How to distinguish retinal disorders from causes of optic nerve dysfunction?

Andrew G. Lee, MD The Methodist Hospital Houston, TX

Learning Objectives Keywords 1. To define the overlapping clinical presentations of 1. Optic Neuropathy acute unilateral visual loss in a young patient that might suggest either retinopathy versus optic neuropathy 2. Retinopathy 2. To describe the big red flags for retinal disease versus 3. Electrophysiology optic neuropathy 4. Optical Coherence Tomography 3. To define the key clinical findings for subtle or occult 5. Macular Photostress Test retinopathy (e.g., acute zonal occult outer retinopathy) 4. To list some specific diagnostic testing that might help Introduction with making the correct diagnosis or retinal versus optic nerve etiologies for visual loss The clinical presentation of acute unilateral visual loss in a young patient can be due to a number of conditions including possible retinopathy or optic neuropathy. Although demyelinating CME Questions optic neuritis is the most common unilateral optic neuropathy to present in a young adult to a neuro-ophthalmologist, the 1. Which of the following ocular symptoms is most likely possibility of acute retinopathy should also be in the differential to be associated with an optic nerve rather than retinal diagnosis especially when specific red flags for retinal disease etiology for visual loss? are present. The overlapping clinical presentation of retinal and a. Flashing lights or photopsias optic nerve disorders in this setting can be challenging and will b. Metamorphopsia (including micropsia/macropsia) affect the patient’s evaluation, treatment and prognosis. The c. Day or night blindness (i.e., hemeralopia or nyctalopia) main diagnostic dilemma is that a young otherwise healthy d. Pain with eye movement female patient who presents with acute unilateral visual loss may have idiopathic or demyelinating optic neuritis or a subtle 2. Which of the following is more likely to be a sign of or occult retinopathy (e.g., acute zonal occult outer retinopathy). optic neuropathy than retinopathy as the etiology of This manuscript will describe the key differentiating clinical unexplained visual loss? symptoms and signs and the specific diagnostic testing that might help with making the correct diagnosis. a. Red color desaturation in the affected eye b. An equal inter-eye subjective light brightness test c. Normal Ishihara or HRR color vision testing Illustrative case d. A positive prolonged macular photostress test A 22-year-old white woman presents with a chief complaint 3. Which of the following abnormal electrophysiologic of acute unilateral loss of vision in the right eye (OD). She findings would be expected to differentiate had some vague flashing lights OD as well as glare but no loss maculopathy from optic neuropathy as the etiology for of brightness or color. The left eye is asymptomatic. She has visual loss? no other neurologic symptoms. There is mild pain with eye movement OD. She has a family history of multiple sclerosis a. Visual evoked potential (MS) in a maternal aunt but no other medical disorders b. Full field electroretinogram run in her family. Her past medical and surgical histories c. Multifocal electroretinogram were negative. Her social history was non-contributory d. Electrooculogram and she did not smoke or drink alcohol. She was taking no medications and had no medical allergies. The remainder of her review of systems was negative and she specifically denied any prior neurologic signs or symptoms. She denied any metamorphopsia, micropsia, macropsia or day or night blindness (i.e., hemeralopia or nyctalopia).

2013 Annual Meeting Syllabus | 361 On neuro-ophthalmologic examination the visual acuity retinal disease (e.g., bull’s eye maculopathy). An enlarged blind was 20/25 OD and 20/20 OS. The examination of the left spot (Figure 1) would be a very atypical presenting visual field eye was completely normal. The pupils were isocoric and defect (perhaps < 2%) for optic neuritis and suggests a problem reactive OU but there was a trace right relative afferent with the peripapillary retina. pupillary defect (RAPD). The slit lamp biomicroscopy showed no uveitis. External, extraocular motility, and In most cases of retinal disease the fundus exam is diagnostic intraocular pressure exams were all normal. She correctly (e.g., cystoids macular edema, macular hole, epiretinal identified 13/14 Ishihara color plates OD and 14/14 OS. membrane, chorioretinal scarring, retinal detachment, etc.) Humphrey visual field showed an enlarged blind spot but in some cases the fundus exam is near normal or perhaps (Figure 1) with some breakout superiorly and inferiorly OD but was normal OS. The fundus examination showed a normal macula, vessels, and periphery OU. There was no optic disc edema or optic atrophy. There were no vitreous cells noted. There was no peripapillary atrophy, cystoid macular edema, or epiretinal membrane formation.

She was seen by a comprehensive ophthalmologist who referred the patient to outside retina specialist who confirmed the normal retinal exam. An optical coherence tomography (OCT) of the macula and a fluorescein angiogram were both normal. A contrast cranial magnetic resonance imaging (MRI) study was negative for optic nerve enhancement and no demyelinating white matter lesions were seen. The patient was told that she might have “multiple sclerosis” and then referred to neuro- ophthalmology as “possible demyelinating optic neuritis.” Figure 1. Automated perimetry shows enlargement of the Clinical questions blindspot. 1. Is this a case of retrobulbar optic neuritis? 2. Is this retinal or neuro-ophthalmic disease? 3. How can we clinically differentiate optic nerve from retinal etiologies for visual loss? 4. What diagnostic testing might be useful at this point?

Ocular symptoms that are suspicious for retinal etiology for the visual loss include flashing lights or photopsias, metamorphopsia (including micropsia/macropsia) in macular disease (e.g., epiretinal membrane), or day or night blindness (i.e., hemeralopia or nyctalopia). In contrast, some clinical features on exam Figure 2. Spectral-domain OCT shows attenuation of the IS/OS that might suggest optic neuropathy over retinopathy include junction between the fovea and optic disc. abnormal color testing, nerve fiber layer field defect, and optic disc edema or pallor.1,2 Red color desaturation and more severe dyschromatopsia are more common in patients with optic neuritis than in acute maculopathy. The light brightness test in this patient showed no subjective light or color desaturation in either eye and color testing was near normal by Ishihara testing.3 A macular photostress test might be useful in patients with central loss. In this test, the patient is shown a moderate light stimulus for 10 seconds of light exposure in each eye. The time to recovery of one line of vision over the best corrected visual acuity line is recorded. In most normal individuals the macular photostress time is less than 60 seconds of recovery time. In a patient with suspected optic neuropathy the result also would be expected to be 60 seconds or less but in macula disease it might be prolonged (e.g., more than 60–90 seconds).4 A formal visual field might show a ring scotoma (rather than a central or cecocentral scotoma or Figure 3. Multifocal ERG shows flattening of the 3D plot. nerve fiber layer defect) on automated or kinetic perimetry in

362 | North American Neuro-Ophthalmology Society completely normal. Although it is not within the scope of to raise the suspicion for retinopathy over optic neuropathy this manuscript to describe other ancillary testing for retinal in this case. The patient subsequently had mild improvement disease, the clinician might consider macular optical coherence in her blind spot enlargement and did not develop any tomography (OCT) to look for subtle evidence for maculopathy recurrence. Over time subtle RPE change appeared in the that can escape ophthalmoscopic detection. OCT in patients peripapillary region of the affected eye but no new visual or with peripapillary derangement or acute zonal occult outer neurologic symptoms occurred after five years of follow up. retinopathy (AZOOR) might show abnormalities in the outer retina (e.g., inner segment and outer segment junction, Figure Summary 2). In addition, fluorescein angiography still has a role for There is considerable overlap in the clinical presentation detecting leakage from occult vascular pathology (e.g., macular of some acute retinal disorders and optic neuritis. The nonperfusion or leakage from an underlying neovascular comprehensive ophthalmologist might have difficulty membrane). Over time even in patients who present with an determining who they should call first for consultation, occult retinopathy and a normal fundus exam, subtle or more retina or neuro-ophthalmology. In a young otherwise obvious and visible retinal pigment epithelial (RPE) change healthy female with acute unilateral visual loss, pain might develop in the area of initial retinal dysfunction. with eye movement, and an RAPD optic neuritis is one of the top etiologies in the differential diagnosis. These If the clinical symptoms are suggestive of a retinal origin overlapping demographic and clinical features between or if an optic neuropathy cannot be established clinically acute retinopathy (e.g., the big blind spot syndrome) then electrophysiologic testing might be useful. Full field and acute optic neuritis can be challenging even for the electroretinogram (ERG) might show depression of waveforms neuro-ophthalmologist. The potential differentiating for diffuse retinal dysfunction but multifocal ERG (MERG) clinical symptoms suggesting retinal disease are photopsias, might be necessary to detect localized macular (central or ring metamorphopsia, and lack of pain with eye movement. scotoma) dysfunction or peripapillary (big blind spot) retinal The possibly helpful differentiating clinical signs suggesting dysfunction (Figure 3). As a mass response test, the full field retinal etiology are a big blind spot or ring scotoma on visual ERG might be normal in patients with focal, zonal, or macular field testing, normal color and brightnesss, the lack of an only disease. I sometimes will combine the full field ERG and/ RAPD, or an abnormal macular photostress test. A negative or MERG testing with a visual evoked potential (VEP) if there high quality gadolinium enhanced cranial and orbital MRI is suspicion for nonorganic overlay or if I am deprived of the is another red flag that should raise suspicion for a retinal luxury of a confirmatory relative RAPD because of bilateral and etiology for the visual loss. OCT and fluorescein angiography symmetric ocular disease. In patients with an abnormal ERG might be helpful or might be normal and the key diagnostic or MERG the possibility of occult autoimmune retinopathy test for differentiating retinal from optic nerve pathology (e.g., autoimmune related retinopathy and optic neuropathy in these cases might be electrophysiology. Full field ERG or paraneoplastic retinopathy (e.g., cancer associated might be useful for diffuse retinal disease but MERG might retinopathy or melanoma associated retinopathy) should be be necessary for focal retinal disease especially the acute considered. In these cases retinal antibody testing and specific idiopathic blind spot enlargement syndrome. paraneoplastic antibody testing might be warranted.

