Bilateral acute macular neuroretinopathy after Epstein-Barr virus encephalitis

En face optical coherence tomography for diagnosis of unexplained snowflake scotoma

Objective To observe the clinical features of acute macular neuroretinopathy (AMN). Methods Six patients (11 eyes) with AMN were included in this study, with every 2-week follow-ups till six months. Among them, five had preceding dengue fever (83.3%), one had history of head trauma (16.7%). All patients received routine examination, fundus photography, infrared reflectance (IR) imaging, spectral-domain optical coherence tomography (SD-OCT) scanning and fluorescein fundus angiography (FFA) initially, and fundus photography, IR, SD-OCT during follow-up. Results Sudden onset of central/paracentral scotoma in one eye or both eyes was the main visual symptom. There were 1 eye with normal fundus, 2 eyes with wedge-shape lesions, 8 eyes with yellow-white or brown sheet lesion. IR imaging demonstrated localized areas of hypo-reflection in the macula. SD-OCT scanning through these areas revealed hyper-reflection in the photoreceptor layer and disruption of its normal reflective structures. Subsequent SD-OCT demonstrated that the hyper-reflection of the photoreceptor layer regressed gradually, followed by thinning of the outer nuclear layer. The external limiting membrane and ellipsoid zone became continuous; however, the interdigitation zone was not restored. There was no remarkable findings of the AMN lesions on FFA. The scotomas persisted in all 6 patients (11 eyes) by the last visit. Conclusions IR imaging demonstrated localized areas of hypo-reflection in the macula. SD-OCT revealed hyper-reflection in the photoreceptor layer in acute stage and the interdigitation zone was not restored in late stage. AMN has a relative poor prognosis with persistent scotomas through at least 6 months. Key words: Macula lutea/injuries; Retinal diseases/ diagnosis; Disease attributes

BackgroundIn this study, we report a case series of acute macular neuroretinopathy (AMN) associated with COVID-19 infection.MethodsThis retrospective observational study was conducted at Beijing Tongren Hospital. We reviewed patients who were diagnosed with AMN within one month of testing positive for COVID-19 using real-time reverse transcription-polymerase chain reaction (RT-PCR).ResultsA total of 11 AMN patients (20 eyes) were included in the study. The mean age was 33.8 ± 12.6 years. The average interval between a positive COVID-19 PCR test and the onset of ocular symptoms was 2.8 ± 2.5 days. The mean follow-up period for the patients was 12.5 ± 3.8 weeks. Imaging characteristics of AMN patients following COVID-19 infection included areas of low reflectivity on near-infrared reflectance (NIR) imaging, hyperreflective lesions at the level of the outer plexiform layer (OPL) and outer nuclear layer (ONL) and disruption of the ellipsoid zone (EZ) on spectral domain optical coherence tomography (SD-OCT) B-scans. Visual field examinations revealed parafoveal scotomas that closely corresponded to the clinical lesions. Optical coherence tomography angiography (OCT-A) demonstrated impaired perfusion in the deep retinal vascular plexus. Fluorescein angiography (FA), indocyanine green angiography (ICGA), and spontaneous fundus autofluorescence showed no significant abnormalities. During follow-up, partial improvement in retinal lesions was observed in NIR imaging and SD-OCT in some patients, but a proportion of patients still exhibited persistent retinal damage and no improvement in visual field scotomas.ConclusionCOVID-19-related AMN share similar clinical and imaging features with AMN due to other causes, as evidenced by the persistent presence of visual field scotomas over a longer duration.Trail registrationhttps://www.chictr.org.cn/; identifier: ChiCTR2100044365

IntroductionSpectral-domain optical coherence tomography findings in a patient with acute macular neuroretinopathy, and correlation with functional defects on microperimetry, are presented.Case presentationA 25-year old Caucasian woman presented with bitemporal field defects following an upper respiratory tract infection. Her visual acuity was 20/20 in both eyes and a dilated fundus examination revealed bilateral hyperpigmentary changes in the papillomacular bundle. Our patient underwent further evaluation with spectral-domain optical coherence tomography, infrared and fundus autofluorescence imaging. Functional changes were assessed by microperimetry. Infrared imaging showed the classic wedge-shaped defects and spectral-domain optical coherence tomography exhibited changes at the inner segment-outer segment junction, with a thickened outer plexiform layer overlying these areas. Fluorescein and indocyanine green angiography did not demonstrate any perfusion defects or any other abnormality. Microperimetry demonstrated focal elevation in threshold correlating with the wedge-shaped defects in both eyes.ConclusionSpectral-domain optical coherence tomography findings provide new evidence of the involvement of the outer plexiform layer of the retina in acute macular neuroretinopathy.

