This case is submitted by Drs. Javier Montero-Hernández, Lidia Remolí-Sargues, and Enrique Cervera-Taulet, Department of Ophthalmology, Consorcio Hospital General Universitario of Valencia, Valencia, Spain; Dr. Roberto Gallego-Pinazo, Macula Department, Oftalvist Clinic, Valencia, Spain; and Dr. Brandon J. Lujan, Casey Eye Institute, Oregon Health and Science University, Portland, OR; and Commented by Drs. Oleg Alekseev and Eleonora M. Lad (Durham, NC). Case Report A 15-year-old adolescent girl presented with blurry vision in her right eye (OD) for a few weeks. The patient denied any history of eye disease, and her medical history was unremarkable, except for having received the second dose of the human papillomavirus vaccine 3 months before the onset of symptoms. Best-corrected visual acuity (BCVA) was 20/30 Snellen equivalent in the right eye (OD) and 20/20 Snellen equivalent in the left eye (OS). Anterior segment examination was normal, and no inflammatory cells were observed in the anterior chamber or the vitreous in either eye. Fundus examination of the right eye showed granular retinal pigment epithelium changes in the central macula (Figure 1A). Fundus examination of the left eye showed an abnormal foveal reflex (Figure 2A). These changes were more evident in the infrared imaging. Infrared imaging in the right eye revealed multiple punctate lesions grouped centripetally (Figure 1B). Infrared imaging in the left eye demonstrated rounded perifoveal petaloid lesions (Figure 2B). All these changes were not prominently seen on blue light fundus autofluorescence (Figures 1C and 2C).Fig. 1.: Multimodal imaging of the right eye. A. Color fundus imaging showed granular retinal pigment epithelium (RPE) changes in the central macular. B. These pigmentary changes were more evident in the infrared (IR) image and were grouped and centered in the macula. C. Blue fundus autofluorescence revealed similar changes but not as evident as in the infrared. D. Fluorescein angiography, in which we observed a slight irregularly shaped screen defect in the fovea. E. Indocyanine green angiography in late frames was normal. F. Optical coherence tomography showed a preserved foveal pit, with cysts in the inner nuclear layer and the outer nuclear layer. In addition, OCT demonstrated hyperreflective columns with an oblique trajectory from the outer plexiform layer to the retinal pigment epithelium layer, at both sides of the fovea. Moreover, the outer retinal layers were highly attenuated, being difficult to differentiate between the outer limiting membrane, the EZ, and the IZ. INL, inner nuclear layer; IZ, interdigitation zone; ONL, outer nuclear layer.Fig. 2.: Multimodal imaging of the OS. A. Color fundus imaging showed an abnormal foveal reflex. B. The infrared image revealed round and grouped perimacular lesions. C. Blue fundus autofluorescence was unremarkable. D. Fluorescein angiography (FA) illustrated a slight alteration in the inferior–temporal region of the macula but without signs of vasculitis or aneurysmal lesions. Moreover, we observed a light staining of the intraretinal cysts in the FA. E. Indocyanine green angiography showed a subtle increase of the staining in the temporal side of the macula. F. Optical coherence tomography revealed hyperreflective columns, which start from the outer plexiform layer, crossing the external limiting membrane, and depressing and attenuating the EZ. The direction of these columns reminded us the arrangement of the Henle fibers. In addition, some cysts could be seen in the inner nuclear layer. INL, inner nuclear layer; IR, infrared.Fluorescein angiography and indocyanine green angiography revealed a perfused capillary network without exudation, vasculitis, or ischemia. Fluorescein angiography demonstrated a slight hypofluorescence in the fovea of the right eye and mild staining of the cystic spaces in the fovea of the left eye (Figures 1 and 2, D and E). Optical coherence tomography (OCT) in the right eye showed a preserved foveal pit with cysts in the inner nuclear layer and the outer nuclear layer, and hyperreflective columns with an oblique trajectory involved the outer nuclear layer, variably affected the Henle fiber layer, and terminated at a disrupted ellipsoid zone (EZ) and interdigitation zone on both sides of the fovea (Figure 1F). In the left eye, the OCT revealed small cystic changes in the inner nuclear layer, along with fewer hyperreflective columns that seem to affect the perifoveal outer nuclear layer, the Henle fiber layer, and the interdigitation zone, primarily. In addition, we appreciated a slight disruption, attenuation, and outward bowing of the EZ in that area (Figure 2F). A complete laboratory evaluation was performed, including complete blood count, C-reactive protein, renal and liver function tests, and blood coagulation test. A posterior uveitis panel study was conducted to exclude noninfectious and infectious diseases and include antinuclear antibodies, antineutrophil cytoplasmic antibodies, antiphospholipid antibodies, onconeuronal antibodies, interferon-gamma release assay testing (QuantiFERON Gold), syphilis serology, toxoplasma serology, Bartonella spp. serology, HIV serology, yellow fever serology, dengue serology, Zika serology, Epstein–Barr virus serology, cytomegalovirus serology, and hepatitis viruses serology (A, B, and C). Furthermore, we made a hormonal study, and we evaluated tumor markers. All the studies were within normal limits or negative. Treatment with oral corticosteroids 0.5 mg/kg/day for 2 weeks was initiated. However, the patient experienced no improvement