Outer Retinal ToxoplasmosisJOHN D. MATTHEWS, MD, JOHN J. WElTER, MD, PhD

Abstract: Toxoplasma gondii is a neurotrophic organism that affects the neu­rosensory retina in humans. Typical ocular toxoplasmosis involves the innerretina and is associated with marked vitreous reaction. A subset of this clinicalspectrum is characterized by gray-white macular lesions at the level of theouter retina. This outer retinal lesion is associated with little or no vitreousreaction. The authors report five additional cases of outer retinal toxoplasmosis.Recognition of this variation is important; prompt treatment, before serologicconfirmation, resulted in marked visual improvement in all cases. [Key words:ocular toxoplasmosis, retinitis, toxoplasmosis, uveitis.] Ophthalmology 95:941­946, 1988

Ocular toxoplasmosis is a leading cause of posterioruveitis in humans. The clinical ocular presentation ofacute recurrent toxoplasmic retinitis is thought to betypical and varies from small « 1disc diameter [DD]) tomoderate (1-3 DD) inflammatory lesions at the edge ofan old chorioretinal scar to a severe inflammation withan extremely hazy vitreous described as "headlights inthe fog." These lesions usually are accompanied by anoverlying vitritis, leading to the belief that the inner reti­nal layers are the part of the eye primarily involved inocular toxoplasmosis. I

A recent report/ noted a subset of ocular toxoplas­mosis characterized by the presence of multifocal,punctate outer retinal lesions with little or no vitreousinvolvement. Two earlier reports'< described outer reti­nal inflammatory lesions that were considered to be anunusual form of ocular toxoplasmosis. We report fiveadditional cases of outer retinal toxoplasmosis, whichwill verify this form of presentation and further delin­eate its clinical characteristics.

Originally received: November 9, 1987.Revision accepted: February 16, 1988.

From the Southeastern Eye Center, Greensboro, and Retina Associatesand the Eye Research Institute of Retina Foundation, Boston.

Presented at the American Academy of Ophthalmology Annual Meeting,Dallas, November 1987.

Reprint requests to John D. Matthews, MD, Southeastern Eye Center,3312 Battleground Ave, Greensboro, NC 27410.

CASE REPORTS

Case 1. A 15-year-old white girl was referred with a 2-dayhistory of a blacked-out area in the paracentral visual field ofher left eye. Ocular and medical history were negative. Shetook no medications and denied any recent viral illness. Best­corrected visual acuity was 20/20 in the right eye and 20/25 inthe left. Pupils were equally reactive to light without aMarcus-Gunn defect. Extraocular movements were intact. In­traocular pressure by applanation tonometry was 12 mmHg ineach eye. The anterior segments were normal, and there wereno keratic precipitates or anterior chamber reaction. On oph­thalmoscopy, the right eye was unremarkable. In the left eye,two retinal lesions were noted adjacent and just temporal tothe fovea (Fig 1). One lesion was 1000 ~m in size and creamcolored. The edge was soft, and on stereo biomicroscopy thelesion was located at the level of the deep retina. No vitreousreaction was noted over the lesion. The second lesion was 500~m in size and white in color with three central pigment gran­ules. The border of the lesion was discrete, and no vitreousreaction was noted. On fluorescein angiography (Figs 2, 3), thesoft, cream-colored spot showed slight hypofluorescence in theearly phase. This area stained with fluorescein in the late study,and the margin was quite indistinct. The second, white discretelesion showed early staining at the edge and late staining oftheentire lesion with leakage on the edge. The retinal vasculatureand optic nerve were normal, and no other focal lesions werenoted.

A working diagnosis of outer retinal toxoplasmic retinitiswas made, and serum for toxoplasmosis titer was drawn. Clin­damycin (300 mg every 6 hours) and prednisone (40 mg daily)were started. The acute toxoplasmosis titer result was 1:512.Over the next month, the visual acuity in the left eye returned

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Fig 1. Case I. Top left. onediscrete parafoveal lesionwith a sharp border (olderlesion) and one soft with afuzzy margin (acute lesion).Fig 2. Case I. Top right.early angiogram. Earlystaining of a discrete lesion.Blockage of choroidal fluo­rescence by a soft. acute le­sion. Fig 3. Case I. Secondrow left. late-phase angio­gram. Leakage from themargin of a discrete lesion.Late staining of a softer le­sion ofretinitis. Fig4.Case 1.Second row right . finalfundus appearance . Twosmall, discrete, retinal scars.Fig 5. Case 2. Third rowleft.retinal lesion occupying halfof the fovea. Fig 6. Case 2.Third row right. early an­giogram with hyperfluores­cence of the inflamed edgeof the lesion. Fig 7. Case 2.Bottom left. late angiogram.Fluorescein staining andleakage from the lesion. Fig8. Case 2. Bottom right .final fundus appearance.Small scar occupying half ofthe fovea.

MATIHEWS AND WElTER • TOXOPLASMOSIS

to 20/20. The pigmented lesion did not change, but the outerretinal lesion became discrete and 400 JIm in size (Fig 4). Themedications were continued for 4 weeks. The patient has hadno further problem, and visual acuity is 20/20 in each eye.