This study evaluates the morpho-functional alterations associated with acute macular neuroretinopathy (AMNR). Prospective observational case series study carried out at the University Vita-Salute, Scientific Institute San Raffaele. Five out of six eyes (three patients) showed the typical features of AMNR. The patients underwent an ophthalmological examination, including best-corrected visual acuity (BCVA) measurement, electroretinogram and electroculogram (ERG/EOG), multifocal electroretinogram (mfERG), infrared reflectance, short wavelength and near-infrared-fundus autofluorescence (SW-FAF/NIR-FAF), spectral-domain optical coherence tomography (SD-OCT) and microperimetry. Microperimetric alterations in the two SD-OCT subtypes of AMNR. The BCVA was 20/20 in all patients. ERG and EOG were normal; mfERG revealed a generally reduced response with a more reduced signal in the areas corresponding to the macular lesions. SD-OCT demonstrated two different patterns of retinal alterations. In case 1, SD-OCT revealed a hyperreflective, plaque-like band at the junction of the outer plexiform layer (OPL) and the inner nuclear layer (INL), extending into the INL (type 1 lesion). In cases 2 and 3, SD-OCT disclosed a hyperreflectivity of the OPL associated with outer nuclear layer thinning and disruption of the outer segment/retinal pigment epithelium junction (type 2 lesion). Microperimetry revealed a wide scotoma involving the entire macular area in all eyes, including the unaffected eye of case 1. The reduction in retinal sensitivity was greatest in type 1. SD-OCT confirms that AMNR may occur in different patterns. Microperimetry demonstrated that functional alterations are also discernible in apparently uninvolved areas. Both examinations are extremely valuable in characterizing the changes associated with AMNR.

PurposeTo study the topographical relationship between acute macular neuroretinopathy (AMN) lesions and the choroidal watershed zone (CWZ) or patchy choroidal filling (PCF) using multimodal imaging.MethodsLesions in patients diagnosed with AMN were clinically examined using multimodal imaging, including fundus photography, near-infrared reflectance imaging, spectral-domain optical coherence tomography (OCT), fluorescein angiography, indocyanine green angiography, OCT angiography, and microperimetry. The topographical relationship between AMN and the CWZ or PCF was evaluated.ResultsSeven eyes of six patients were included in the study. The mean age of the patients was 35.8 ± 11.7 years. The AMN lesions were collocated with the CWZ in five eyes and the PCF in one eye. Among these eyes, three had complete patterns, and three had partial patterns. Only one eye showed no topographical relationship between AMN and the CWZ or PCF.ConclusionThe colocation of AMN and CWZ/PCF suggests that the AMN lesions were within an area with a dual-watershed zone: the watershed zone between the retinal deep capillary plexus and choriocapillaris, and the choroidal watershed zone or patchy choroidal filling. This retinal area was highly vulnerable to hypoperfusion. Our results suggest a novel pathophysiological mechanism for AMN.

