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■ C L I N I C A L S C I E N C E ■

Multimodal Imaging of Punctate Outer Retinal Toxoplasmosis Nicolas A. Yannuzzi, MD; Orly Gal-Or, MD; Elie Motulsky, MD, PhD; Swarup S. Swaminathan, MD; Emmett T. Cunningham Jr., MD, PhD, MPH; Janet L. Davis, MD; Yale Fisher, MD; Giovanni Gregori, PhD; Philip J. Rosenfeld, MD, PhD; K. Bailey Freund, MD

BACKGROUND AND OBJECTIVE: To describe the mul-timodal imaging characteristics associated with punctate outer retinal toxoplasmosis (PORT).

PATIENTS AND METHODS: Multicenter, retrospec-tive, observational case series of three patients who presented with PORT. Multimodal imaging was reviewed including optical coherence tomography (OCT), fundus autofluorescence, optical coherence tomography angiography, and conventional dye-based angiography.

RESULTS: Patient ages ranged from 13 years to 55 years. Each patient had multiple white, punctate outer retinal lesions in the affected eye at initial diagnosis. OCT showed both inner and outer reti-nal changes, including disruption of the ellipsoid and interdigitation zones and retinal pigment epi-thelium/Bruch’s membrane complex, as well as punctate, preretinal, hyperreflective lesions at the vitreoretinal interface, which regressed with treat-ment.

CONCLUSION: Multimodal imaging is useful in diag-nosing and monitoring treatment response in PORT, an uncommon presentation of ocular toxoplasmo-sis that must be differentiated from white dot syn-dromes or other causes of unilateral retinitis.

[Ophthalmic Surg Lasers Imaging Retina. 2019;50:281-287.]

INTRODUCTION

Although classic ocular infection by toxoplasmo-sis initially presents as focal retinochoroiditis and is associated with prominent vitreous cell and haze, the variant of punctate outer retinal toxoplasmosis (PORT), first described by Doft and Gass,1,2 is charac-terized by multifocal gray-white lesions at the level of the deep retina and retinal pigment epithelium (RPE) with minimal vitritis. With treatment, these lesions were described to resolve as fine, granular white dots, which were hypothesized to be outer retinal gliotic scars or infectious cysts. The purpose of the current report was to describe three cases of unilateral PORT using multimodal imaging, including swept-source optical coherence tomography (SS-OCT), to localize the location of the lesions on the surface of and with-in the neural retina.

PATIENTS AND METHODS

This study was approved by each governing insti-tutional review board at the three separate study cen-ters. It complies with the Health Insurance Portability and Accountability Act of 1996 and follows the tenets of the Declaration of Helsinki. Patients were evalu-ated at three centers. Multimodal imaging included color fundus photography, spectral-domain OCT an-giography (SD-OCTA) and SS-OCTA, fundus autoflu-orescence (FAF), and fluorescein angiography (FA). The diagnosis of PORT was made based on clinical findings, positive serology, and a favorable response to treatment.

From Bascom Palmer Eye Institute/University of Miami Miller School of Medicine, Department of Ophthalmology, Miami (NAY, EM, SSS, JLD, YF, GG, PJR); Vitreous Retina Macula Consultants of New York, New York (OGO, YF, KBF); Rabin Medical Center, Petach-Tikva, Israel (OGO); the Department of Ophthal-mology, California Pacific Medical Center, San Francisco (ETC, KBF); the Department of Ophthalmology, Stanford University School of Medicine, Stanford, California (ETC, KBF); The Francis I Proctor Foundation, UCSF School of Medicine, San Francisco (ETC, KBF); West Coast Retina Medical Group, San Francisco (ETC, KBF); and the Department of Ophthalmology, New York University School of Medicine, New York (KBF).

Originally submitted August 18, 2018. Revision received August 18, 2018. Accepted for publication November 6, 2018.Supported by the Macula Foundation, New York.Dr. Davis has received personal fees from Allergan and Abbvie, and grants from EyePharma and Nightstar Therapeutics outside the submitted work. Dr. Gregori received grants from Carl Zeiss Meditec during the conduct of the study. Dr. Freund is a consultant for Optovue, Allergan, Heidelberg Engineering, Zeiss, and Novartis and receives research support from Genentech/Roche. Dr. Rosenfeld receives research support from Carl Zeiss Meditec and the Salah Foundation; is a consultant for Boehringer-Ingelheim, Carl Zeiss Meditec, Chengdu Kanghong Biotech, Genentech, Healios K.K, F. Hoffmann-La Roche Ltd., Isarna Pharmaceuticals, MacRegen, Ocudyne, Ocunexus Therapeutics, Tyrogenex, and Unity Biotechnology; and has equity interests in Apellis, Digisight, and Ocudyne. The remaining authors report no relevant financial disclosures.Address correspondence to K. Bailey Freund, MD, Vitreous Retina Macula Consultants of New York, 460 Park Avenue #5, New York, NY 10022; email: kbfnyf@aol.com.doi: 10.3928/23258160-20190503-04