In this particular patient the full field ERG showed a depressed CME Answers waveform and especially a lower amplitude in the b wave in 1. d the affected eye consistent with the diagnosis of the acute idiopathic blind spot enlargement syndrome (the “big blind 2. a spot syndrome”) which some authors believe is a subset of 3. c acute zonal occult outer retinopathy (AZOOR).5,6 The diagnostic dilemma often occurs in the acute setting when one of the retinal “white dot disorders” (e.g., multiple evanescent white References dot syndrome or MEWDS) occurs without the “white dots” (i.e, MEWDS without the MEWDS”). In this setting, even an 1. Nikoskelainen E. Symptoms, signs and early course of optic neuritis. Acta Ophthalmol. 1975;53:254–72. experienced retina doctor who sees a young female patient with acute loss of vision, an RAPD, and a normal initial 2. Hart WM Jr. Acquired dyschromatopsias. Surv Ophthalmol. 1987;32:10–31. fundus exam might be tempted to refer the patient to neuro- ophthalmology for an evaluation for demyelinating optic 3. Sadun AA, Lessell S. Brightness-sense and optic nerve disease. Arch Ophthalmol. 1985;103:39–43. neuritis. In this patient, an MRI was performed that showed no contrast enhancement of the optic nerve (which is atypical for 4. Glaser JS, Savino PJ, Sumers KD, et al. The photostress recovery 7 test: in the clinical assessment of visual function. Am J Ophthalmol. acute demyelinating optic neuritis ) and no confirmatory white 1977;83:255–60. matter lesions for MS. Unfortunately, a normal MRI cannot 5. R H Gray. Unilateral enlargement of the blind spot: a diagnostic rule out demyelinating optic neuritis especially if the study dilemma. Br J Ophthalmol 2002;86:936–938. was not a fat suppressed, dedicated orbit, post-gadolinium study. Nevertheless, the normal MRI is an additional “red flag”

2013 Annual Meeting Syllabus | 363 364 | North American Neuro-Ophthalmology Society How to Distinguish Pseudopapilledema from Papilledema

Anthony C. Arnold, MD Jules Stein Eye Institute UCLA Dept. of Ophthalmology Los Angeles, CA

Learning Objectives This presentation will discuss each modality, with examples, advantages, and disadvantages for each. Findings in ODD 1. Review the cardinal clinical signs of papilledema versus will be compared with those in ODE. pseudo-papilledema in patients presenting with an elevated optic nerve appearance 2. Describe the best use ancillary tests and tailor the Illustrative Case investigative approach in patients with possible A 36-year-old obese woman reports a 3-week history of papilledema versus pseudo-papilledema headache, increased in frequency over her baseline migraine pattern. She has occasional blurring of vision but no transient visual obscurations. She denies pulse synchronous tinnitus CME Questions or diplopia. Her only medications include occasional over the counter analgesia for her headaches. 1. Does the patient in the case presented have papilledema or pseudo-papilledema? Examination shows the visual acuity is 20/15 each eye, with 2. Is this a case of optic disc drusen? equivocally sluggish pupils but no relative afferent pupillary defect. Eye movements are normal as is the remainder of 3. How can we differentiate benign causes of an elevated the neuro-ophthalmic examination except for the fundus. optic nerve appearance from causes of raised The optic discs are elevated, with blurred margins and no intracranial pressure? visible cup, as shown in the fundus photos (Figure 1). No spontaneous venous pulsations are observed. Visual fields demonstrate bilateral inferior constriction (Figure 2). Keywords 1. Papilledema 2. Pseudopapilledema 3. Optic Disc Drusen 4. Ultrasonography 5. Fluorescein Angiography

Introduction Figure 1 The differentiation of optic disc drusen (ODD) from true optic disc edema (ODE) is of critical importance, because ODE may represent a life-threatening condition requiring urgent and costly ancillary testing, whereas ODD is most often a benign process requiring only observation. In cases of ODD located on the disc surface, diagnosis may be straightforward, but with intrapapillary ODD (“buried drusen”), the optic disc appearance may mimic that of ODE. Ancillary testing has been utilized to aid in identification of ODD, including B-mode ultrasonography1, CT imaging, and fluorescein angiographic “autofluorescence.” 2–5 Recently, specific fluorescein angiography (FA) criteria for differentiating ODD from ODE have been published6. Optical coherence tomography (OCT) is also evolving as a modality for differentiation of ODD from ODE9–11. Figure 2

2013 Annual Meeting Syllabus | 365 Audience Response Question What test would you use to determine whether this is a case of papilledema versus pseudo-papilledema?

The diagnostic test options are:

1. B-scan ultrasonography 2. Fluorescein angiography with assessment for autofluorescence 3. OCT, both time domain and spectral domain. 4. Cranial and orbital MRI with venography 5. Lumbar puncture

Panel Discussion What would you choose as your “money test” and why?”

Case Conclusion Figure 3 B-scan ultrasonography was negative for calcified ODD (Figure 3). Fluorescein angiography did not demonstrate autofluorescence(Figure 4). Time-Domain OCT showed nerve fiber layer thickening but no characteristic feature to differentiate ODD from ODE (Figure 5)

The entire angiographic sequence showed no early leakage, with progressive circumferential peripapillary staining with nodularity; no disc hyperfluorescence was present (Figure 6).

The findings were typical for buried ODD.

Discussion When ODD are visible on the optic disc surface, identification is straightforward. The clinical features of intrapapillary (buried) ODD include optic disc elevation, blurred optic disc margins without obscuration of peripapillary retinal vessels, and nodular border of the optic disc, in the absence of features of optic disc Figure 4 edema, such as retinal nerve fiber opacification with obscuration of retinal vessels, microvascular abnormalities such as optic disc surface capillary net dilation, telangiectasia, retinal hemorrhages, and exudates. In this scenario, it is not infrequently difficult to distinguish ODD from ODE with certainty.

The detection of autofluorescence of the optic disc on pre- injection photography is confirmatory for ODD (Figure 7), but the technique is most effective when the ODD are on or near the disc surface, in which case ancillary testing is unnecessary. For intrapapillary ODD, sensitivity is low; Kurz-Levin and Landau1 documented autofluorescence in only 15 of 82 (18%) cases of “buried” ODD. Computed tomography (CT) (Figure 8) is limited not only by 1.5 mm thickness of orbital sections, which often may miss ODD, but by the requirement for calcification of ODD for their detection. B-mode ultrasonography (Figure 9) similarly detects only calcified ODD. While no study has clearly identified the percentage of ODD which are calcified, Kurz-Levin and Landau1 found positive ultrasonography in only 39 of 82 (48%) of eyes with “buried” ODD. 1 In the study of Pineles and Arnold, 30 eyes with proven ODD had also undergone B-scan Figure 5 ultrasonography, 8 of which were negative6.

366 | North American Neuro-Ophthalmology Society Fluorescein angiography has been studied as a tool to identify ODD and differentiate from ODE. Sanders and Ffytche4 and Mustonen and Nieminen5 reported on FA findings in ODD, describing “early fluorescence” and “nodular, well demarcated late hyperfluorescence” seen without leakage. Cartlidge, et al.7 compared the FA findings of eyes diagnosed with “pseudo-papilledema” to those of eyes with true papilledema, emphasizing the “increased vascularity seen more often in papilledema.” Others2,8 have commented on findings in ODD, and a simplified criterion of “disc leakage vs disc staining” has been the standard discriminating feature. A clear distinction between “hyperfluorescence,” staining, and leakage, a critical appraisal of intrapapillary vs peripapillary hyperfluorescence, and a comparison of the findings of the entire FA sequence between ODD and ODE was recently published6. Intrapapillary ODD are characterized by either no early staining, or a characteristic early nodular staining (Figure 10a), unlike ODE, which is characterized by early diffuse leakage (Figure 10b). Intrapapillary ODD also often demonstrate a characteristic late peripapillary staining, either nodular, circumferential, or both (Figure 11a), not seen in ODE, in which capillary dilation Figure 6 and tortuosity, early and late fluorescein leakage (Figure 10b) are seen. Coexistent ODE and ODE may be distinguished by these features. Our case demonstrated the late nodular and circumferential peripapillary stain without leakage characteristic of buried ODD, despite a fundus appearance which suggested ODE.

Figure 7

Figure 9

Figure 8

Figure 10a Figure 10b

2013 Annual Meeting Syllabus | 367 Johnson et al9 suggested time-domain (TD) OCT criteria for differentiating ODD from ODE, based on the internal optic nerve contour and the subretinal hyporeflective space (Figure 12a).

More recently, Yi et al10, Lee et al11 , and Sarac et al12 have documented that the increased resolution of spectral- domain (SD) OCT may provide a clearer image of buried ODD (Figure 12b) and may also distinguish superimposed ODE.

Summary Figure 11a Figure 11b FA in our case confirmed the presence of ODD without ODE. Ultrasonography, autofluorescence, and TD-OCT were not useful in differentiating ODD from ODE. The use of SD- OCT may be the preferred diagnostic modality in the future.

CME Answers 1. Pseudopapilledema 2. Yes 3. Fluorescein angiography is an accurate and reliable method of differentiating pseudopapilledema from papilledema

References 1. Kurz-Levin M, Landau, K. A comparison of imaging techniques for diagnosing drusen of the optic nerve head. Arch Ophthalmol117:1045–1049, 1999. Figure 12a 2. Friedman A, Beckerman, B, Gold, DH, et al. Drusen of the optic disc. Surv Ophthalmol 21:375–390, 1977. 3. Kelley J. Autofluorescence of drusen of the optic nerve head. Arch Ophthalmol 92:263–264, 1974. 4. Sanders M, Ffytche, TJ. Fluorescein angiography in the diagnosis of drusen of the disc. Trans Ophthalmol Soc UK 87:457–468, 1968. 5. Mustonen E, Nieminen, H. Optic disc drusen—a photographic study I. Autofluorescence pictures and fluorescein angiography. Acta Ophthalmol 60:849–858, 1982. 6. Pineles SL, Arnold AC. Fluorescein angiographic identification of optic disc drusen with and without optic disc edema. J Neuro-Ophthalmol 32:17–22, 2012. 7. Cartlidge N, Ng RC, Tilley PJ. Dilemma of the swollen optic disc: a fluorescein retinal angiography study. Br J Ophthalmol 61:385–389, 1977. 8. Arnold AC. Optic disc drusen. Ophthalmol Clin N Amer 4:505–517, 1991. 9. Johnson L, Diehl, ML, Hamm, CW, et al. Differentiating optic disc edema from optic nerve head drusen on optical coherence Figure 12b tomography. Arch Ophthalmol 127:45–49, 2009. 10. Yi K, Mujat M, Sun W, et al. Imaging of optic nerve head drusen. Improvements with spectral domain optic coherence tomography. J Glaucoma 18:373–8, 2009. 11. Lee, KM, Woo SJ, Hwang J-M. Differentiation of optic nerve head drusen and optic disc edema with spectral-domain optical cohernec tomography. Ophthalmology 118:971–977, 2011. 12. Sarac O, Tasci YY, Gurdal C, Can I. Differentiation of optic disc edema from optic nerve head drusen with spectral-domain optical coherence tomography. J Neuro-Ophthalmol 32:207–211, 2012.

368 | North American Neuro-Ophthalmology Society How to Best Measure Afferent Visual Pathway Damage in Neuro-ophthalmic Disorders—the Optic Nerve, Retinal Nerve Fiber Layer, and Beyond!