and subsequently discontinued to avoid potential side effects. The possibility of treating the patient with an intravitreal dexamethasone implant was considered, but in agreement with the patient and her family, we decided to just observe. The subsequent evolution of the right eye was a slight worsening during the first 6 months, followed by a progressive normalization of both the intraretinal fluid and the outer retinal layers at 18 months of follow-up. In the left eye, however, first, we observed a worsening until adopting an appearance similar to the image observed in the right eye at its peak (specifically at 17 months of follow-up), and then, it stabilized and progressed favorably toward a practically complete normalization of the retina. Best-corrected visual acuity dropped just as OCTs showed their worst image of edema to 20/40 Snellen equivalent in both eyes, and at the patient's final visit, when OCT showed the resolution of the intraretinal fluid, there was marked atrophy of the outer nuclear layer, obliquely, oriented hyperreflectivity of the Henle fiber layer in both eyes, perifoveal EZ and interdigitation zone attenuation in the left eye, and nasally only in the right eye (Figure 3). Best-corrected visual acuity had improved to 20/25 and 20/20 Snellen equivalent.Fig. 3.: Optical coherence tomography of both eyes during the follow-up. In the right half, we can see the images of the right eye, and in the left half, we can visualize the images of the left eye. In the upper line, the “en face” images of photoreceptor slab can be seen, and the lower lines correspond to the optical coherence tomography B scan. These images allow us to see the different stages that both eyes go through asynchronously. Finally, it seems that the retina of both eyes has been restructured, with an almost normalized image.We have a case of unknown etiology, in which known infectious, autoimmune, or toxic etiologies have been excluded. In this case, the use of corticosteroids did not seem to be effective in both anatomical and functional terms. The differential diagnosis has been complex because the lesions have not followed a previously reported pattern and have evolved over time. The similarity of the OCT findings of hyperreflective columns and hyporeflective perifoveal lesions on infrared imaging led to consideration of acute macular neuroretinopathy. However, the nonpetaloid appearance of the lesions, the presence of retinal fluid, and the time course of progression are not consistent with this diagnosis. With punctate lesions affecting the outer retina, laser pointer maculopathy was also considered. However, there was no exposure to photic energy, and the regular distribution and time course of lesions evolution also argued against the diagnosis. We performed serological studies to rule out autoimmune retinopathy (AIR) and a gynecological examination to exclude neoplasms or other gynecological disorders that could be related. Furthermore, the study of posterior uveitis as well as lack of vitritis, foci of neuroretinitis, or vasculitis made us rule out some of the known causes of posterior uveitis, such as multiple evanescent white dot syndrome, multifocal choroiditis, or punctate internal choroiditis. We do not know whether the second dose of the human papillomavirus vaccine that was given 3 months before the symptom onset could have played a role in this pathology, because no previous publications in the literature exist. However, it remains plausible hypotheses, given our patient is healthy, free of toxic habits, and with no relevant family or medical history. Nevertheless, we have no evidence to support this or another hypothesis as the cause of the pathology that our patient suffered. Drs. Oleg Alekseev and Eleonora M. Lad (Durham, NC) Montero-Hernández et al presented an intriguing case of a 15-year-old adolescent girl with binocular cystoid macular edema (CME) of unknown etiology. The patient with an otherwise unremarkable ocular and medical history presented with blurred vision 3 months after receiving the human papilloma virus (HPV) vaccine. Optical coherence tomography revealed parafoveal EZ disruption and central cystoid fluid corresponding to mild staining of fluorescein angiography. Cystoid macular edema subsequently worsened over the course of 18 months, plateaued, and then spontaneously resolved. Progression was asynchronous, with OCT findings and vision decline in the left eye lagging behind those in the right eye. The lowest BCVA recorded during the course of disease was 20/40 Snellen equivalent in both eyes, corresponding with the peak of CME on OCT. The patient underwent an extensive workup for infectious, inflammatory, toxic, and paraneoplastic etiologies, which yielded negative outcomes. She received a 2-week-long treatment with 0.5 mg/kg/day oral corticosteroids, which was discontinued because of the absence of clinical improvement. At the patient's final visit, CME was fully resolved and BCVA almost completely normalized. However, OCT showed only partial recovery of the outer retinal layers, with residual parafoveal EZ loss in both eyes. An important differential diagnosis appropriately considered by the authors in the workup of this patient was AIR, an often overlooked cause of CME. The clinical presentation of AIR is notoriously variable,1 requiring a high degree of clinical suspicion to establish the diagnosis. Autoimmune retinopathy is a masquerader that can mimic conditions such as retinitis pigmentosa and white dot syndromes. Autoimmune retinopathy is typically binocular but asymmetric,2 a characteristic that was