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RESULTS

Case SummariesThe medical records and multimodal imaging of

three patients diagnosed with and treated for PORT were reviewed. Ages ranged from 13 years to 55 years. All patients had unilateral findings of multiple punc-tate, white outer retinal lesions at initial diagnosis. Two of three patients were noted to have focal retino-choroidal scars at initial diagnosis. All cases involved the fovea. All lesions were hyperfluorescent on FA and were associated with punctate hypoautofluo-rescence on FAF. OCT showed both inner and outer retinal changes with disruption in the photoreceptor bands and retinal pigment epithelium (RPE), as well as punctate preretinal hyperreflective lesions that fad-ed with treatment. SD-OCTA and SS-OCTA showed enlargement of the foveal avascular zone (FAZ).

Case 1: A 21-year-old woman with unremarkable medical and ocular histories presented with an acute

decrease in visual acuity (VA) and vitreous floaters in her right eye. She was born in Cuba and immigrated to the United States as a child. She had a cat in her residence. Best-corrected VA (BCVA) was 20/100 in the right eye and 20/25 in the left eye. Slit-lamp ex-amination showed quiet anterior chambers and 2+ vitreous cells in her right eye. Fundus examination revealed mild temporal pallor of the optic nerve and white, punctate macular deposits (Figure 1A). FA showed multiple perifoveal areas of punctate leak-age, as well as mild staining at the nerve (Figure 1B). FAF showed multifocal areas of discrete hypoauto-fluorescence (Figure 1C). SD-OCT showed focal dis-ruption of the ellipsoid zone (EZ) and interdigitation zone (IZ), as well as hyperreflective superficial retinal deposits and inner retinal involvement (Figure 1D) that largely resolved and became inactive following treatment (Figure 1E). SS-OCT demonstrated vitreous cells and multiple discrete hyperreflective lesions at the vitreoretinal interface with foveal thinning

Figure 1. Multimodal imaging of the right eye in a 21-year-old woman with punctate outer retinal toxoplasmosis. (A) Color fundus photo-graph shows white, punctate, perifoveal retinal lesions. (B) Ultra-widefield fluorescein angiogram shows hyperfluorescence of the retinal lesions and optic nerve staining. (C) Fundus autofluorescence demonstrates punctate areas of hypoautofluorescence. The green line has been added to show the position of the B-scans in (D) and (E). (D) Optical coherence tomography shows findings of focal disruption of the ellipsoid and interdigitation zones. Within the hyporeflective pre-macular bursa, there are hyperreflective superficial retinal deposits that have largely resolved and become inactive (E) following treatment.

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and focal disruption of the EZ and IZ (Figure 2A-C). QuantiFERON-TB Gold (QIAGEN, Germantown, MD), angiotensin converting enzyme, rapid plasmin reagin, and fluorescent treponemal antibody absorbed returned negative. The patient was treated initially with oral prednisone (30 mg/day) for 1 week without clinical improvement as a diagnosis of an inflamma-tory white dot syndrome was considered. Additional laboratory investigations revealed negative Bartonel-la henselae and B. quintana immunoglobulin G (IgG) and IgM titers, positive Toxoplasma gondii IgG titers, and negative IgM titers. The patient was then treated with double-strength trimethoprim sulfamethoxazole twice daily and clindamycin 300 mg three times dai-

ly, and the oral corticosteroids were continued. One month after initiation of oral antibiotics, vision im-proved to 20/80. SD-OCT showed restoration of the EZ (Figure 1E). SS-OCT showed a resolution of the deposits at the vitreoretinal interface with now inac-tive lesions but resultant foveal thinning and atrophy (Figures 2D-2F).

