Bilateral acute macular neuroretinopathy after Epstein-Barr virus encephalitis

Abstract

Purpose

To report a case of a 11-year-old girl, who developed a bilateral acute macular neuroretinopathy (AMN) after Epstein-Barr virus (EBV) encephalitis.

Observations

Clinical findings and multimodal imaging including fundus photography, near-infrared reflectance, spectral-domain, and enhanced-deep imaging optical coherence tomography (OCT) of a patient with bilateral acute macular neuroretinopathy after Epstein-Barr virus encephalitis.

Conclusions and importance

After conducting a literature review in August 2024 using PubMed and Google Scholar, using the keywords “acute macular neuroretinopathy”, “AMN”, “Epstein-Barr”, “Epstein-Barr virus”, “EBV”, “encephalitis” “Epstein-Barr encephalitis” “EBV encephalitis” we did not find any previous reports of AMN associated with EBV encephalitis, such as in our case. Near infrared imaging and spectral-domain optical coherence tomography are key diagnostic tools for this condition, even when fundoscopic findings are subtle.

1. Introduction

Acute macular neuroretinopathy (AMN) is a rare disorder characterized by sudden onset of photopsias, and paracentral scotoma, typically associated with mild visual impairment. Initially described by Bos and Deutman in 1975 in four women using oral contraceptives,¹ AMN is defined by the presence of intraretinal, reddish-brown, wedge-shaped lesions in the macula pointing toward the fovea, often forming a petalloid or teardrop configuration.² This condition predominantly affects young women, and is commonly associated with flu-like symptoms and contraceptive use.³ Other risk factors include caffeine intake, sympathomimetics, COVID-19 infection or vaccination, and systemic hypotension.^2,3 We report a case of a 11-year-old patient with AMN associated with Epstein-Barr virus (EBV) encephalitis.

2. Case report

A 11-year-old healthy black girl, from Rio de Janeiro, Brazil, sought assistance at the emergency department of the Hospital Federal dos Servidores do Estado do Rio de Janeiro with a 4-day history of high-grade fever, followed by the onset of refractory generalized tonic-clonic seizures. She was admitted to the intensive care unit and underwent orotracheal intubation. A comprehensive serologic workup was performed, including VDRL, FTA-ABS, toxoplasmosis, human immunodeficiency virus (HIV), and Bartonella serology, all of which were normal. QuantiFERON-TB Gold (IGRA), and chest computed tomography (CT) were also unremarkable. However, serology revealed positive EBV IgM and IgG, and EBV PCR in the cerebrospinal fluid (CSF) was positive. Central nervous system CT was normal, while magnetic resonance imaging (MRI) demonstrated hyperintensity on T2/FLAIR sequences involving the caudate nucleous and putamen. Based on these findings, the diagnosis of EBV encephalitis was established. Levetiracetam, phenobarbital, carbamazepine, haldol, immunoglobulin 1.5g/kg, and steroids were prescribed. During hospitalization no vasopressor drugs were prescribed, as the patient remained hemodynamically stable, without hypotension or hypovolemic shock. She responded well to treatment, and extubation was successfully performed. After 10 days of hospitalization, she started complaining of decreased visual acuity in both eyes (OU), being referred to ophthalmological evaluation.

At presentation, her best corrected visual acuity (BCVA) was 20/60 in the right eye (OD) and 20/50 in the left eye (OS). Slit-lamp examination showed no anterior segment inflammation in both eyes (OU). The intraocular pressure was 14 mmHg bilaterally. Fundoscopy showed reddish-brown petaloid macular lesions in both eyes. Near-infrared imaging demonstrated dark images in the same topography (Fig. 1), and spectral-domain optical coherence tomography (SD-OCT) showed thinning of the outer nuclear layer (ONL) and disruption of the photoreceptor inner and outer segments (Fig. 2). Based on these findings and clinical history, a diagnosis of acute macular neuroretinopathy was made. She was followed for 18 months, during which her BCVA improved to 20/40 in both eyes. Final fundoscopy and tomography findings are shown in Fig. 3.