Editor, A 23-year-old woman had fatigue, nasal congestion, headache, vertigo and sweating for two weeks without fever. The next day, she noticed photopsias which evolved to several paracentral scotomas in both eyes. Ophthalmologic examination in the emergency room revealed best-corrected visual acuity of 20/20 in both eyes. Ishihara colour vision testing revealed dyschromatopsia only in the left eye. Pupillary reaction, ocular motility, biomicroscopy and funduscopy were within normal limits. Spectral-domain optical coherence tomography (SD-OCT, Heidelberg, Germany) of the macula and the optic nerve of both eyes were normal. Because of her preceding systemic symptoms, PCR testing for SARS-CoV-2 using nasopharyngeal swab was performed, and she tested positive. MR imaging of the brain was normal, and serologic testing of blood and cerebrospinal fluid was done for various infectious and inflammatory disorders, and the result was negative. No specific diagnosis or treatment was proposed. Ten days after presentation in the emergency room, the patient had a painful vesicular eruption on the upper lip. This was diagnosed as herpes labialis (herpes simplex-1, HSV-1) and treated with topical antiviral cream with a positive outcome in 6 days. After three weeks, all symptoms spontaneously disappeared except the visual disturbance for which she was then referred for neuro-ophthalmologic consultation. The paracentral scotomas had become semi-transparent but were otherwise unchanged. The dyschromatopsia of the left eye was cured; funduscopy was still normal. Visual field testing with Amsler grid and Octopus 900 perimetry, 30-degree field analysis (Haag Streit, Bern, Switzerland) showed several paracentral scotomas within the central fifteen degrees of both eyes. Spectral-domain optical coherence tomography (SD-OCT) now revealed disruption of the ellipsoid and interdigitation zones with hyperreflectivity within the outer nuclear layers in the paracentral macula. Near-infrared reflectance (NIR) imaging showed large, bilateral confluent hyporeflective lesions and smaller petaloid-shaped lesions around the fovea, corresponding to the region of OCT abnormalities. (Fig. 1A–D). Fluorescein angiography and indocyanine green angiography were normal in both eyes. Optical coherence tomography angiography (OCT-A, Angiovue RTx 100, Optovue, Inc, Fremont, CA, USA), however, showed decreased vascular flow signal at the level of the deep capillary plexus (DCP) in the region of the OCT and NIR abnormalities (Fig. 1E, F). A final diagnosis of bilateral acute macular neuroretinopathy (AMN) was made. Given her excellent visual acuity, no specific treatment was recommended. One month later, the examination and ancillary testing did not show any remarkable changes. In a previous review of 101 cases of AMN (Bhavsar et al. 2016), almost half were associated with a preceding respiratory or influenza-like illness. Our patient had preceding flu-like symptoms from COVID-19, and shortly after noticing the visual disturbance, she had a herpes labialis eruption. We believe this was either concomitant infection with SARS-CoV-2 or reactivation by SARS-CoV-2. The published literature does not implicate HSV-1 virus with AMN. The pathophysiology of AMN is a non-inflammatory vaso-occlusive disorder of retinal capillaries. Optical coherence tomography (OCT) and OCTA changes related to capillary vasculopathy have been reported in the DCP and/or choriocapillaris (Casalino et al. 2019), (Fawzi et al. 2012). The typical fundus abnormality of AMN is one or more wedge-shaped, well-delineated lesions pointing to the fovea (Bhavsar et al. 2016). AMN following COVID-19 infection is rare. Two previous published cases (Gascon et al. 2020; Virgo & Mohamed 2020) reported small, focal petaloid lesions in one affected eye. However, our patient demonstrated unusually large, confluent lesions in both eyes, which suggested a large area of retinal pathology. We wonder whether endotheliopathy due to direct SARS-CoV-2 infection predisposes to greater retinal ischaemia and larger lesions of AMN (Iba et al. 2020). Systematic ophthalmologic examination of patients with coronavirus disease may clarify the prevalence and clinical profile of AMN associated with COVID-19.Open Access Funding provided by Universite de Lausanne.

PurposeTo study the usefulness of multicolor imaging (MC) photographs in addition to near infrared reflectance (NIR) and spectral domain optical coherence tomography (SD-OCT) in the detection and follow up of acute macular neuroretinopathy (AMN).Patients and methodsSix patients with a complaint of paracentral scotomas in at least one eye due to AMN were included. They underwent full ophthalmic examination and multimodal imaging including color fundus photographs, (SD-OCT), NIR, and MC at baseline and follow up.ResultsFour females and two males, aged 19-64 years, and eight eyes affected by AMN, were included. Acute phase SD-OCT in all patients confirmed the diagnosis of type 2 AMN with partial recovery of the outer retina in the convalescent phase. NIR and MC elicited in all cases hypo-reflective AMN lesions pointing toward the fovea. MC exhibited a higher contrast between the affected and the physiologic retina that slowly attenuated during the follow up showing a decrease in the hypo-reflectance of the lesions.ConclusionMC imaging was more detailed than fundus color photographs and as detailed as NIR in the detection of AMN. When available, MC imaging should complement SD-OCT and NIR in the diagnosis and follow up of this rare inflammatory condition that may be underdiagnosed.