Case 2: A 13-year-old girl with unremarkable med-ical and ocular histories presented with reduced vi-sion in her right eye for 3 months. BCVA was 20/250 in the right eye and 20/20 in the left eye. There was a mild afferent pupillary defect in the affected right eye. Slit-lamp examination showed no anterior chamber or vitreous cells. Fundus examination of the right eye

Figure 2. Swept-source optical coherence tomography (SS-OCT) of the right eye in a 21-year-old woman with punctate outer retinal toxoplasmosis (same patient as shown in Figure 1) at initial presentation (A-C) and after treatment (D-F). (A) En face SS-OCT segmented at the level of the vitreoretinal interface shows an attached vitreous with punctate hyperreflective vitreous cells found mostly outside of the central hyporeflective pre-macular bursa. Within the bursa, there are hyperreflective superficial pre-retinal deposits (yellow arrows in A-D). (B) Structural OCT B-scan corresponding to the blue line in A. The dashed magenta lines show the segmentation slab. Adjacent to the focal preretinal deposits was also a larger, near-full-thickness hyperreflective lesion. (C) Structural OCT B-scan corresponding to the blue line in A demonstrates the location of the deposits at the vitreoretinal interface. (D) En face SS-OCT image segmented at the level of the vitreoretinal interface shows a reduction in superficial retinal deposits and partial resolution of the active lesions. (E) Structural OCT B-scan corresponding to the blue line in D. The dashed magenta lines show segmentation boundaries. (F) Structural OCT B-scan corresponding to the blue line in D shows inactive disease with a decrease in size of the lesions after treatment. There is thinning of the inner nuclear layer at the prior site of the lesion with an upwardly contracted outer plexiform layer.

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revealed a retinochoroidal scar in the superior macula with surrounding retinal whitening and punctate and superficial white lesions. There was mild temporal pallor of the optic nerve (Figure 3A). SD-OCT through the fovea showed hyperreflective round discrete le-sions at the inner fovea with loss of the EZ and IZ and obscuration of the RPE (Figure 3B). There were mid-posterior vitreous cells visible by OCT. FA showed hypofluorescence in the area of the retinochoroidal

scar surrounded by speckled hyperfluorescence (not shown). A diagnosis of diffuse unilateral subacute neuroretinitis (DUSN) was suspected and the patient was treated with albendazole (Albenza; Impax Labo-ratories, Fort Washington, PA) for 1 month without improvement. No worm was visualized on serial ex-aminations. Serologies for T. gondii revealed positive IgG titers. The patient was treated with trimethoprim sulfamethoxazole and oral prednisone taper. Three

Figure 3. Recurrent punctate outer retinal toxoplasmosis in the right eye of a 13-year-old girl. (A) Color fundus photograph at initial pre-sentation shows a retinochoroidal scar and several small, white parafoveal lesions. (B) Spectral-domain optical coherence tomography (SD-OCT) shows the foveal lesions involving the inner retina with underlying disruption of the ellipsoid zone (EZ) and interdigitation zone (IZ) and focal splitting of the retinal pigment epithelium (RPE)/Bruch’s membrane complex. (C) Color photograph shows progression of the parafoveal lesions 3 years after initial presentation. (D) SD-OCT shows apparent migration of the inner retinal lesions to the vitreo-retinal interface. (E) Progression of the macular lesions 5 years after initial presentation shows evolution into full-thickness retinitis. (F) SD-OCT shows disorganized and edematous inner retinal layers nasal to the fovea with foveal thinning and mild overlying vitritis as well as choroidal thickening and bowing and splitting of the RPE/Bruch’s membrane complex, evolving into a near-full-thickness retinitis. (G) Color photograph at most recent follow-up shows macular atrophy with pigment clumping. (H) SD-OCT shows atrophic scarring at the foveal with central loss of the EZ and IZ and subretinal hyperreflective material.

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years later, the patient developed more punctate white lesions (Figure 3C), and SD-OCT showed su-perficial hyperreflective deposits at the fovea along with mild disruption of the EZ and focal splitting of the RPE/Bruch’s membrane complex (Figure 3D) and was treated for recurrent toxoplasmic retinocho-roiditis with trimethoprim/sulfamethoxazole double strength twice daily for 4 weeks. Five years after ini-tial presentation, the patient developed more conflu-ent white macular lesions. SD-OCT showed thicken-ing of the perifoveal retina, vitreous cells, and foveal thinning consistent with an evolution into full-thick-ness retinitis (Figures 3E and 3F), and the patient was again treated with trimethoprim/sulfamethoxazole double strength twice daily for 4 weeks. The choroid appeared mildly thickened and there was partial an-terior bowing of the RPE/Bruch’s membrane complex. At last follow-up 6 years after initial presentation, the perifoveal lesions had progressed to atrophy with pig-

ment clumping. There was an atrophic appearance on SD-OCT with diffuse photoreceptor loss, a mild epiretinal membrane, and prominent foveal thinning (Figures 3G and 3H). FAF at last follow-up revealed diffuse hypoautofluorescence associated with loss of the RPE, which correlated with the appearance on en face SD-OCT at the level of EZ-RPE (Figure 4). BCVA at last examination was 20/160 in the affected eye.

