infiltrates and Retinal Folds.

Neuroretinitis is a form of papillitis associated with the delayed onset of an exudative macular star among other inflammatory ocular findings. We describe 4 patients with neuroretinitis who displayed several distinctive and novel findings on spectral-domain optical coherence tomography (OCT) that include "epipapillary infiltrates" and an atypical pattern of inner retinal folds. The recognition of these findings on OCT may help in the early diagnosis of neuroretinitis.

Optic Nerve Sheath Melanoma Presenting as a Central Retinal Vein Occlusion.

A 64-year-old woman, with a history of diabetes and melanoma, developed a central retinal vein occlusion (CRVO) in her left eye. On exam, she had severe disc edema with retinal nerve fiber layer thickening, and anterior deformation of the peripapillary retinal pigment epithelium (RPE)/Bruch membrane layer (ppRPE/BM) toward the vitreous on spectral domain optical coherence tomography (SD-OCT) suggesting an optic nerve sheath (ONS) meningioma. Magnetic resonance imaging findings and ONS biopsy later confirmed a metastatic melanoma. This case demonstrates that the shape of the RPE/BM on SD-OCT may aid in the decision to consider imaging in patients with isolated CRVO.

Optical coherence tomography shape analysis of the peripapillary retinal pigment epithelium layer in presumed optic nerve sheath meningiomas.

BACKGROUND: Geometric morphometrics (GM) was used to compare the shape of the peripapillary retinal pigment epithelium-Bruch's membrane (ppRPE) layer imaged on spectral domain optical coherence tomography (SD-OCT) of patients with presumed optic nerve sheath meningiomas (pONSM) and normal subjects. METHODS: We compared 2 groups: 30 normals to 10 patients (11 eyes) with pONSM. We digitized 20 equidistant semi-landmarks on OCT images of the ppRPE-layer, spanning 2500 µm on each side of the neural canal opening (NCO). Data were analyzed using standard GM techniques including a generalized least squares Procrustes superimposition, principal component analysis (PCA), thin-plate spline, and permutation statistical analysis to evaluate differences in shape. We also analyzed other variables with respect to shape including tumor size-proximity to the globe, age, retinal nerve fiber layer, and optic disc height. RESULTS: All pONSM patients were female (age 37-66 years); 10 had unilateral and 1 had bilateral optic nerve involvement. Ten of the eyes had optic disc edema at presentation, 4 went on to develop shunt vessels, and 4 had optic atrophy. The ppRPE-layer bordering the NCO in normals is V-shaped pointing away from the vitreous; the ppRPE-layer in pONSM is indented causing an inverted-U shaped deformation skewed nasally toward the vitreous. PCA showed a significant difference between normals and pONSM (permutation, n = 10,000, P = 0.001). The size and proximity of the tumor to the globe correlates with the shape of the ppRPE-layer (r = 0.75, P = 0.04). Correlation between shape variables and RNFL thickening (r = 0.51), optic disc height (r = 0.67), and age (r = 0.67) were not statistically significant. CONCLUSION: The shape of the RPE layer in pONSM is characterized by an inverted-U shape or indentation that differs significantly from normals. It is indistinguishable from the shape we previously reported in papilledema and is not caused by disc edema. The mechanism in pONSM is unknown but may involve a change in the compliance of the nerve and/or localized sequestration of cerebrospinal fluid in the distal optic nerve sheath.

Peripapillary Hyperreflective Ovoid Mass-like Structures (PHOMS) in Children: The Copenhagen Child Cohort 2000 Eye Study.

PURPOSE: To determine the prevalence of peripapillary hyperreflective ovoid mass-like structures (PHOMS) in a population-based child cohort and to study their association with other optic nerve head features and myopia. DESIGN: Observational, population-based cohort study of 1407 children aged 11-12 years. METHODS: Optical coherence tomography scans of optic nerve heads were graded for PHOMS, disc tilt, prelaminar hyperreflective lines, and scleral canal diameter and investigated for associated prenatal and ocular parameters. Children with optic disc drusen or optic disc edema were excluded. RESULTS: PHOMS were found in 8.9% of children. The location of PHOMS was predominantly in the superonasal section of the optic disc. Myopia and optic nerve head tilt were more common in children with PHOMS than in children without PHOMS (P < .001 and P < .001, respectively). Prelaminar hyperreflective lines were found in 17.9% of children with PHOMS compared to 7.3% of children without PHOMS (P < .001). Prelaminar hyperreflective lines with and without PHOMS were associated with a shorter axial length of the eye (P < .001). There were no prenatal factors associated with PHOMS. Prelaminar hyperreflective lines were associated with higher birth weight and continued maternal smoking during pregnancy (P = .01 and P = .02, respectively). CONCLUSIONS: PHOMS had a prevalence of 8.9% in healthy children without optic disc drusen or optic disc edema and was associated with increasing myopic refraction and the presence of a tilted optic nerve head and prelaminar hyperreflective lines. Given the high prevalence of PHOMS, they should not unreservedly be taken as evidence of optic neuropathy.