notably observed in this patient. Although CME is certainly not a required feature to make a diagnosis of AIR, it is frequently present in this condition and is considered to be a marker of more aggressive disease.3 Autoimmune retinopathy classically involves damage to the outer retinal layers, particularly loss of peripheral EZ with a remaining central island of photoreceptor preservation.4 For this reason, AIR should always be included in the differential diagnosis of retinitis pigmentosa.5 The disease presentation demonstrates wide phenotypic variability, and early cases of AIR may show minimal or atypical patterns on imaging studies. Thus, AIR should also be considered in the differential diagnosis of pericentral retinitis pigmentosa, macular dystrophies, posterior uveitis, and toxic retinopathies, such as those due to hydroxychloroquine or pentosan. Full-field electroretinography is a useful modality to diagnose and monitor AIR,2 and Goldman visual field perimetry is often used to monitor the progression of disease and response to treatment. Despite these supportive functional modalities, definitive diagnosis of AIR is complex and remains a contested issue, mostly because of the lack of standardized testing modalities and established diagnostic criteria.6 This makes AIR a diagnosis of exclusion in most clinical practice settings. Serum testing for retinal autoantibodies has improved significantly and currently includes a panel of well-established retinal targets. Nevertheless, this panel is by no means exhaustive, although it continues to expand because new targets are validated. Two additional approaches provide greater sensitivity in diagnosing AIR: 1) immunohistochemistry analysis of serum reactivity against human retinal sections and 2) Western blot analysis of serum reactivity against human retinal lysates. Because these diagnostic tests are target-agnostic, they are capable of detecting the presence of antiretinal autoantibodies even in those patients who may otherwise have an initially negative autoantibodies panel test. However, these results must be interpreted with caution and as part of a greater clinical image because of the lack of specificity inherent to these tests. Thus, it is possible that the patient presented in this case could have fallen into this category and may have displayed autoreactivity on further immunohistochemistry and Western blot testing. Of particular interest in this case is the temporal proximity of the onset of the patient's visual symptoms to her HPV vaccination. Although HPV vaccination has not been reported as a cause of CME, this possibility cannot be excluded. Although this etiology remains to be formally established, in our clinics, we have anecdotally observed several cases of new onset or worsening autoimmune or inflammatory retinal pathology after an immune challenge, such as vaccination or contracting an infectious illness (unpublished data). Published case reports have documented patients developing uveitis after the administration of most known vaccines, including the HPV vaccine.7,8 The presence of uveitis may or may not be complicated by CME; however, this patient was noted to have the absence of anterior chamber and vitreous cells and was not reported to have any other features to suggest a uveitic process, thus making this scenario far less likely. Yet, it remains possible that the HPV vaccination may have served as an immunologic insult to trigger the development of AIR, as discussed above. Editor's Note Drs. Montero-Hernandez, Remoli-Sarques, Gallego-Pinazo, Cervera-Taulet, and Brandon J. Lujan presented a 15-year-old adolescent girl with bilateral CME and no known etiology. Her blurred vision occurred 3 months after receiving the HPV vaccine. Drs. Alekseev and Lad have consulted on this case and provided an analysis. They began by ignoring the bait of a direct association between CME and the HPV vaccine and concentrated on the possibility that autoimmune retinopathy might have caused the cystic change. Autoimmune retinopathy may mimic a variety of conditions, including retinitis pigmentosa and white dot syndromes, and frequently results in cystoid edema. They made the point that AIR is a diagnosis of exclusion and that serum testing for retinal autoantibodies is not fool-proof. Our consultants point out that immunochemistry analysis of serum reactivity against human retinal sections and Western blot analysis of serum reactivity against human retinal lysates provide great sensitivity in diagnosing AIR. They opined that these diagnostic techniques may detect the presence of antiretinal autoantibodies in those who have an initial negative autoantibody panel test. The issue of vaccine-related adverse reactions has been with us for some time, and a healthy degree of caution and skepticism is warranted. It is a tricky business trying to prove a symptom or sign is causative rather than coincidence. Drs. Alekseev and Lad approached this by stating the possibility that HPV vaccination has caused CME cannot be ruled out, although it has not been reported previously. They noted anecdotally, however, that they have seen cases of new or worsening autoimmune or inflammatory retinal pathology after an immune challenge. They cited papers documenting uveitis after vaccine administration, but they pointed out that this patient had no cells in the anterior chamber or vitreous. However, they left the door open for the HPV to serve as a trigger for the development of autoimmune retinopathy. We thank our presenters for their case, and Drs. Alekseev and Lad for their measured and sober analysis.