Fiona Costello, MD, FRCP University of Calgary Cagary, Canada

Learning Objectives Introduction 1. To demonstrate the utility of multi-focal visual Neuro-ophthalmologists have traditionally relied upon the history evoked potential testing in capturing the effects of and physical examination to localize visual problems in their demyelination and remyelination in the afferent visual patients. While these clinical tools represent the cornerstones pathway of optic neuritis and multiple sclerosis patients of our discipline, there are many ancillary testing techniques which can enhance the diagnostic process. In the following 2. To illustrate how motion perception techniques can be presentation, the merits of both well-established and relatively used to capture visual perception disturbances after novel diagnostic tests will be discussed in the context of a typical optic neuritis case of optic neuritis. The relative contributions of various disease mechanisms: demyelination, axonal loss, neuronal damage, and 3. To highlight the potential role of optical coherence cortical compensation will be reviewed. So too, the utility of topography in detecting the effects of primary and different tests in capturing specific pathogenic processes in optic secondary changes in retinal architecture in multiple neuritis will be highlighted. Several techniques will be described sclerosis patients with reference to the case example provided, optic neuritis; yet, the principles of how these tests may be used apply to a variety of optic nerve disorders. CME Questions 1. What are four ancillary tests that can be used prospectively to capture structural changes in the anterior visual pathway in response to an inflammatory optic nerve injury? 2. How can we differentiate differences in form versus motion perception after optic neuritis? 3. How can optical coherence tomography be used to capture changes in retinal architecture in optic neuritis and multiple sclerosis patients?

Keywords 1. Optical Coherence Tomography 2. Ganglion Cell Layer 3. Motion erceptionP Testing 4. Retinal Nerve Fiber Layer 5. Multi-Focal Visual Evoked Potentials

Figure 2: A Baseline SD-OCT shows peripapillary retinal nerve fiber layer thickening in the left eye (180µm) relative to the right eye (103µm), which is consistent with the observed optic disc edema in the left eye in the case example provided.

2013 Annual Meeting Syllabus | 369 Figure 3: Three months after the ON event, there is peripapillary retinal nerve fiber layer thinning in the left eye (77µm) relative to the right eye (101µm). The macular volume in the left eye remains within normal limits (9.6mm3) at the 3-month follow up point.

Figure 4: Six months after the acute ON event, there is peripapillary retinal nerve fiber layer thinning in the left eye (61µm) relative to the right eye (104µm). There is also associated macular volume loss in the left eye (9.3 mm3).

370 | North American Neuro-Ophthalmology Society Case Example: Optic Neuritis to 2 years, as suggested by reported progressive shortening A 30-year old woman presents with a 3-day history of vision of (initially) prolonged visual evoked potential latencies.2 loss in the left eye. She reports no other medical problems. Reorganization of cortical activation has also been reported She states that her vision loss progressed over a 72 hour after optic neuritis.2 Thus, visual recovery after ON can occur period, beginning as a “smudge” in the central visual field through several mechanisms: remyelination, development of of the left eye. She describes pain with eye movements, continuous conduction through sodium channels that develop and notes that colors appear “washed out” in the left eye along the demyelinated segment, and cortical plasticity.1 The relative to the right eye. On examination the visual acuity substrate for permanent vision loss after ON is likely disruption is 20/20 in the right eye and 20/100 in the left eye (Snellen of axonal and neuronal integrity in the afferent visual pathway, equivalent). There is a left relative afferent pupil defect. which can arise from persistent acute inflammation and lack of Visual field testing with Goldmann perimetry shows normal trophic support from myelin. results in the right eye and a cecocentral scotoma in the left eye. Color vision measures 10/10 HRR pseudoisochromatic From a functional stand-point, high and low contrast letter plates in the right eye and 0/10 plates in the left eye. External acuity testing, perimetry, and color vision testing can ocular examination, extraocular movements, and slit lamp reliably quantify the acute and chronic effects of optic nerve assessment are normal. Dilated fundus examination shows inflammation. Acutely, vision loss is at its nadir, resulting a normal right optic nerve, and left optic disc hyperemia in marked functional deficits. Over time, as inflammation (Figure 1). Based on the clinical presentation, the patient is abates, there is gradual recovery in visual function. diagnosed presumptively with left optic neuritis (ON). Tests of Afferent Visual Pathway Function: High-Contrast Letter Acuity:High contrast visual acuity testing is a relatively insensitive means of capturing vision loss in the setting of most optic nerve disorders, including ON. In the Optic Neuritis Treatment Trial (ONTT)3, mean visual acuity 1 year after entry into the ONTT was better than 6/5 (Snellen equivalent), with less than 10% of patients manifested visual acuity worse than 6/12.2,3 A baseline (or 1-month) visual acuity < 20/50; contrast sensitivity < 1.0 log units; and visual field mean deviation < -15 dB have been shown to be good predictors of abnormal vision 6-months after ON.4 Figure 1: Dilated fundscopy shows a normal appearing right optic nerve (on left) and left optic disc edema (on right). Low Contrast Letter Acuity & Contrast Sensitivity: Numerous studies have shown that low contrast letter acuity and contrast sensitivity are sensitive means of Measuring the effects of acute and capturing vision loss, even in patients with (Snellen chronic optic nerve inflammation in vision equivalent) 20/20 vision after ON.5 In 2006, Fisher Optic Neuritis and colleagues5 conducted a cross-sectional study that In ON, the affected optic nerve serves as a “window” to compared RNFL thickness between ON-affected eyes of understand mechanisms of symptom onset and recovery MS patients (MS ON eyes), MS eyes without a history applicable to isolated and recurrent demyelination elsewhere of ON (MS non-ON eyes), and the eyes of disease-free in the central nervous system (CNS).1 There are alternations controls. In addition to optical coherence tomography in myelin integrity and in the oligodendrocyte–axon1 unit in (OCT) measurements, they performed low-contrast letter the acute and chronic phases of ON that underpin symptom acuity, contrast sensitivity (Pelli-Robson charts), and high- onset and recovery. In addition, given the capacity for contrast visual acuity testing. The authors found that RNFL functional adaptation in the CNS, clinical recovery may arise thickness was reduced significantly among MS patients not only as a consequence of structural repair at the site of (92µm) relative to control eyes (105µm, P < 0.001), with the primary lesion, but also from compensatory changes the lowest RNFL values detected in MS ON eyes (85µm, p in the afferent visual pathway at a distal location.1 After < 0.001). Furthermore, lower visual function scores were ON, acute cytokine release induces transient conduction associated with reduced mean peripapillary RNFL values block in the affected portion of the optic nerve.1 With intact in MS eyes: for every 1 line decrease in low-contrast myelination and preserved axons, the recovery occurs with letter acuity or contrast sensitivity score, the mean RNFL removal of inflammatory mediators; and, in turn reversal of thickness decreased by 4µm. In this study, MS patients the visual deficit.1 The initial period of recovery is often rapid, were excluded if Snellen visual acuity equivalents were in response to early resolution of acute inflammation.2 Further worse than 20/200 in both eyes, because this degree of improvement in vision can be seen up to a year after the acute vision loss precluded testing of low-contrast letter acuity.5 ON episode.2 Notably, remyelination may continue for up Hence, there may be a more robust role for low contrast

2013 Annual Meeting Syllabus | 371 letter acuity and contrast sensitivity in detecting subtle symptoms in the left eye, which was commensurate with the manifestations of vision loss in the post-acute phase of ON severity of the central vision loss. Hence, color vision testing rather than the acute phase of optic nerve inflammation, may not be particularly discriminating in patients with severe when vision loss is more severe. vision loss in the context of acute optic nerve inflammation. With time however, color vision deficits may be detectable in Frequency Doubling Perimetry: Conventional automated the post-acute phase of ON, even when high contrast visual perimetry is a reasonable means of capturing functional acuity has returned to “normal.” defects referable to optic nerve inflammation; albeit the utility of this testing modality tends to hampered in the acute Critical Flicker Fusion Frequency (CFF): CCF is defined as the phase for patients with Snellen visual acuity equivalents frequency at which an intermittent light stimulus appears to worse than 20/200. In a recent consecutive case series, 20 be completely steady to the observer. In a practice, patients patients with resolved ON were compared to 20 healthy view a flickering light to test the ability of the optic nerve to controls, with the aim of examining the performance of conduct impulses with uniform speed. This quick and simple full-threshold 30–2 frequency-doubling perimetry (FDP) in test method has proven to be very useful in identifying visual comparison with standard automated perimetry (Swedish loss due to optic nerve damage. In a recent study, CFF was interactive threshold algorithm 30–2 program) in patients measured in response to red and blue stimuli for ON patients with resolved ON.6 Standard automated perimetry and FDP and patients with diabetic retinopathy.10 The results showed showed general depression in the fovea and extrafoveal that CFF was impaired for red stimuli in ON patients, and areas.6 Correlations between SAP and FDP were statistically for blue stimuli in patients with diabetic retinopathy, which significant for mean deviation (Pearson r > 0.75; p < 0.001) distinguished the two groups.10 In a second study, 25 patients and pattern standard deviation (r > 0.6; p<0.005).5 Defects (31 affected eyes) with acute ON were followed serially with detected with FDP were larger than with SAP in 14 eyes CFF.11 The CFF results were 100% abnormal in ON eyes at initial (70 %).6 In follow-up after 2 weeks and again after 2 and onset, and then gradually improved over time.11 However, 5 months, FDP indicated slower improvement in visual even in recovery CFF abnormalities were noted in 37% of ON field defects in the fovea and extrafoveal areas, whereas eyes.10 There were also CFF abnormalities in the fellow eyes of SAP indicated rapid improvement in these defects.6 From patients with unilateral ON.11 Thus, CFF was also shown to be a their findings, the authors concluded that FDP is at least sensitive indicator for detecting visual dysfunction in patients comparable with and potentially more sensitive than SAP in with ON and could be used to track recovery in vision over detecting visual field defects in resolved ON.6 time from the acute to chronic phases of an ON event.