Case 3: A 55-year-old woman with a history of hyperopia and an unremarkable medical history presented with decreased vision in her left eye for 2 days. Travel history included a recent trip to South Africa. BCVA was 20/20 in the right eye and 20/50 in the left eye. Slit-lamp examination in the affected left eye showed no anterior chamber cells and a 1+ vitreous cells. Fundus examination of the left eye re-vealed perifoveal white lesions, as well as a larger atrophic lesion in the inferior macula (Figure 5A). FAF showed mottled hypoautofluorescence perifo-

Figure 4. Multimodal imaging of a 13-year-old girl with outer retinal toxoplasmosis in her right eye (same patient as shown in Figure 3). (A) Fundus autofluorescence shows multiple areas of hypoautofluorescence corresponding to retinal pigment epithelium (RPE) loss. (B) En face spectral-domain optical coherence tomography (SD-OCT) segmented to the level of photoreceptor inner and outer segments and RPE and corresponding structural SD-OCT B-scan (C) demonstrate atrophy of the outer retina. Red segmentation lines show the level of the slab presented in panel B.

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veally and a discrete area of hypoautofluorescence in the inferior macula (Figure 5B). FA demonstrated hyperfluorescence perifoveally and of the inferior macula lesion, as well as late leakage of the optic nerve (Figures 5C). SD-OCTA of the central macula showed an enlarged foveal capillary ring (Figures 5D and 5E). At initial presentation, SD-OCT of the left eye revealed disruption of the EZ and IZ with hyper-reflectivity at the level of the RPE and generalized foveal thinning (not shown). Enhanced depth imag-

ing OCT (EDI OCT) showed a mildly thickened cho-roid (not shown). Blood serology returned positive for T. gondii IgG and IgM. The patient was treated with double-strength trimethoprim sulfamethoxa-zole twice daily and azithromycin. SD-OCT at 6 months showed superficial punctate hyperreflective deposits, mild vitreous cells, and continued hyper-reflectivity at the fovea with generalized atrophy and loss of the EZ and IZ (Figures 5F and 5G). VA re-mained stable at 20/50.

Figure 5. Multimodal imaging of a 55-year-old woman with punc-tate outer retinal toxoplasmosis in her left eye. (A) Color fundus photograph shows a retinocho-roidal scar in the inferotemporal macula (arrow) as well as mul-tiple punctate, white perifoveal lesions. (B) Fundus autofluores-cence demonstrates hypoauto-fluorescence of the retinochoroi-dal scar (arrowhead) and mottled perifoveal hypoautofluorescence. (C) Late arteriovenous phase fluorescein angiogram dem-onstrates a hyperfluorescent window defect corresponding to the inferior lesion, perifoveal staining, and leakage of the op-tic nerve. En face optical coher-ence tomography angiography (top) and structural OCT with flow overlay (bottom, flow shown in red) of the superficial (D) and deep (E) capillary plexuses show a disrupted and enlarged foveal capillary ring. The green line (E, top) shows the location of the OCT B-scans in D and E. The green and red lines (bottom) show the segmentation boundar-ies used for the corresponding en face images. (F) Structural SD-OCT B-scans before and after (G) treatment show foveal thin-ning, vitreous cells, loss of outer retinal bands, a central area of full-thickness retinal disorganiza-tion, and hyperreflective deposits at the vitreoretinal interface.

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DISCUSSION

Twenty-four years after the initial description by Doft and Gass, de Souza and Casella3 described five cases of PORT imaged by time-domain OCT and hypothesized that the outer retinal lesions were a granulomatous im-mune response to infection. The cases described by de Souza et al. showed mild exudation associated with the lesions as they regressed. Of note, the authors felt that the outer retinal variant may represent a successful immune response to disease and might be early patho-logical findings in a spectrum of disease leading to ex-tension of the infectious organism into the inner retina (resulting in punctate inner retinal toxoplasmosis) fol-lowed by fulminant expansion into the inner retina and vitreous (causing the “light in the fog” presentation).