Acute macular neuroretinopathy (AMN) is a rare, idiopathic condition resembling other acute maculopathies such as paracentral acute middle maculopathy. The pathophysiology of AMN is not well understood, and the role of the choroid in the pathogenesis of AMN remains controversial. To describe initial and serial multimodal imaging findings in AMN, with attention to choroidal vascular changes. Retrospective case series at a single institution, tertiary referral center. The case series included 7 patients with clinical diagnosis of AMN. Multimodal imaging findings, including fundus photography, fluorescein angiography, spectral-domain optical coherence tomography (OCT), en face near-infrared imaging, fundus autofluorescence, optical coherence tomography angiography (OCTA), and automated quantification of the regional structural context of choroidal flow interest between different imaging modalities, using an automatic algorithm. Nine eyes from 7 patients (5 women and 2 men; mean age, 40.1 years) with a diagnosis of AMN were included. Mean duration of follow-up was 11 weeks (range, 1-25 weeks). All eyes had inner choroidal flow void on OCTA that topographically corresponded to regions of abnormal hyperreflectance of the outer retinal layers on spectral-domain OCT and hyporeflectance on en face near-infrared imaging (dice similarity coefficient, 0.76). For each patient, these areas of choroidal flow void on OCTA persisted during the follow-up period, while the abnormal hyperreflectance of outer plexiform layer and inner nuclear layer on spectral-domain OCT was observed to improve. These findings suggest that areas of inner choroidal vascular flow void on OCTA are seen in patients with AMN. These areas may persist weeks after the onset of symptoms and suggest that vascular compromise of the inner choroid may be involved in the pathogenesis of AMN.

Acute Macular Neuro-retinopathy (AMN) is a rare clinical entity. We present a case of 26 years old male who presented with one-week old history of sudden onset of decrease vision in left eye associated with paracentral scotomas. Dilated fundus examination of the left eye showed multiple reddish brownish petalloid para-foveal lesions with apex pointing toward the fovea. OCT showed hyper-reflective bands in the Outer Nuclear Layer and Outer Plexiform Layer along with disruption of ellipsoid zones. Amsler grid drawn by the patient and the visual field showed scotoma corresponding to the macular lesion. The cause turned out to be undiagnosed essential hypertension. Purpose of presenting this case is that High Definition Optical coherence tomography (SD-OCT) makes diagnosis of some rare conditions easy and fast for an ophthalmologist, that might be misdiagnosed or missed with conventional OCT and FFA imaging test.
 Key Words: Acute Macular Neuro-retinopathy, Spectral Domain Optical Coherence Tomography, Paracentral Scotoma.

To assess the cone photoreceptor mosaic in acute macular neuroretinopathy (AMN) using adaptive optics (AO) imaging. Four patients with AMN were evaluated retrospectively by near-infrared reflectance (IR) confocal scanning laser ophthalmoscopy (SLO), spectral-domain optical coherence tomography (SD-OCT), and a flood-illuminated retinal AO camera. Microperimetry was performed in one patient. The cone photoreceptor density was decreased at the level of the AMN lesions. The cone mosaic disruption appeared heterogeneous and more widespread than the lesion detected in the IR-SLO and SD-OCT images. The areas of cone loss correlated with SD-OCT and microperimetry. After resolution of the AMN lesion on IR-SLO, there was incomplete recovery of the cone photoreceptor mosaic. Cone photoreceptor damage and reconstitution were documented in vivo at the cellular level in AMN using AO imaging. AO imaging appeared more sensitive than combined IR-SLO and SD-OCT to detect and follow photoreceptor damage in patients with AMN.

To assess the interobserver variability (IOV) in indicating retreatment for neovascular Age-related macular degeneration 4 weeks after three Ranibizumab loading doses using spectral domain OCT (SD-OCT) as the primary objective diagnostic tool. Four observers decided for or against 4th Ranibizumab injection in 108 patients by six different rating rounds (RR) based on the SD-OCT findings after the loading doses. Postoperative OCT images were supplemented consecutively with information from a chart review as the 'patients subjective estimation of vision (SE)', the course of best-corrected visual acuity (BCVA) and the preoperative OCT as well as all information collectively. Agreement rates (AR) and Kappa statistics were calculated. Based on post-treatment OCT findings only (RR1), mean reinjection rate of all observers was 37.5%. Adding supplementary information, mean reinjection rate decreased to 20% when all information was available reflecting the 'real' situation (RR 6). Interobserver agreement rates varied from 66.7% to 90.7% depending on rating rounds and interobserver pairs. Mean AR and Kappa values (KV) were as following: AR 81.6%, KV 0.61 (RR1: 'only post-OP OCT'); AR 76.7%, KV 0.33 (RR2: post-OP OCT + SE); AR 80.3%, KV 0.45 (RR3: post-OP OCT + BCVA); AR 80.7%, KV 0.46 (RR4: pre- and post-OP OCT); AR 82.2%, KV 0.49 (RR5: post-OP OCT + SE + BCVA); and finally AR 83.6%, KV 0.47 (RR6: pre- and post-OP OCT + SE + BCVA). The overall mean agreement rate was 80.9% with a Kappa of 0.47. IOV for indicating retreatment after three Ranibizumab loading doses reveals only moderate agreement in Kappa statistics, which seems to be too low considering the high costs for retreatments. More concise guidelines based on the post-treatment OCT scans as the presumably most sensitive and noninvasive objective tool to follow choroidal neovascularization activity by judging the course of sub- and intraretinal fluid are necessary.