Color Vision: Color vision testing is useful in detecting Tests of Afferent Visual Pathway Structure disorders of the optic nerve, as often the color vision deficit Recent innovations in para-clinical testing techniques allow is disproportionately impaired relative to the visual acuity, us to capture structural manifestations of demyelination, particularly in mild ON. For example, many patients with ON remyelination, axonal damage, and neuronal degeneration who have vision deficits in the Snellen visual acuity range of in ON patients. 20/20–20/50 can score poorly on Ishihara plate testing, which is sensitive to picking up red-green color loss. Alternatively, Optical Coherence Tomography: Since the invention of the Hardy-Rand-Rittler (HRR) pseudo-isochromatic plates may ophthalmoscope in 1851, the structural consequences of be used, which have an advantage over the Ishihara method, optic nerve in­jury have been visualized acutely as optic disc because they are more sensitive to neuro-ophthalmic causes edema, followed by optic disc pallor and corresponding of vision loss, and they detect red-green and blue- yellow defects in the retinal nerve fiber layer (RNFL), which lacks deficits.7 In a recent cross sectional study, Villoslada and myelin.12 In 1974, Frisén and Hoyt interpreted RNFL defects colleagues8 studied the association between high-contrast as axonal attrition in MS patients.13 The advent of OCT visual acuity, low contrast visual acuity, color vision [HRR plates has allowed us to quantify changes in RNFL thickness in and Lanthony D15 (LD15) tests]; and, both high-resolution the immediate on convalescent phases of ON. In prior spectral-domain OCT (SD-OCT) and time domain OCT generations of OCT, high-resolution cross-sectional images (TD-OCT) testing in a cohort of 213 MS patients (52 with of the retina were generated by an optical beam being previous ON) and 47 matched controls. They noted that MS scanned across the retina, using the principles of low patients had impairments in high and low contrast visual acuity coherence interferometry, which allowed the magnitude and (p < 0.001), and that they also suffered from even more echo time delay of backscattered light to be measured with profound abnormalities in color discrimination (p < 0.0001).8 high temporal accuracy.14–22 With the recent development There was a strong correlation between color vision and SD- of “Fourier” or “Spectral” domain OCT light echoes are OCT measures of RNFL thickness and papillomacular bundle detected in simultaneous fashion, increasing the sensitivity thickness. Farnsworth D15 and Farnsworth—Munsell 100 hue that enabling high-speed imaging with this technique.14 Since testing are highly sensitive tests of color vision loss in the post- SD-OCT technology became commercially available in 2006, acute phase of ON9 but generally require more time than is it has been possible achieve an axial image resolution of practical in a typical clinic setting. In the case example provided, 5–7μm with imaging speeds of 25,000 axial scans per second, the patient had a marked deficit in color vision at the onset of which is approximately 50-fold faster than the previous

372 | North American Neuro-Ophthalmology Society generations of OCT.15 Studies have shown at the time of varied significantly among the patients, it was, on average, an acute inflammatory ON event, when the functional very high, indicating considerable reduction of amplitude deficit in vision is most dire, patients often manifest RNFL in the affected eye. The inter-eye asymmetry in mfVEP measurements that are either comparable to or increased in amplitude decreased over time indicating ongoing functional their ON-affected eye relative to their fellow eye15 as in the recovery.28 There was negative correlation between the case example provided (Figure 2). Correspondingly, the optic inter-eye asymmetry of RNFL thickness and that of mfVEP nerve in the ON eye may be mildly edematous or hyperemic amplitude at 1 month, consistent with vasogenic edema in secondary to axoplasmic flow stasis (Figure 1). In the the acute phase, causing an increase in RNFL thickness, with ensuing 2 to 3 months, optic disc pallor and RNFL thinning a corresponding reduction in mfVEP amplitude. 28 During evolve, with earliest signs of significant RNFL atrophy mani­ recovery, the correlation became progressively more robust, festing in the temporal RNFL region.23 In the case described, suggesting the diminishing role of optic nerve edema in the patient presented with optic disc edema and RNFL measured RNFL thickness and unmasking the association thickening in the ON eye (Figures 1, 2) at the time of initial between RNFL atrophy and low mfVEP amplitudes.28 The OCT testing; yet, with time optic atrophy, RNFL thinning, and potential correlation between OCT-measured RNFL values macular volume loss evolved in the ON eye (Figures 3, 4). and mfVEP measures of anterior visual pathway damage was Recent OCT studies23–25 have shown that RNFL thinning and demonstrated by the same group, who evaluated 32 patients macular volume loss progress in ON eyes for up to 6-months, with unilateral ON and 25 control subjects with mfVEP plateauing thereafter. testing and OCT.26 The mean RNFL thickness in ON eyes (85μm) was reduced by 19.2% compared with control eyes Visual Evoked Potentials: The visual evoked potential (VEP) (104μm) (P < 0.0001).26 There was a 39.8% reduction in the is a response of the brain to repeated visual stimulation amplitude of the mfVEP in ON eyes relative to control eyes (p and is recorded when visual field is stimulated with a < .0001).26 Linear regression analysis demonstrated a strong single checkerboard pattern [full-field VEP (FF-VEP)]. The correlation between inter-eye asymmetry values of RNFL VEP is an objective means for measuring function of the thickness and mfVEP amplitude (r = 0.90, P < .0001).26 Lower visual pathway and is known to be generated at the level RNFL values were also associated with increased mfVEP of striate cortex by the combined activity of post-synaptic latency (r = −0.66, P < .002).26 In addition to demonstrating potentials.26–30 The magnitude of the VEP reflects the the utility of mfVEP in tracking optic nerve injury in ON number of functional afferent fibers reaching the striate patients, this study further confirmed the significant cortex and the degree of synaptic activity in V1.26–30 In correlations between structural and functional measures patients with ON, the number of functional afferent fibers is of optic nerve integrity and showed that demyelination determined by a combination of two factors: the severity of contributes to axonal loss in the anterior visual pathway.26 the inflammation and axonal degeneration along the visual Hence, to capture the acute and chronic effects of pathway. Therefore, diminished VEP amplitude indicates inflammation in ON, one could pair mfVEP and OCT testing inflammatory conduction block, axonal atrophy, or a to capture the synergistic effects of acute demyelination and combination of both. The increase in amplitude, on the other axonal loss over time. hand, is a consequence of resumed conduction in previously blocked fibers due to resolution of inflammation and edema; Magnetic Resonance Imaging Texture Analysis: Image texture or possibly, to expansion of synaptic activity along the refers to a local characteristic pattern of image intensities visual pathway up to the level of V1. Delayed conduction and can be quantified using texture analysis methods with of VEP is recognized as one of the earliest features of acute conventional magnetic resonance imaging (MRI) techniques. ON; with the subsequent shortening of latency thought Texture is fine in regularized tissue, such as normal white to represent the process of remyelination.26–30 The clinical matter; and coarse in damaged structure in MS lesions. T2 MRI usefulness of the FF-VEP is limited by the fact that it provides texture has been shown to be a sensitive measure of tissue a summed response of all neuronal elements stimulated injury and repair in MS associated with an acute inflammatory and is greatly dominated by the macular region due to demyelinating event;31 and texture property at baseline its cortical overrepresentation.26 Being the vector sum correlates with the degree of disability progression over two of numerous differently oriented dipoles, the waveform years in MS patients.32 In a recent study,33 ON patients and of the full-field VEP is prone to unpredictable change 8 healthy control subjects underwent MRI. Within 14 days depending on the part of the nerve or visual field affected of symptom onset, optic nerve lesion texture was coarser leading sometimes to detection of apparent rather than in the affected relative to non-affected eyes, and control real latency delay and waveform distortion.26 A recent eyes. Over time, the lesion texture became less coarse in advance in VEP technology in the form of multifocal VEP ON eyes. 33 Lesion texture of the optic nerve was the only (mfVEP) eliminates limitations of full-field stimulation by variable that predicted the extent of visual recovery in the providing simultaneous, but independent stimulation of affected eyes. The findings from this study suggest that acute plurality of visual field locations.27 In a study by Klistorner tissue injury as measured by image texture analysis helps and colleagues28 mfVEP was used to study 25 subjects with predict functional recovery after optic neuritis. In the case acute unilateral ON with serial mfVEP and OCT testing example provided, T2 texture could be followed over time to over time. While mfVEP amplitude asymmetry at baseline determine to what extent the texture signal normalized, and

2013 Annual Meeting Syllabus | 373 how this corresponded with visual recovery in the left eye. Of visual acuity and contrast sensitivity after ON, suggesting further interest, the T2 texture could be compared to mfVEP that these visual functions depend on a sufficient amount amplitude and latency to determine whether this is a tenable of visual information reaching the cortex.35 Yet, motion MRI surrogate measure of demyelination and remyelination in perception was impaired even in patients with intact VEP the anterior visual pathway. amplitudes, suggesting that an intact amount of visual projection alone does not impact dynamic visual function.35 Question: How can we differentiate While the magnitude of contrast sensitivity improvement differences in form versus function related to the extent of VEP amplitude restoration, the perception after acute ON? magnitude of OFM improvement depended on the extent Motion Perception Testing: Recent studies with functional of VEP latency reduction post-ON.35 The authors concluded MRI (fMRI) have shown that cortical reorganization may that conduction velocity in the visual pathways correlated play an adaptive role in visual recovery after ON, along closely with dynamic visual function, suggesting that there with remyelination in the injured optic nerve. In a study is a need for rapid transmission of visual input to perceive that aimed to assess motion perception and the associated motion.35 Thus, motion perception testing may serve as a cortical response after ON, 21 patients with were evaluated tool to assess the magnitude of myelination in the visual over a 1 year period with repeat visual acuity, color pathways. Moreover, implementing motion perception perception, visual field, contrast sensitivity, dynamic visual testing in our standard testing procedures may allow us to function (motion perception), fMRI and VEP testing.34 better capture the acute and chronic consequences of optic During motion perception testing patients were presented nerve inflammation in a manner that is clinically relevant to with moving dot arrays and stationary dots and asked subjective experience of patients post-acute ON. whether they detected a movement in each stimulus. In an object from motion (OFM) extraction, subjects viewed Question: How can we capture changes motion defined objects and were asked to identify and in retinal architecture that might could name the object. In ON eyes visual acuity, visual field, insights about disease mechanisms in ON and colour vision deficits were at their worse in the acute and MS patients? phase, and subsequently improved after 1-month.34 Most ON patients recover vision over a period of weeks to Contrast sensitivity deficits persisted longer, and improved months, during which time optic disc pallor may evolve as 4-months after symptom onset.34 In contrast to routine a “footprint” of the inflammatory injury, indicating axonal visual tests, motion perception was impaired during the loss. Traditionally, changes in RNFL have been attributed to full follow up period of 1 year. 34 Furthermore, fMRI studies retrograde axonal degeneration. There is an evolving body showed that the behavioral deficit in motion perception of literature, however, which suggests that there may be was associated with reduced cortical activation during primary and secondary changes in the RNFL “and beyond” motion processing.34 Thus while, previous longitudinal in MS patients, which could impact our understanding of studies suggested that measures of low-contrast vision pathogenic mechanisms in this disease. testing is a sensitive marker of visual dysfunction in MS patients, this study demonstrated that motion perception Optical Coherence Tomography: Retinal Nerve Fiber Layer testing revealed the most significant and prolonged Thinning: Two to 3 months after an acute ON event, optic impairment after ON.34 Moreover, the motion perception disc pallor and RNFL thinning evolve, with earliest signs of problems were independent of contrast sensitivity levels. 34 significant RNFL atrophy mani­festing in the temporal RNFL region.23, 24 TD-OCT studies have shown that RNFL values In a follow up study, the same group35 aimed to identify continue to decrease for 6 months after symptom onset, mechanisms underpinning the sustained deficit in dynamic plateauing thereafter.23, 24 Lower RNFL values correlate with visual functions following ON. They hypothesized that reduced visual acuity, visual field mean sensitivity, and color dynamic visual processes, such as motion perception, may vision testing scores after ON.9, 23–28, 37–40 There are also strong be more vulnerable to slowed conduction in the optic correlations between the ex­tent of RNFL thinning after ON, nerve, which could be measured with VEP testing. To delayed mfVEP laten­cies, and reduced mfVEP amplitudes, explore this hypothesis they did serial motion perception implicating a direct relationship between the severity of and FF-VEP testing at presentation, 1-month, 4-months, acute inflammatory demyelination and consequent axonal and 12-months after ON.35 The FF-VEP amplitudes in ON loss.26 In a recent meta-analysis of TD-OCT studies (2,063 eyes were significantly reduced compared to fellow eyes in eyes) comparing eyes with MS and ON to the eyes of the acute phase but these differences disappeared in later healthy controls showed an estimated average RNFL loss phases of recovery.35 In contrast to static visual tests, ON of 20.4µm in ON eyes.41 There was an estimated RNFL loss eyes demonstrated a sustained deficit in motion perception, of 7.1μm in non-ON eyes of MS patients relative to control as evident in the OFM extraction task 12 months after eyes.40 Primary Retinal Damage: Recent work by Green ON.35 Visual performance 1 month after ON was highly and colleagues42 provided the first large-scale pathological predictive of visual recovery, as determined from testing description of retinal involvement in MS patients (n=82), visual acuity, contrast sensitivity and OFM function.35 including patients with different subtypes, ages, and stages Intact VEP amplitudes were associated with recovered of disease severity. In this study, changes were seen not