The current report describes the multimodal im-aging characteristics of PORT. All patients had only a mild vitritis, which did not obscure the ophthalmo-scopic details, and punctate, multifocal white lesions, associated, but not contiguous with, a retinochoroidal scar in two of three cases. All three patients displayed angiographic findings of optic nerve leakage and hyper-fluorescence of the active macular lesions. Furthermore, all patients had hyperreflective inflammatory deposits at the vitreoretinal interface that also extended to the in-ner retina and were associated with outer retinal chang-es including disruption of the EZ, IZ, and RPE/Bruch’s membrane complex. One of the three cases showed a chronic and recurrent course, whereas the other two cases showed a moderate response to treatment. How-ever, all three cases, despite appropriate treatment, de-veloped foveal thinning and persistent visual changes. PORT may occasionally be associated with choroidal neovascularization,4 yet none of the three cases in this series had developed choroidal neovascularization at their most recent follow-up.

A report by Lujan5 described a case of PORT where SD-OCT disclosed surrounding intraretinal and subreti-nal fluid at initial presentation that resolved, leaving a retinochoroidal scar with alternating hypertrophy and atrophy of the RPE and a defect in Bruch’s membrane. None of our cases had prominent intraretinal or subreti-nal fluid. With SS-OCT, Chen et al.6 described a case of conventional acute toxoplasmosis chorioretinitis that showed thickening of the posterior hyaloid, vitreous cells emanating from retinal blood vessels, thickening and disorganization of all retinal layers, and increased choroidal thickening under the lesion. SS-OCT was use-ful in the current report to visualize the inflammatory deposits at the level of the vitreoretinal interface. The cells appeared suspended in the formed vitreous out-side of the pre-macular bursa but may have collected at the vitreoretinal interface within the bursa. All of these patients were young and had an attached hyaloid.

Though highly speculative, perhaps the presence of the bursa influences this particular central presentation of toxoplasmosis. Furthermore, these deposits could also potentially be followed to assess for response to treat-ment.

In summary, the current report describes three cases of PORT, an uncommon but important variant of toxo-plasmosis that may masquerade as an idiopathic white dot syndrome or DUSN. For instance, both DUSN and PORT may exhibit multifocal deep inflammatory le-sions: outer retinal in PORT and choroidal in DUSN. PORT also tends to show disruption of multiple retinal layers, whereas DUSN tends to be photoreceptors and RPE/Bruch’s complex. Last, PORT, which is hyper-acute, often produces serous retinal detachment, which is uncommon in DUSN. Other uveitic conditions such as sarcoidosis, tuberculosis, and cat-scratch, may also show overlapping features with PORT.

Multimodal imaging and, in particular, OCT, may be extremely useful in localizing the active lesion and obtaining a diagnosis. The detection of more superficial retinal involvement is pathognomonic of this condi-tion and helps clinicians rule out other diseases such as multifocal choroiditis, punctate inner choroiditis, or DUSN, where there is no superficial retinal involve-ment. It is important to note that although all three cases in this series were consistent with a clinical diagnosis of PORT, as it has been described classically, multimodal imaging revealed that there was evidence of involve-ment and disruption of both outer and inner retinal lay-ers at various points in the disease process.

The lesions in PORT may be small but come to medi-cal attention because of visual symptoms and their mac-ular location. Small scars of this type in other fundus locations might be easily passed over as inconsequen-tial. Despite the subtleties of this clinical presentation, it is important to note that PORT is still treated the same as classically appearing toxoplasmosis and may have a similar response to therapy.

REFERENCES

1. Doft BH, Gass DM. Punctate outer retinal toxoplasmosis. Arch Ophthal-mol. 1985;103(9):1332-1336.

2. Doft BH, Gass JD. Outer retinal layer toxoplasmosis. Graefes Arch Clin Exp Ophthalmol. 1986;224(1):78-82.

3. de Souza EC, Casella AM. Clinical and tomographic features of macular punctate outer retinal toxoplasmosis. Arch Ophthalmol. 2009;127(10):1390-1394.

4. Fujiwara T, Machida S, Hasegawa Y, Tazawa Y. Punctate outer reti-nal toxoplasmosis with multiple choroidal neovascularizations. Retina. 2006;26(3):360-362.

5. Lujan BJ. Spectral domain optical coherence tomography imag-ing of punctate outer retinal toxoplasmosis. Saudi J Ophthalmol. 2014;28(2):152-156.

6. Chen KC, Jung JJ, Engelbert M. Single acquisition of the vitreous, retina, and choroid with swept-source optical coherence tomography in acute toxoplasmosis. Retin Cases Brief Rep. 2016;10(3):217-220.

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