To evaluate macular morphology and function in diabetic macular edema (DME) over the course of intravitreal anti-vascular endothelial growth factor (VEGF) treatment with Ranibizumab. A consecutive series of 39 study eyes with centre-involving DME were included in this study. In all subjects, best-corrected visual acuity (BCVA) according ETDRS protocol, fluorescein angiography (FA), microperimetric macular sensitivity (MP) and Spectral Domain optical coherence tomography (SD-OCT) cross-sectional scans were obtained before treatment and after 3 monthly applied intravitreal Ranibizumab injections. Six different morphological qualities [IS/OS layer integrity, outer nuclear layer (ONL) cysts, ONL cyst size, inner nuclear layer (INL) cysts, blocking phenomenon and subretinal fluid] were graded of each cross-sectional OCT scan before and over the course of treatment by two experienced graders. Correlation analyses between functional and morphological parameters were obtained. Mean BCVA increased from 26 ± 14 to 33 ± 13 letters after 3 consecutive monthly applied Ranibizumab injections (p < 0.001). Central retinal thickness (CRT) decreased from 504 ± 144 to 387 ± 122 μm (p < 0.001). Over the course of treatment, IS/OS continuity improved (index: 0.56 ± 0.52 to 0.43 ± 0.49, Z = -1.415, p = 0.157), ONL cyst prevalence and size decreased significantly (index: 0.61 ± 0.44 to 0.56 ± 0.35, Z = -3.41, p = 0.001 and 1.75 ± 0.88 to 1.17 ± 1.05, Z = -4.02, p < 0.001), INL cyst prevalence decreased (index: 0.35 ± 0.52 to 0.28 ± 0.52, Z = -1.60, p = 0.109), blocking phenomenon did not change significantly (index: 00.12 ± 0.16 to 0.13 ± 0.15, Z = -0.45, p = 0.656) and subretinal fluid almost disappeared (index: 0.10 ± 0.24 vs. 0.00 ± 0.01, Z = -2.56, p = 0.011). Correlation analyses revealed highest significant correlations between ONL cyst prevalence and their size and CRT as well as BCVA and MP before treatment and over the course of treatment. ONL cysts and their size as morphological parameters correlate with retinal function measured with BCVA and microperimetry before and over the course of anti-VEGF therapy with Ranibizumab in patients with DME.

Multimodal imaging techniques were performed in a patient with a newly emerged visual field defect; a missing retinal lesion on fundus examination made the diagnosis challenging but infrared imaging showed a larger area of retinal abnormality temporal to the fovea. Indocyanine green angiography (IA) showed late hypofluorescence and there was mild hyperautofluorescence which is known from acute zonal occult outer retinopathy (AZOOR). Despite normal fluorescein angiography (FA) results, a perfusion loss in the outer retinal layer was detected by OCT-A. Similar OCT-A findings were recently described in patients with acute macular neuroretinopathy (AMN). Methods. The methods included FA and IA, spectral domain optical coherence tomography (SD-OCT), near infrared imaging, and autofluorescence imaging (AF), as well as OCT-A. Patient. A 36-year-old patient who suffered from acute symptoms of photopsia and scotoma on her left eye. She had an influenza-like illness two weeks earlier. The scotoma could be verified by visual field testing. Results. The affected retinal zone showed mild fading of external limiting membrane (ELM) and a disorganisation of the ellipsoid zone (EZ) on SD-OCT. OCT-A revealed a large area of reduced perfusion in the outer retinal vascular layer. Conclusion. OCT-A can help to detect reduced capillary network in patients with visual field defects and no visible fundus changes. This case seems to have features of different occult retinal disorders such as AZOOR and AMN.

Concurrent vascular flow defects at the deep capillary plexus and choriocapillaris layers in acute macular neuroretinopathy on multimodal imaging: A case series