374 | North American Neuro-Ophthalmology Society only in the RNFL and retinal ganglion cell layer, but also CME Answers in the inner nuclear layer, suggesting that retinal injury 1. Any combination of high and low contrast letter acuity; is more widespread than previously appreciated in MS.42 contrast sensitivity, color vision testing (with Ishihara From these findings the authors postulated that exploring plates, HRR pseudoisochromatic plates, LD15 color the relationships between the different types of retinal desaturation tests), perimetry, CFF, T2 Texture analysis pathology may aid us in understanding the factors that drive with MRI, OCT measured RNFL thickness/macular both inflammation and tissue atrophy in MS.42 Subsequent volume, mfVEP amplitude and latency. SD-OCT studies have explored the hypothesis that retinal damage may be a primary mechanism of injury in MS. 2. Motion perception testing. Saidha and colleagues43 identified 50 MS patients with what they termed as the predominantly macular thinning 3. Spectral domain OCT measures of RNFL thickness; phenotype (defined as having normal RNFL thickness with retinal segmentation techniques showing thinning of average macular thickness < 5th percentile).43 By utilizing a the inner and outer nuclear layers of the retina; and in novel retinal segmentation protocol, we they noted that MS the case of ON, secondary ganglion cell layer thinning. patients with the predominant macular thinning phenotype of MS had significant thinning of both the inner and outer nuclear layers, with relative sparing of the retinal ganglion References cell layer; whereas inner and outer nuclear layer thicknesses 1. Miller D, Barkhof F, Montalban X, et al. Clinically isolated syndromes in patients with typical MS were not different from healthy suggestive of multiple sclerosis, part 2: non-conventional MRI, recovery processes, and management. Lancet Neurol; 4: 341–48, 2005. controls. These findings supported the possibility of primary retinal pathology in a subset of patients with MS.43 In related 2. Hickman SJ, Dalton CM, Miller DH, Plant GT. Management of acute optic neuritis. Lancet; 360:1953–1962, 2002. work the same group reported SD-OCT—measured thinning in the ganglion cell layer of eyes affected by acute ON, 3 and 3. Beck RW, Cleary PA, Anderson MM, et al. A randomized, controlled 44 trial of corticosteroids in the treatment of acute optic neuritis. N Engl 6 months after onset (P < 0.001). No pathology was seen J Med; 326:581–588, 1992. in the inner or outer nuclear layers of ON eyes, suggesting 4. Kupersmith MJ, Gal RL, Beck RW; Optic Neuritis Study Group. Visual that retrograde degeneration after ON may not extend function at baseline and 1 month in acute optic neuritis: predictors of into the deeper retinal layers.44 Baseline ganglion cell layer visual outcome. Neurology; 69(6):508–14, 2007. thickness did not demonstrate swelling when compared 5. Fisher JB, Jacobs DA, Markowitz CE, et al. Relation of visual with contralateral unaffected eyes, whereas peripapillary function to retinal nerve fiber layer thickness in multiple sclerosis. RNFL edema was observed in ON eyes (P = 0.008) and Ophthalmology; 113: 324–332, 2006. decreased over the course of this study.44 Of all patient 6. Sakai T, Matsushima M, Shikishima K, Kitahara K. Comparison of groups investigated, those with neuromyelitis optica and a standard automated perimetry with matrix frequency-doubling technology in patients with resolved optic neuritis. Ophthalmology; history of ON exhibited the greatest reduction in ganglion 114(5):949–56, 2007. cell layer thickness.44 From their findings the authors 7. Aroichane M, Pieramici DJ, Miller NR, Vitale S. A comparative study of Hardy- concluded that axonal injury may cause neuronal pathology Rand-Rittler and Ishihara colour plates for the diagnosis of nonglaucomatous 44 45 in MS patients. Finally, Green and colleagues detected optic neuropathy. Can J Ophthalmol; 31 (7):350–5, 1996. microcystic macular edema with SD-OCT in 15 of 318 (4.7%) 8. Villoslada P, Cuneo A, Gelfand J, Hauser SL, Green A. Color vision is MS patients who harboured no other established reason strongly associated with retinal thinning in multiple sclerosis. Mult (drugs, co-morbidities) for this finding. The microcystic Scler;18(7):991–9, 2012. edema predominantly involved the inner nuclear layer of 9. Trip SA, Schlottmann PG, Jones SJ, et al. Retinal nerve fiber layer the retina and tended to occur in discrete patches.45 They axonal loss and visual dysfunction in optic neuritis. Ann Neurol; 58: postulated that the presence of microcystic macular edema 383–391, 2005. in MS suggests that there may be breakdown of the blood- 10. Gregori B, Papazachariadis O, Farruggia A, Accornero N. A differential retinal barrier and tight junction integrity in a part of the color flicker test for detecting acquired color vision impairment in 45 multiple sclerosis and diabetic retinopathy. J Neurol Sci; 300(1– nervous system that lacks myelin. 2):130–4, 2011. 11. Woung LC, Wakakura M, Ishikawa S. Critical flicker frequency in acute Summary: and recovered optic neuritis. Jpn J Ophthalmol;37(2): 122–9, 1993. With advances in ocular imaging, evoked potential testing, 12. Costello F, Klistorner A, Kardon R. Optical Coherence Tomography motion perception techniques, we may be able to improve in the Diagnosis and Management of Optic Neuritis and Multiple upon our approach to the localization and diagnosis Sclerosis. Ophthalmic Surg Lasers Imaging;48: S28-S40, 2011. of many neuro-ophthalmic problems. Yet, it should be 13. Frisén L and Hoyt WF. Insidious atrophy of retinal nerve fibers reiterated that the role of these tools is to complement; not in multiple sclerosis. Funduscopic identification in patients with supplant the clinical examination. andwithout visual complaints. Arch Ophthalmol;92:91–97, 1974. 14. Galetta KM, Calabresi PA, frohman EM, Balcer LJ. Optical Coherence Tomography (OCT): Imaging the Visual Pathway as a Model for Neurodegeneration. Neurotherapeutics;8(1):117–32, 2011.

2013 Annual Meeting Syllabus | 375 15. Frohman EM, Fujimoto JG, Frohman TC, et al. Optical coherence 31. Zhang Y, Zhu H, Mitchell JR, Costello F, Metz LM. T2 MRI texture tomography: a window into the mechanisms of multiple sclerosis. analysis is a sensitive measure of tissue injury and recovery resulting Nat Clin Pract Neurol;4:664–675, 2008. from acute inflammatory lesions in multiple sclerosis. Neuroimage 1;47(1):107–11, 2009. 16. Huang D, Swanson EZ, Lin CP, et al. Optical coherence tomography. Science;254:1178–1181, 1991. 32. Loizou et al. , 2010 Loizou CP, Murray V, Pattichis MS, Seimenis I, Pantziaris M, Pattichis CS. Multiscale amplitude-modulation frequency- 17. Jindahra P, Hedges TR, Mendoza-Santiesteban CE, Plant GT. Optical modulation (AM-FM) texture analysis of multiple sclerosis in brain MRI coherence tomography of the retina: applications in neurology. Curr images. IEEE Trans Inf Technol Biomed;15(1):119–29, 2011. Opin Neurol;23:16–23, 2010. 33. Zhang Y, Costello F, Scott J, Metz L. Correlating MRI Texture Measures 18. Lameril C, Newman N, Biousse V. The use of optical coherence of Tissue Integrity with Structural and Functional Assessments of tomography in neurology. Rev Neurol Dis;6:E105–120, 2009. Vision in Optic Neuritis. Presented in the Tour of Posters, NANOS 19. Sakata LM, DeLeon-Ortega J, Sakata V, Girkin CA. Optical coherence Annual Meeting, Vancouver, British Columbia, February 2011. tomography of the retina and optic nerve—a review. Clin Exp 34. Raz N, Dotan S, Benoliel T, et al. Sustained motion perception Ophthalmol;37:90–99, 2009. deficit following optic neuritis. Behavioral and cortical evidence. 20. Glisson CC, Galetta SL. Nonconventional optic nerve imaging in Neurology;76:2103–2111, 2011. multiple sclerosis. Neuroimag Clin N Am; 19:71–79, 2009. 35. Raz N, Dotan S, Chokron S, Ben-Hur T, Levin N. Demyelination 21. Kallenbach K, Simonsen H, Sander B, et al. 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376 | North American Neuro-Ophthalmology Society How to Capture Disease Activity in the Longitudinal Follow-Up of Optic Neuropathies?