Ocular Deformations in Spaceflight-Associated Neuro-Ocular Syndrome and Idiopathic Intracranial Hypertension.

Purpose: Spaceflight-associated neuro-ocular syndrome (SANS) shares several clinical features with idiopathic intracranial-hypertension (IIH), namely disc edema, globe-flattening, hyperopia, and choroidal folds. Globe-flattening is caused by increased intracranial pressure (ICP) in IIH, but the cause in SANS is uncertain. If increased ICP alone causes SANS, then the ocular deformations should be similar to IIH; if not, alternative mechanisms would be implicated. Methods: Using optical coherence tomography (OCT) axial images of the optic nerve head, we compared "pre to post" ocular deformations in 22 patients with IIH to 25 crewmembers with SANS. We used two metrics to assess ocular deformations: displacements of Bruch's membrane opening (BMO-displacements) and Geometric Morphometrics to analyze peripapillary shape changes of Bruch's membrane layer (BML-shape). Results: We found a large disparity in the mean retinal nerve-fiber layer thickness between SANS (108 um; 95% confidence interval [CI] = 105-111 um) and IIH (300 um; 95% CI = 251-350.1 um). The pattern of BML-shape and BMO-displacements in SANS were significantly different from IIH (P < 0.0001). Deformations in IIH were large and preponderantly anterior, whereas the deformations in SANS were small and bidirectional. The degree of disc edema did not explain the differences in ocular deformations. Conclusions: This study showed substantial differences in the degree of disc edema and the pattern of ocular deformations between IIH and SANS. The precise cause for these differences is unknown but suggests that there may be fundamental differences in the underlying biomechanics of each consistent with the prevailing hypothesis that SANS is consequent to multiple factors beyond ICP alone. We propose a hypothetical model to explain the differences between IIH and SANS based on the pattern of indentation loads.

Incidence and Progression of Chorioretinal Folds During Long-Duration Spaceflight.

Importance: The primary contributing factor for development of chorioretinal folds during spaceflight is unknown. Characterizing fold types that develop and tracking their progression may provide insight into the pathophysiology of spaceflight-associated neuro-ocular syndrome and elucidate the risk of fold progression for future exploration-class missions exceeding 12 months in duration. Objective: To determine the incidence and presentation of chorioretinal folds in long-duration International Space Station crew members and objectively quantify the progression of choroidal folds during spaceflight. Design, Setting, and Participants: In this retrospective cohort study, optical coherence tomography scans of the optic nerve head and macula of crew members completing long-duration spaceflight missions were obtained on Earth prior to spaceflight and during flight. A panel of experts examined the scans for the qualitative presence of chorioretinal folds. Peripapillary total retinal thickness was calculated to identify eyes with optic disc edema, and choroidal folds were quantified based on surface roughness within macular and peripapillary regions of interest. Interventions or Exposures: Spaceflight missions ranging 6 to 12 months. Main Outcomes and Measures: Incidence of peripapillary wrinkles, retinal folds, and choroidal folds; peripapillary total retinal thickness; and Bruch membrane surface roughness. Results: A total of 36 crew members were analyzed (mean [SD] age, 46 [6] years; 7 [19%] female). Chorioretinal folds were observed in 12 of 72 eyes (17%; 6 crew members). In eyes with early signs of disc edema, 10 of 42 (24%) had choroidal folds, 4 of 42 (10%) had inner retinal folds, and 2 of 42 (5%) had peripapillary wrinkles. Choroidal folds were observed in all eyes with retinal folds and peripapillary wrinkles. Macular choroidal folds developed in 7 of 12 eyes (4 of 6 crew members) with folds and progressed with mission duration; these folds extended into the fovea in 6 eyes. Circumpapillary choroidal folds developed predominantly superior, nasal, and inferior to the optic nerve head and increased in prevalence and severity with mission duration. Conclusions and Relevance: Choroidal folds were the most common fold type to develop during spaceflight; this differs from reports in idiopathic intracranial hypertension, suggesting differences in the mechanisms underlying fold formation. Quantitative measures demonstrate the development and progression of choroidal folds during weightlessness, and these metrics may help to assess the efficacy of spaceflight-associated neuro-ocular syndrome countermeasures.