Fig. 1.

Right eye (A) and left eye (B) fundus and near-infrared reflectance. Fundoscopic evaluation showing wedge-shaped lesions toward the fovea in a petaloid configuration (red arrow). NIR showing dark or gray lesions, with well-demarcated margins in both eyes (red arrow). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2.

Optical coherence tomography at presentation of OD (A) and OS (B) showing hyperreflective plaque at the level of OPL/ONL (white rectangles).

Fig. 3.

Fundoscopy of the right (A) and left (B) eyes after 18 months of follow up, showing partial improvement of the petaloid macular image, which continues to be more evident using NIR (red arrows) (C and D). OCT showing residual hyperreflectivity at the level of OPL/ONL in OD (E) and OS (F) (white rectangle). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

3. Discussion

AMN is a rare condition primarily affecting women in the reproductive age group. The largest review on the topic, conducted by Bhavsar, analysed 156 eyes from 101 patients, of whom 80 % were female, with over half in their third decade of life.

Patients with AMN typically present with paracentral scotomas, decreased visual acuity, floaters, and metamorphopsia. At presentation, visual acuity (VA) is 20/40 or better in 80 % of cases, although outcomes may vary.³ Persistent scotomas are reported in more than 50 % of patients.²

The typical fundus reveals a petaloid, oval, teardrop, or horseshoe-shaped reddish-brown to orange lesion, centered at the fovea. A minority of patients may have a normal-appearing fundus in which near-infrared imaging is essential to detect the retinal lesion.

Diagnosis relies on multimodal imaging. Near-Infrared reflectance shows dark lesions with well-defined margins. Fundus autofluorescence (FAF) is typically unremarkable, with some cases showing mild hypoautofluorescence corresponding to the clinically evident lesion. Fluorescein angiography and indocyanine green angiography (ICGA) are usually normal, but may be useful in excluding other causes of acute vision loss, such as white dots syndromes.

SD-OCT commonly reveals early hyperreflective plaques at the interface of outer plexiform layer (OPL) and outer nuclear layer (ONL), associated with disruptions of ellipsoid zone (EZ) and interdigitation zone (IZ). In most cases, attenuation of the EZ/IZ resolves over time, with persisting ONL as the main residual finding. OCT is considered the most sensitive diagnostic tool for AMN: in the largest review, 98.7 % of patients had one or more OCT abnormalities, compared to 73.7 % on visual field testing.² Multifocal electroretinogram (mERG) may show diminished amplitudes or diminished implicit time, while full field ERG is usually normal.² Visual field reveals paracentral scotomas.

This condition is bilateral in more than 50 % of patients,² often following a flu-like illness of fever. Other associations include oral contraceptives use – even though some considers it as a confusing factor, as most patients are women of childbearing age³; sympathomimetics agents, trauma, dehydration, dengue fever,⁴ anemia, ulcerative colitis, thrombocytopenia, leukemia,⁵ and caffeine intake. More recently, links with COVID-19 infection and vaccination have been described.^6,7

The exact etiology of AMN remains uncertain. While infectious and inflammatory mechanisms have been proposed, current evidence favours a vascular hypothesis. The retina is supplied by a dual circulation: retinal capillary plexus, - composed by superficial and deep capillary plexus, the last one being composed by the intermediate capillary plexus (ICP), located on the inner boundary of inner nuclear layer (INL), bordering the inner plexiform layer (IPL); and the deep capillary plexus (DCP), located on the outer boundary of INL, bordering the outer plexiform layer (OPL) – and a choroidal circulation. Given that AMN lesions localize at the level of OPL and ONL, ischemia of the DCP is considered a likely pathophysiologic mechanism. The frequent finding of normal FAF supports this, as the retinal pigment epithelium remains unaffected.