Eric R. Eggenberger, DO Michigan State University East Lansing, MI Presented by Julie Falardeau, MD

Learning Objectives Keywords 1. To understand clinical tools for documenting optic 1. Optic Nerve nerve function 2. Optical Coherence Tomography (OCT) 2. To establish that no one test is perfect for all individual patients with optic nerve dysfunction 3. Visual Evoked Potential (VEP) 3. To review the advantages and disadvantages of each 4. Visual Acuity optic nerve assessment technique 5. Perimetry

CME Questions Introduction Optic neuropathy is a common neuro-ophthalmic diagnosis. 1. Which of the following is an objective assessment of Although it is often easy enough to recognize and anatomically optic nerve function? localize in its typical forms, it is more challenging to precisely a. Visual acuity follow for any significant change over time. Many of the b. Color vision tools we use to evaluate and follow optic nerve function are c. Visual fields with onfrontationc psychophysical such as acuity and perimetry, and accordingly d. Pupil assessment suffer from subjectivity and variability-related errors. The pupil e. isual field with Humphrey perimetry is useful in optic nerve assessment, and although objectively judged by the physician, it is infrequently quantified, and 2. Which of the following is a true advantage of visual thus less suitable as a long-term follow up marker. Imaging evoked potential (VEP) testing? and electrophysiology provide objective metrics for optic a. It is easily reproduced in any office setting nerve anatomy and physiology, but may be cumbersome, b. It provides an objective assessment of optic nerve expensive, or demonstrate unfavorable sensitivity, specificity function without regard to patient cooperation and variability across clinics and visits. There is no ‘perfect’ or c. It provides a real time assessment of optic nerve gold standard clinical measure of optic nerve function, and the physiology clinician must rely upon different combinations of these tools d. It can capture not only central but also peripheral in individual patients to reliably detect meaning visual change. visual function information 3. What is a true disadvantage of optical coherence Case: A 40-year old woman with a known non-secreting tomography (OCT)? pituitary macroadoma (with radiological evidence of chiasm compression) presents for repeat neuro-ophthalmic a. It has the ability to provide objective anatomic assessment. She has previously demonstrated no significant information impairment in high contrast visual acuity, color vision, or visual b. The time delay required for OCT to reflect an optic field function. Best-corrected Snellen visual acuity is 20/20 nerve insult’s effect on anatomy in both eyes. Pupils measure 5mm in darkness and constrict c. The easy correlation between the overall RNFL and to 3mm in bright light, with no relative afferent pupil defect. meaningful optic nerve function Color vision measures 10/10 HRR pseudo-isochromatic plates d. It is a low cost technology in both eyes. Ocular motility is normal. Fundus examination shows normal appearing optic nerves). Repeat automated perimetry shows some worsening of her visual field suggesting possible enlargement of the pituitary lesion.

Question: What tests can be used to capture disease progression in this patient?

2013 Annual Meeting Syllabus | 377 Psychophysical Tests to most optic nerve disease, it remains subjective. The utility High Contrast Visual Acuity: Visual acuity is defined as the of low contrast letter acuity and contrast sensitivity testing “spatial resolving capacity” of the eye,1 and represents has been exemplified in following optic neuritis and MS the most commonly used tool to assess visual function patients. Three contrast levels have been used in MS trials including that related to optic neuropathies. There are and research studies, including 100% (high-contrast, used to numerous charts used for visual acuity testing, but the measure visual acuity as a descriptor of the study cohorts), most commonly employed are the Snellen and Early 2.5%, and 1.25% (lightest contrast level). Visual improvement Treatment Diabetic Retinopathy Study (ETDRS) charts. as determined by the low-contrast acuity chart has been Of the two, the Snellen chart is the current standard for defined as a 7-letter change in score; and a 5-letter change measurement of visual acuity in clinical practice. The chart in high-contrast visual acuity is now considered clinically has letters of different sizes arranged from largest at the significant.2 This threshold represents a change that exceeds top to smallest at the bottom, which are read, one eye at a that which would be expected from repeated testing when time, at a distance of 6 meters or 20 feet. Snellen acuities there was no real change in visual acuity, and correlates are usually expressed as a fraction with the numerator with retinal nerve fiber layer (RNFL) loss in patients with equal to the distance from the chart and the denominator MS. Furthermore, these 5- and 7-letter mean changes have being the size of the smallest line that can be read.1 High been shown to correlate significantly with vision-specific and contrast letter acuity has many advantages including rapid overall quality of life measures in MS patients.2 administration, and ease of understanding and translation to lay public. Ideally, this psychophysical test should give a Visual Field: Perimetry has evolved through stages precise, reproducible result that is impervious to external since original confrontation-based techniques to allow factors; but, in reality several disadvantages exist including quantification and statistical analysis in its currently used variability between offices (and even between exam rooms computerized forms. This provides critical information about in the same office), function pertaining to central vision visual function including both central and peripheral channels, only, subjectivity of testing which can be easily manipulated and many of the perimeters in common use today are readily by the patient, reliance on black-on-white high-contrast available in most cities around the developed world allowing letters with diminished generalizability to real life visual for easier comparisons across offices over time. Despite acuity function. Snellen charts, in particular are hindered these advantages, perimetry remains a subjective technique by variable letter size, with varying numbers of letters per and significant variability exists even in very reliable subjects line: The poor vision lines (20/200 and 20/400) usually with optic nerve dysfunction. In a prospective case control contain only 1 or 2 letters, while the good acuity lines study, 17 patients with ON and 10 healthy control subjects contain up to 8 letters.1 Furthermore, when testing Snellen underwent intraday and interday repeat perimetry testing acuity, the tester uses a ‘line assignment” method. This (five Humphrey 30-2 tests were administered during a 7-hour means that not being able to read 1 letter on the good period on the same day and at the same period on 5 separate acuity lines has less effect than missing 1 letter on the days).3 Patients with ON demonstrated variations in visual field poor vision lines.1 Thus, a loss or gain in a line of vision sensitivity that were outside the entire range of variability with Snellen testing does not have the same meaning in for normal controls.3 These variations occurred for multiple different parts of the chart. Another disadvantages of high tests performed on the same day, at specific times; and for contrast Snellen visual acuity testing include the fact that tests performed at specific times on different days.3 Thus, the letters on a chart are not always the same legibility. when using automated perimetry to follow ON patients with Some letters (e.g., C, D, E, G, O) are easier to read than visual field defects, distinguishing true systematic changes in others (e.g., A, J, L);1 and the distance between letters and sensitivity from variability should be undertaken with caution; rows is not standardized.1 Finally, the term “Snellen chart” and requires more than comparing a current visual field test has never been standardized, and consequently, Snellen with the most recent previous visual field test.3 charts from different manufacturers may use different fonts, different letters, and different spacing ratios, and Pupil Response: Pupil response driven perimetry has the they may be illuminated or projected differently.1 Because potential to capture widespread information concerning if the deficiencies of Snellen visual acuity testing, (ETDRS) optic nerve function based on objective pupil reactivity, but charts have become the “gold standard” for most current this is not widely available or standardized, and the variable clinical trials. In neuro-ophthalmic practice high contrast effect on pupil-related retinal function based on specific letter acuity as determined by Snellen or ETDRS method pathology remains to be elucidated. The relative afferent is a relatively crude metric of optic nerve dysfunction, as pupil defect (RAPD) is the quickest objective bedside test for patients can have profound deficits of visual field and color the documentation of asymmetric optic neuropathy. The vision function and maintain 20/20 vision. test is objective, but not often quantified, which renders it less useful in serial assessment of optic neuropathies. Low Contrast Letter Acuity/Contrast Sensitivity:Low-contrast In addition, optic nerve dysfunction in the fellow eye can acuity appears to mimic real life visual function with rarity of diminish or eliminate an RAPD, however in this scenario, a high contrast objects of regard. Although it is more sensitive decreasing or resolving RAPD indicates clinical worsening.

378 | North American Neuro-Ophthalmology Society Ocular Imaging OCT were performed before and after treatment. In eyes Optical Coherence Tomography: Optical coherence with a visual field defect before treatment, the odds of tomography (OCT) offers an objective, non—invasive, complete recovery after three months was multiplied by and highly sensitive means of quantifying axon loss 1.29 for each 1-micron increase in mean RNFL thickness in the anterior visual pathway due to any optic nerve (odds ratio [OR], 1.29; P = 0.037).5 These data suggest injury, irrespective of the mechanism involved. Recent that OCT—measured RNFL values may be used to predict studies have shown that retinal nerve fiber layer (RNFL) the potential for visual recovery for compressive injuries of values often increase during the acute phase of an optic the anterior visual axis, such that preserved RNFL integrity nerve injury, particularly when there is visible optic increases the likelihood that visual function will improve disc edema, as in the case of anterior ischemic optic after the intervention.5 neuropathy (AION). Furthermore, OCT testing reveals that mild increases in RNFL thickness frequently occur In patients with papilledema caused by idiopathic intracranial in the context of presumed retrobulbar optic nerve hypertension (IIH), it would be expected that RNFL values injuries, which not may be apparent with standard would be elevated at the time of presentation when optic ophthalmoscopy techniques. With time, often 3–6 disc edema is maximal; and, in turn, decline with resolution months after the acute optic nerve insult, optic nerve of optic disc swelling over time. Accordingly, in a prospective atrophy and RNFL thinning ensue. Thus OCT is a sensitive study, Rebolleda and colleagues6 studied peripapillary RNFL means of detecting occult optic nerve insults, which may thickness with in patients with mild papilledema associated escape clinical detection. Therefore, OCT may represent with idiopathic intracranial hypertension (IIH). Patients a marker for axon loss in the anterior visual pathway underwent OCT testing at diagnosis; and 3, 6, and 12 months caused by: optic neuritis, neuromyelitis optica, traumatic after presentation.6 At the time of diagnosis, RNFL thickness optic neuropathy, compressive lesions, ischemic was 183.3 +/- 74µm and 74.9% (78.5µm) greater than in optic neuropathy, toxic damage to the optic nerve, control eyes. Mean RNFL thickness values in all quadrants papilledema due to raised intracranial pressure, optic were significantly greater in eyes with papilledema.6 The disc drusen, and inherited disorders of the optic nerve. RNFL thickness decreased significantly, as visual field function improved at each follow-up visit.6 Regression analysis showed Previous studies have evaluated the role of OCT in that for every 10µm of mean RNFL thickness increase at characterizing RNFL changes due to anterior visual axis baseline, there was a 0.6-dB decrease in visual field function compression. The predictive value of baseline RNFL at the last follow-up visit.6 Therefore, peripapillary RNFL thickness for visual recovery post—surgical intervention thickness quantitatively correlated with visual field sensitivity has been studied in patients with known parachiasmal losses in IIH. From their findings, the authors suggest this lesions. Danesh Meyer and colleagues,4 studied 40 patients data support the application of OCT as a noninvasive method undergoing surgical resection for parachiasmal lesions to monitor patients with papilledema. prospectively, and performed OCT testing before and after surgery. Patients with normal preoperative RNFL Optical coherence tomography has also been used to track had significant improvement in visual acuity scores after RNFL changes from in the acute and chronic phases of surgery [from 20/40 to 20/25 (P = 0.028)], whereas patients non-arteritic ischemic optic neuropathy (NAION). Contreras with RNFL atrophy did not improve [(20/80 to 20/60, P = and colleagues7 used OCT to study 27 patients with 0.177]. 4 Similarly, patients with preserved pre-operative NAION at baseline, 6-weeks; and 3, 6, and 12 months after RNFL values showed greater improvement in visual field presentation. The initial mean RNFL thickness (200.9µm) function after surgery than did patients with evidence was increased by 96.4% increase relative to the fellow of RNFL atrophy (-15.3 dB before and -13.3 dB after eye.7 Percentages of RNFL loss 3, 6, and 12 months after surgery, p = 0.191). 4 These authors noted that eyes with onset were 38.9%, 42.3%, and 43.9%, respectively.7 Using severe visual field defects but normal preoperative RNFL regression analysis, it was found that for every 1-µm of thickness showed significant improvement after surgery. mean RNFL thickness lost there was a 2-dB decrease in 4 The results of this study suggest that patients with visual field function.7 Furthermore, there was a 1-line drop objective measurable RNFL loss at the time of surgery for in Snellen visual acuity for every 1.6µm deficit. 7 chiasmal compressive lesions are less likely to have return of visual acuity or visual field function after surgery. The Retinal nerve fiber layer atrophy has been demonstrated findings of Danesh—Meyer et al4 were supported by the in patients affected by Leber’s hereditary optic neuropathy results of a second study, which evaluated 19 consecutive (LHON), and in carriers for this disorder. Savini et al8 used patients with pituitary adenomas to determine whether OCT to study RNFL thickness in unaffected carriers with OCT may offer a reliable prediction of visual outcome after LHON mutations. Sixty-six unaffected carriers (44 females medical or surgical decompression for anterior visual axis and 22 males) were analyzed and compared with an age- compression.5 Jacob and colleagues5 studied 17 patients matched control group of 70 patients (40 females and 30 who underwent trans-sphenoidal surgery and 2 patients males).8 As compared to the control group, unaffected male treated with dopamine agonists. Visual field testing and carriers showed thicker RNFL measurements in the temporal and inferior RNFL quadrants and in the 360 degrees average