High-dose cyclophosphamide for moderate to severe refractory multiple sclerosis: 2-year follow-up (investigational new drug No. 65863).

High-dose cyclophosphamide (HDC) is a chemotherapy treatment designed to eradicate autoreative B- and T-cells responsible for lymphocyte-mediated autoimmune illness while sparing the pluripotent blood stem cell of any ill effects. Multiple sclerosis (MS) is the most common inflammatory and demyelinating immune-mediated disorder of the central nervous system in young adults. Patients with moderate to severe, refractory MS, defined as an Expanded Disability Status Scale (EDSS) score of 3.5 or higher after two or more Food and Drug Administration-approved disease-modifying agents, received 200 mg/kg of cyclophosphamide over 4 days. For the next 2 years, quarterly EDSS score evaluations and biannual brain magnetic resonance imaging and neuro-ophthalmologic evaluations were obtained. Fifteen patients were evaluated for clinical response. During follow-up, one patient increased their baseline EDSS score by 1.0. EDSS score stability of decrease was realized in five of seven (71%) patients with relapsing-remitting MS and six of eight (75%) patients with secondary progressive MS. Four patients required additional immunomodulatory treatment after treatment. Treatment response was seen regardless of the baseline presence or absence of contrast lesion activity. HDC can effectively decrease symptoms, stop disease progression, and allow for disability regression in relapsing-remitting MS and secondary progressive MS patients. The most appropriate candidates for HDC, its duration of benefit, and the potential need for prophylactic preventative immune manipulation after HDC all require further investigation.

The sensitivity and specificity of retinal and choroidal folds to distinguish between mild papilloedema and pseudopapilledema.

PURPOSE: To determine if the presence or absence of retinal and choroidal folds on SD-OCT imaging can distinguish between mild papilloedema and pseudopapilledema. DESIGN: Cross-sectional cohort study METHODS: Subjects with optic disc elevation (Frisen grades 1 and 2 only) were eligible to be enrolled prospectively. Pseudopapilledema was defined as a lack of change in optic disc appearance between two visits <6 months apart, and papilloedema was defined as change in optic disc appearance between two visits <6 months apart determined by review of fundus photographs by a masked neuro-ophthalmologist. Three masked neuro-ophthalmologists independently reviewed en face and axial optical coherence tomography (OCT) images of the optic nerve of the study subjects for the presence or absence of retinal and choroidal folds. Concordance was determined when there was agreement between at least 2 of the 3 observers. RESULTS: Forty-five subjects (78 eyes) met inclusion criteria. There were 32 eyes with papilloedema and 46 eyes with pseudopapilledema. Choroidal and/or retinal folds were detected in 38% of eyes (12/32) with papilloedema and 19.6% of eyes (9/46) with pseudopapilledema. Post-hoc analyses eliminated six questionable cases of pseudopapilledema that had ancillary testing suggestive of elevated intracranial pressure and resulted in one remaining eye (2%) with more certain pseudopapilledema that was found to have folds. En face OCT imaging was more sensitive (71%) in detection of folds than axial OCT imaging (57%). CONCLUSIONS: Choroidal and/or retinal folds on OCT are commonly observed in patients with mild papilloedema and are uncommon in those with pseudopapilledema. The presence of folds on OCT in patients presenting with disc elevation suggests papilloedema.

Ischemic optic neuropathy after Descemet-stripping automated endothelial keratoplasty.

An 82-year-old woman presented with a failed Descemet-stripping automated endothelial keratoplasty (DSAEK) in her right eye performed a month earlier. The patient underwent uneventful repeat DSAEK. Six days after the procedure, the patient was found to have an afferent pupillary defect and optic nerve swelling in her right eye on fundoscopy and optical coherence tomography. A comprehensive workup, including bilateral temporal artery biopsies and magnetic resonance imaging, for vasculitic etiologies was negative. A diagnosis of nonarteritic anterior ischemic optic neuropathy (NAION) was made. Although NAION has been reported after various ocular surgeries, to the authors' knowledge, this is the first reported case of NAION after uneventful corneal transplantation. Therefore, NAION should be considered a rare complication of corneal transplantation surgery. Meticulous preoperative and postoperative evaluation, including an attentive pupillary and dilated fundus examination, are essential in assessing a patient's risk factors for this condition and monitoring for its occurrence in the perioperative period.