The advent of OCT angiography (OCT-A) has provided further insights into AMN, as FA is not able to detect the flow in DC, OCT-A studies have shown reduced perfusion in both DCP and the choriocapillaris (CC) within AMN lesions, reinforcing the vascular etiology.⁸

Differential diagnosis includes the white dots syndromes and paracentral acute middle maculopathy (PAMM). The latter is defined by hyperreflective plaque at the level of INL, instead of OPL/ONL in AMN.

Although AMN is well-described in adults, paediatric cases remain rare. Recent case reports describe AMN in children following viral illness, including SARS-CoV-2 infections.^9,10 These cases underscores the importance of considering AMN in the differential diagnosis of visual disturbances in paediatric patients, especially when associated with systemic infections. Also, the diagnosis may be delayed in children due to their limited ability to describe visual symptoms, such as scotomas.

EBV is a highly prevalent virus, infecting up to 95 % of the global population.¹¹ It belongs to the Herpesviridae family, and is usually transmitted by contact with oral secretions. Primary infection in children is common, and often asymptomatic. However, it can cause infectious mononucleosis (IM), with self-limited symptoms including fever, fatigue, hepatosplenomegaly, and cervical lymphadenopathy. Neurological manifestations occur in up to 18 % of patients,¹² and include: meningitis, cerebellar ataxia, acute disseminated encephalomyelitis (ADEM), transverse myelitis, Guillain-Barré syndrome, Bell's palsy, and encephalitis.¹³ The Herpesviridae family is well known for its central nervous system (CNS) pathogenicity, and despite its scarcity, EBV encephalitis is the third most common Herpesviridae encephalitis – only after herpes simplex and varicella zoster – and the seventh most frequent cause of infectious encephalitis,¹¹ being responsible for 2–9.7 % of children with encephalitis.¹² Diagnosis is made by serology and CSF evaluation. Computed tomography scan is usually normal or may demonstrate mild edema, while magnetic resonance imaging (MRI) shows multiple foci of T2-weighted or FLAIR hyperintensity in the hemispheric cortex, brainsteam, bilateral thalami, and basal ganglia, as EBV has tropism for the deep nuclei.¹¹ There is no standard treatment for this condition, however, acyclovir, steroids, and intravenous immunoglobulins can be options. The outcome is usually based on the involved region, and sequelae are more frequent with thalamic involvement.¹³

4. Conclusions

Acute macular neuropathy is a rare retinal condition characterized by paracentral scotomas and mild visual impairment, with variable degrees of recovery. Although it is mostly associated with flu-like illness and hormonal contraceptive use, other potential triggers include caffeine intake and viral infection, such as dengue, COVID-19, and, as illustrated in this case, EBV. Near-infrared reflectance and spectral-domain OCT is the most sensitive diagnostic tools, as they are capable of detecting subtle retinal changes even when the fundus appears normal on clinical examination.

CRediT authorship contribution statement

Daniella Socci da Costa: Methodology, Investigation, Conceptualization. Raul N.G. Vianna: Formal analysis, Data curation, Conceptualization. Remo Turchetti Moraes: Formal analysis, Data curation, Conceptualization. Gilberto dos Passos Junior: Formal analysis, Data curation, Conceptualization. Aluisio Rosa Gameiro Filho: Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization.

Patient consent

Written consent to publish potentially identifying information, such as case details and photographs, was obtained from the patient's legal guardian.

Claim of priority

After conducting a literature review in August/2024 utilizing PubMed and Google Scholar, using the keywords “acute macular neuroretinopathy”, “AMN”, “Epstein Barr”, “Epstein Barr virus”, “EBV”, “encephalitis” “Epstein Barr encephalitis” “EBV encephalitis” we did not find any previous reports of AMN associated with EBV encephalitis, such as in our case.

Intellectual property

We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, concerning intellectual property. We confirm that we have followed the regulations of our institutions concerning intellectual property.

Authorship

All authors attest that they meet the current ICMJE criteria for authorship. We attest that all authors contributed significantly to the creation of this manuscript, each having fulfilled criteria as established by the ICMJE.

We confirm that the manuscript has been read and approved by all the named authors.

Funding

No funding was received for this work.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.