2013 Annual Meeting Syllabus | 379 measurements.8 These differences reached statistical Case Conclusion: to be presented. significance in subjects carrying the 11778 mutation, whereas only a trend was detected in those with the 3460 Summary mutation.8 Unaffected female carriers had an increased Optic nerve anatomy and physiology often change in thickness in the temporal quadrant when compared with predictable ways with disease, and no single modality the control group (P = 0.003).8 The increase in temporal embodies the ideal tool or captures all the useful clinical sectors was statistically significant in females with the 11778 information for all patients over time. All the currently mutation, whereas a trend was detected in those with the available modalities have advantages and disadvantages 3460 mutation.8 A thickening of the temporal fibers was defining their role, and the adept neuro-ophthalmologist detected in all subgroups of unaffected carriers.8 needs to be facile with the use of all these techniques in order to properly capture clinical follow up information and Quantitative retinal imaging techniques have vastly improved the make informed management decisions. ability to quantify optic nerve anatomy, which has a complicated relationship with optic nerve physiology and function. Perhaps the major immediate advance these techniques offer is the CME Answers replacement of the ‘old style’ optic nerve descriptors such 1. Pupil assessment as ‘mild temporal pallor’ (a descriptive system that lacks precision, inter-rater reliability, accuracy or serial usefulness) 2. It provides a real time assessment of optic nerve with micron-level quantification of optic nerve and retinal physiology anatomy. This precise quantification offers advantages over qualitative photographic documentation. This quantified 3. The time delay required for OCT to reflect an optic assessment of the optic nerve is necessarily detailed in order nerve insult’s effect on anatomy to capture the most useful information; overall assessment of the RNFL is rarely as useful as quadrant or sector data. However, this makes these retinal imaging techniques more References difficulty to quickly understand and use in assessing change. 1. Kaiser PK. Prospective Evaluation of Visual Acuity Assessment. A In addition, even at the sector level, the relationship between Comparison of Snellen versus ETDRS Charts in Clinical Practice. Trans structure and function remains complex, and the RNFL drop Am Ophthalmol Soc; 107:311-24, 2009. out following optic nerve insults plays out over months. 2. Wall MW, Johnson CA, Kutzko KE, Nguyen R, Brito C, Keltner JL. Long and Accordingly, the use of retinal imaging as study outcome has short term variability of automated perimetry results in patients with optic advantages, but is dependent upon the time of testing. neuritis and healthy subjects. Arch Ophthalmol; 116: 53-61, 1998. 3. Sakai RE, Feller DJ, Galetta KM, et al. Vision in Multiple Sclerosis: Magnetic Resonance Imaging and Computed Tomography The Story, Structure-Functional Correlations, and Models for Neuroprotection. J Neuro - Ophthalmol; 31: 362—73, 2011. Although MRI of the orbits has the ability and emerging 4. Danesh-Meyer HV, Papchenko T, Savino PJ, Law A, et al. In vivo retinal nerve fiber layer thickness measured by optical coherence resolution to quantify optic nerve anatomy, practical tomography predicts visual recovery after surgery for parachiasmal considerations including cost and time prevent this from tumors. : Invest Ophthalmol Vis Sci;49 (5):1879-85, 2008. becoming a mainstream serial clinical tool. CT has similar 5. Jacob M, Raverot G, Jouanneau E, Borson-Chazot F, et al. Predicting limitations in addition to radiation risks. Given these visual outcome after treatment of pituitary adenomas with optical disadvantages, it is extremely unlikely that these techniques coherence tomography. Am J Ophthalmol;147(1):64-70, 2009. will gain wide spread usage. 6. Rebolleda G, Munoz-Negrete FJ. Follow-up of Mild Papilledema in Idiopathic Intracranial Hypertension with Optical Coherence Tomography. Electrophysiology Invest Ophthalmol Vis Sci; Nov 14 [Epub ahead of print] 2008. Visual Evoked Potential (VEP): VEP can provide useful 7. Contreras I, Noval S, Rebolleda G, Muñoz-Negrete FJ. Follow-up of nonarteritic anterior ischemic optic neuropathy with optical information about optic nerve function, but is rarely useful coherence tomography. Ophthalmology;114 (12):2338-44, 2007. in serial assessment. In addition, inter-lab differences, 8. Savini G, Barboni P, Valentino ML, Montagna P, et al. Retinal nerve dependence on patient cooperation, and test-retest fiber layer evaluation by optical coherence tomography in unaffected variability diminish its utility in tracking meaningful optic carriers with Leber’s hereditary optic neuropathy mutations. nerve changes. Multi-focal VEP (mfVEP) provides more Ophthalmology;112(1):127-3, 2005. detailed information about optic nerve function, but suffers 9. Pula J, Marshall J, Wang H, Kattah J, Eggenberger E. Ability of a neuro- from similar drawbacks as a serial tool to detect meaningful ophthalmologist to estimate retinal nerve fiber layer thickness. change, especially between labs. Clinical Ophthalmology 2012.

380 | North American Neuro-Ophthalmology Society Murphy’s Law: When Good Tests Go Bad!

Michael S. Lee, MD University of Minnesota Minnesota, MN

Learning Objectives Introduction 1. Identify potential pitfalls with interpretation of optical For decades, clinicians have utilized office-based testing such coherence tomography (OCT) as fluorescein angiography, b-scan ultrasonography, and full-field ERG in the diagnosis and management of neuro- 2. Become familiar with sources of error using multifocal ophthalmic disorders. More recently development of optical electroretinography (mfERG) coherence tomography (OCT), multifocal electroretinography (mfERG), and fundus autofluorescence (FAF) have improved the diagnostic armamentarium. However, as with all testing, CME Questions faith in and dependence upon these tests can lead to delayed 1. Which of the following most likely causes attenuation or missed diagnoses secondary to artifact, poor quality of the central ring 1 on the mfERG? results, and misinterpretation. This syllabus will describe some of the key issues that lead to errors in selected office- a. Inadequate dark adaptation based test results and diagnoses. b. Inadequate light adaptation c. Eccentric fixation Case 1. Two months prior to presentation, a 30-year-old d. Epiphora man developed sudden bilateral visual loss while driving. He had used crack cocaine just prior to getting into the 2. Which of the following is the most likely cause of a car. He denied any pain or headache. The vision loss had thinned RNFL in a patient with acute papilledema? not progressed. His visual acuities were 20/150 OU. He a. Signal strength of 10 identified all of the Ishihara color plates. His pupils were b. Refractive error of +3.00 diopters mildly sluggish OU without an RAPD. Visual field testing c. Segmentation errors showed bilateral central scotomas (Figure 1). d. Nerve fiber layer loss from papilledema His fundus examination showed mild RPE changes and possible temporal pallor. Brain and orbital MRI showed normal results. Keywords Fluorescein angiogram was interpreted as normal. Time-domain OCT RNFL showed normal results. Multifocal ERG demonstrated 1. Optical Coherence Tomography attenuation of the central waveforms (Figure 2). 2. Multifocal Electroretinogram Multifocal ERG. The individual mfERG waveforms are 3. Artifact derived by cross correlative mathematics from the 4. Optic Neuropathy continuously recorded retinal electrical activity, as measured by the corneal electrode,. as compared to a 61 5. Retinal Nerve Fiber Layer or 103 scaled hexagon stimulus array which changes every 13.3 milliseconds, Depending on the number of hexagons in the display, software derives either 61 or 103 waveforms The stimulus is designed to test the central 50 degrees of visual field if viewed at 1/3 of a meter. The frequency of the stimulus change exceeds the ability of the rods to respond therefore the mfERG waves represent only central cone function. The ganglion cells do not make a significant contribution to the mfERG therefore it can be used to distinguish central loss of retinal origin from that of optic nerve origin. The mfERG is particular helpful for testing patients with focal visual field defects and patients with hydroxychloroquine retinopathy (1,2)

2013 Annual Meeting Syllabus | 381 Figure 1. Automated perimetry (HVF 10–2) demonstrates a central scotoma OU.

Figure 2. Multifocal ERG of Patient 1 shows an attenuated waveform in the center hexagon (left eye on the left and right eye on the right).

Several sources of potential error exist with mfERG testing. result in artifactuous attenuation of the mfERG waveforms, Since the electrode does not distinguish between sources of and this affects the central hexagon disproportionately electrical activity, the test remains sensitive to any excessive (unpublished data). Some disorders, such as melanoma- muscle firing (particularly blinking and eye movements). associated retinopathy (MAR) affect rod rather than cone These movements can result in increased noise. bipolar cells. The cone-driven response of the mfERG may Contamination with 60 cycle electrical activity can also result show normal results in MAR. Finally, patients with a central in noise. Unfortunately, unlike the OCT, the mfERG has no scotoma may not see the central fixation target within the simple quality measure and requires the technician and the mfERG stimulus. If the technician does not recognize this, intrepreter to determine whether the results are acceptable the patient may fixate eccentrically to identify the target. The or not. It is important to review the 3D plot to determine mfERG is exquisitely sensitive to eccentric fixation (1) and the quality and location of patient fixation by looking for will demonstrate abnormal results centrally and may show the presence of a blind spot and its location. Although the supranormal results in adjacent hexagons. mfERG requires the patient to be light adapted, according to the International Society for Clinical Electrophysiology Case conclusion. In Case 1, serologic testing revealed of Vision (ISCEV) standards, testing should be avoided the following abnormalities: B12, 207 pg/ml (nl >210); within 15 minutes of bright light exposure such as fundus methylmalonic acid, 0.49 umol/L (nl 0—0.40); homocysteine photography or funduscopy (2). Bright light exposure can 115.5 umol/L (nl 4–12); and rbc folate, 172 ng/mL (nl 382 | North American Neuro-Ophthalmology Society 280–791). The patient was diagnosed with nutritional optic neuropathy. Oral B6, B12, and folate supplementation resulted in the patient’s acuity improving to 20/30 OU. The visual field defects resolved, but foveal thresholds remained 30 dB OU. Closer examination of the mfERG in Figure 2, shows that the waveforms superior to fixation are larger than normal consistent with eccentric fixation.

Case 2. A 34-year-old woman presented with severe holocranial headaches x 2 years. She described intermittent pulse-synchronous tinnitus. She denied diplopia or transient Figure 3. Fundus photographs of Case 2.

Figure 4. Retinal nerve fiber layer of the optic nerves in Case 2 using spectral-domain OCT. visual obscurations. She was 5 ft tall and weighted 142 lbs (BMI = 27.7 kg/m2). Her visual acuity was 20/20 OU. Her pupils, color vision, extraocular motility, and slit lamp examination were normal. The optic discs appeared elevated and cupless, and showed no spontaneous venous pulsations (Figure 3). Automated perimetry demonstrated normal results OU. Brain MRI and MRV were not available for review, but the reports described normal results. Spectral domain OCT of the right eye showed mild thickening of the RNFL inferiorly and nasally and borderline thinning temporally. The left eye demonstrated of the superotemporal and mean RNFL compared to age-matched controls.

Optical coherence tomography.OCT has become a major Figure 5. OCT of a patient with obvious papilledema and diagnostic tool in the field of neuro-ophthalmology. The OCT choroidal folds. Note in the upper left corner that the disc is records multiple reflected axial images from the ocular tissues decentered in the reference circle. The RNFL thickness is much and combines them into a single. It is most often utilized to greater in the inferior sector (closer to the reference circle) and assess and follow retinal nerve fiber layer (RNFL), to image normal in the superior sector (further from the reference circle). the macula qualitatively (e.g, cystoid macular edema), and to determine the integrity of the outer retinal architecture (e.g. inner segment/outer segment (IS/OS) junction). do not. Both groups of machines depend upon the user to either accept the images or try to obtain better ones. Poor Numerous sources of error can occur with the use of signal quality results in thinner RNFL and macular volume OCT. These generally can be divided into patient, user measurements. It can also make it difficult to see the IS/OS or interpretation issues. Poor signal quality represents a junction, which could be mistaken as attenuation or loss. common source of problems and results from media opacity (cataract, corneal clouding or exposure, vitreous haze), eye Other patient related issues include high refractive error movement or blinking, and poor pupillary dilation (3,4,5). (> 6D of spherical error and > 3D of astigmatism), which Some OCT machines describe a quantitative measure of affects the “true” RNFL measurements because the scan quality (e.g. signal strength) in the output, while others calculations of 3.4 mm diameter measurement circle of

2013 Annual Meeting Syllabus | 383 RNFL depend upon an ideal eye with an axial length 24.5mm. Finally, one large source of error involves segmentation Long eyes tend to produce thinner RNFL measurements. errors (11). OCT machines use algorithms to identify retinal Most OCT machines describe a normative database between layers. Unfortunately, these algorithms can break down in 18 and 85 years of age. Since OCT measurements vary with eyes with significant pathology and sometimes in “normal” age, the database may lack accuracy among children and the eyes. The OCT determines RNFL or macular thickness elderly. Race plays a role in OCT findings. African Americans, by identifying certain layers of the retina and measuring Caucasians, and Asians have significantly different optic the distance between them (varies by machine). These disc parameters. The Heidelberg Spectralis notes that segmentation errors can be subtle affecting a small area of their database is only accurately compared to Caucasian the A-scan but the result may show that area of the RNFL as individuals. Finally, debate exists on whether the optic disc artifactuously thick or thin. The clinician needs to identify size affects the true RNFL measurement (6,7,8). Intuitively, when these segmentation errors occur, because the patient a fixed RNFL circle of 3.4 mm depends upon the distance to may erroneously receive a diagnosis of optic atrophy or the edge of the optic disc, and the RNFL becomes thinner edema. Some machines allow the user to correct these the further from the disc edge (see Figure 5). Others argue errors postimaging, while others do not. that the axial length alone makes the disc vary in apparent size and that axial length rather than true disc size modifies Case conclusion. In case 2, B-scan ultrasound did not show the RNFL. Even if the axial length is truly the culprit, clinicians evidence of optic disc drusen. The MRI/MRV images showed rarely measure the axial length and no conversion factor to a partial empty sella and narrowing of the distal transverse account for it is commercially available. sinuses bilaterally. Lumbar puncture in the left lateral decubitus position showed an opening pressure of 31 cm User errors include poor centration on the optic disc/ H20. The rest of the CSF was unremarkable and the patient macula or poor centration on the visual axis. Poor was diagnosed with idiopathic intracranial hypertension. centration on the disc causes some sectors/quadrants Review of the OCT shows that the discs are small and the of the RNFL to appear thicker and the opposite areas area of edema does not extend to the 3.4 mm scanning thinner. Fortunately, an infrared image of the area sampled circle. Additionally, the “waveform” in the left eye (arrow) is produced for the printout allowing the clinician to shows a lot of noise compared to the right eye (arrowhead), determine how well the photographer centered the OCT which suggests the thinning may not accurately reflect the measurement. Some OCT machines allow the user to true RNFL. The Spectral domain OCT used does not have a redefine the macular centration postprocessing to get an measure of quality listed on the output (e.g. signal strength accurate central foveal thickness. Recently, Hariri et al. on other spectral domain machines). compared macular OCT that entered the pupil along the visual axis to ones that entered eccentric to the visual axis (9). Both OCT groups focused upon the fovea. The CME Answers eccentrically obtained scans showed much thicker macular 1. c. The True Fovea is Not Aligned with Ring 1 and volumes and thicknesses compared to the scans through Therefore the Response in Ring 1 is Calculated From the the center of the pupil. The user can identify these scans Parafoveal Region. This Leads to an Attenuated Response (12). by looking at the A-scan, which will be tilted (e.g. left side higher) rather than horizontally across. 2. c. While Optic Atrophy Can Occur From Papilledema, in the Acute Situation, The OCT is More Likely to Show Interpretive errors abound because interpretation requires Thinning of the RNFL Because of Segmentation Errors. judgement regarding pathophysiology, understanding of the OCT and its limitations, and determination of errors listed earlier. The OCT does not reliably distinguish true References vs. pseudodisc edema. While statistically the mean RNFL 1. Hood DC Odel JG, Chen SC, Winn BJ. The multifocal is much thicker in the true disc edema group, the groups electroretinogram. J Neuroophthalmol 2003;23:225–35. overlap significantly (10). It is possible to follow the RNFL of 2. Hood DC, Bach M, Brigell M, Keating D, Kondo M, Lyons JS, a suspicious disc. Progressive thickening of the RNFL over Marmor MF, McCulloch DL, Palmowski-Wolfe AM, International time would indicate true disc edema instead of pseudodisc Society for Clinical Electrophysiology of Vision. ISCEV standard for clinical multifocal electroretinography (mfERG) (2011 edition). Doc edema. This raises the questions, “What is the test-retest Ophthalmol 2012;124:1–13. reliability?” and, “How much change is fluctuation vs. 3. van Velthoven ME, van der Linden MH, de Smet MD, Faber DJ, true change?” The answer remains unclear and varies by Verbraak FD. Influence of cataract on optical coherence tomography individual patient and device, but a general rule of thumb is a image quality and retinal thickness. change of 10 microns for the mean RNFL. Some devices have 4. Stein DM, Wollstein G, Ishikawa H, Hertzmark E, Noecker RJ, eye registration and eye tracking software, which improve Schuman JS. Effect of corneal drying on optical coherence test-retest reliability. Without this software, it becomes tomography. Ophthalmology 2006;113:985–91. difficult to assess for change in quadrants let alone sectors. 5. Smith M, Frost A, Graham CM, Shaw S. Effect of pupillary dilation on glaucoma assessments using optical coherence tomography. Br J Ophthalmol 2007;91:1686–90.

384 | North American Neuro-Ophthalmology Society 6. Knight OJ, Girkin CA, Budenz DL, Durbin MK, Feuer WJ, Cirrus OCT Normative Database Study Group. Effect of Race, Age, and Axial Length on Optic Nerve Head Parameters and Retinal Nerve Fiber Layer Thickness Measured by Cirrus HD-OCT. Arch Ophthalmol 2012;130:312. 7. Huang D, Chopra V, Lu AT, Tan O, Francis B, Varma R; Advanced Imaging for Glaucoma Study (AIGS) Group. Does optic nerve head size variation affect circumpapillary retinal nerve fiber layer thickness measurement by optical coherence tomography. Invest Ophthalmol Vis Sci.2012;53:4990–7. 8. Savini G, Barboni P, Carbonelli M, Zanini M. The effect of scan diameter on retinal nerve fiber layer thickness measurement using stratus optic coherence tomography. Arch Ophthalmol 2007;125:901–5. 9. Hariri A, Lee SY, Ruiz-Garcia H, Nittala MG, Heussen FM, Sadda SR. Effect of angle of incidence on macular thickness and volume measurement s obtained by spectral-domain optical coherence tomography. Invest Ophthalmol Vis Sci 2012;53:5287–91. 10. Karam EZ, Hedges TR. Optical coherence tomography of the retinal nerve fiber layer in mild papilloedema and pseudopapilloedema. Br J Ophthalmol 2005;89:294–8. 11. Ho J, Sull AC, Vuong LN, Chen Y, Liu J, Fujimoto JG, Schuman JS, Duker JS. Assessment of artifacts and reproducibility across spectral- and time-domain optical coherence tomography devices. Ophthalmology 2009;116:1960–70. 12. Vrabec TR, Affel EL, Gaughan JP, Foroozan R, Tennant MTS, Klancnik JM, Jordan CS, Savino PJ. Voluntary suppression of the multifocal electroretinogram. Ophthalmology 2004;111:169–76.

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