Case 2. A 9-year-old white girl was referred with a recenthistory of unilateral central vision loss. Visual acuity I yearearlier was 20/20 in each eye, ocular and medical history werenegative. She took no medications and had had no recent viralillness.

Best-corrected visual acuity was 20/20 in the right eye and20/80- in the left. Amsler grid showed a paracentral scotomain the left eye. Pupils were equally reactive to light, and therewas no afferent defect. The eyes were straight and the extraoc­ular movements normal. Intraocular pressure was normal topalpation bilaterally. The anterior segments were normal, andthere were no keratic precipitates or anterior chamber cells.Onophthalmoscopic examination, the right eye was unremark­able. In the left eye, a central foveal lesion was noted (Fig 5).The lesion was round, 100JImin size, and occupied half of thefovea. On stereo biomicroscopic examination, the lesion waslocated at the level of the deep retina . There was no vitreousreaction over the lesion. The retinal vasculature and the opticnerve were normal.

On fluorescein angiographic examination (Figs 6, 7), themargin of the lesion began to leak early in the study. Late inthe study, the entire lesion stained and leaked fluorescein dye.Serum was drawn for toxoplasma titer.

When the patient returned several days later, the test resultswere not yet available. The lesion had enlarged, and a clinicaldiagnosis of acute deep retinal toxoplasmosis was made. Afterpediatric infectious disease consultation, clindamycin (10-20mg/kg per day) and prednisone (25 mg per day) were started.These medications were continued for 6 weeks. Then clinda­mycin was stopped and prednisone was tapered. Acute toxo­plasma titer was I:128.

On the last follow-up visit, some 14 months later, the lesionappeared quiet with central and marginal pigmentation (Fig8). Visual acuity in the affected eye was 20/25.

Case 3. A 41-year-old white female computer operator pre­sented with a 3-day history of noting a gray spot on her com­puter screen. The spot, staying fixed in her central field ofvision, was increasing in size and moved as the patient movedher eyes. Her medical and ocular history were otherwise nega­tive. She took no medications and denied any recent viralillness.

Best-corrected visual acuity was 20/20-3 in the right eyeand 20/20 in the left. A horizontally oval, dark gray area ofblur was noted adjacent to fixation on the Amsler grid exami­nation in the right eye. Pupils were equally reactive to lightwithout a Marcus-Gunn defect. Extraocular movements wereintact . Intraocular pressure was 14 mmHg by applanation to­nometry in each eye. The anterior segments were normal , andthere were no keratic precipitates or anterior chamber reac­tion . On ophthalmoscopic examination, the left eye was unre­markable. The right eye showed a 100-/Lm, cream-colored le­sion just below the fovea with white retinal edema extendinginto the fovea. On stereo biomicroscopic examination, the le­sion was located at the level of the deep retina, and the edgeswere soft. There was no vitreous reaction over the lesion, andthe optic nerve head was without signs of inflammation.

On fluorescein angiographic examination, this deep retinallesion blocked the choroidal fluorescence in the early transit ,and the vasculature in the area did not fillwith dye. The lesionstained and leaked in the late phase, and there was no stainingof the optic nerve head.

The clinical diagnosis of deep retinal toxoplasmosis wasconsidered as the cause of retinal inflammation with a second­ary macular vein occlusion. Treatment was begun immedi­ately with clindamycin (300 mg every 6 hours) and prednisone(40 mg each morning for 4 weeks) without significant sideeffects. The lesion regressed, and the area of visual disturbancedecreased over this period. Two weeks later, the toxoplasmatiter was reported as I:256. The final visual acuity of the righteye was 20/20, and the lesion was 50 /Lm in size and slightlypigmented.

Case 4. A 29-year-old male truck driver presented with a2-week history of progressiveblur of the vision in the right eye.Over the past 2 days, he also had noted some floating cobwebsin the same eye. His ocular and medical history were negative.He took no medications. Best-corrected visual acuity wascounting fingers at 2 feet in the right eye and 20/20 in the left.Pupils were equally reactive to light without an afferent defect.Extraocular movements were intact. Intraocular pressure byapplanation tonometry was 22 mmHg in the right eye and 9mmHg in the left. The anterior segments were normal, andthere were no keratic precipitates or anterior chamber reac­tion. On ophthalmoscopic examination of the right eye, alarge, gray-white area offocal retinitis (Fig 9) was seen beneaththe vessels of the lower arcade. The retina involved in thelesion was thickened , and white retinal edema extended fromthe lesion to the lower half of the fovea in a wedgeshape. A fewvitreous cells overlay the lesion. A punctate satellite lesion justnasal to the optic nerve head was located in the deep retina.There was no vitreous reaction over this satellite lesion. Re­sults of ophthalmoscopic examination of the left eye werenormal.

On fluorescein angiographic examination (Figs 10, II), thelarge lesion blocked the choroidal fluorescence in the earlytransit. The focal lesion underlying the major vessels stainedearly and leaked in the late study. A wedge-shaped area ofvasculitis extended from the lesion into the foveal region.There was vascular occlusion with no retinal filling of dye inthis area. The edges of the main lesion were quite blurred withleakage in the late study.

A clinical diagnosis of toxoplasma retinitis with secondaryvascular occlusion leading to profound loss of vision wasmade, and serum for toxoplasma titer was drawn. Treatmentwas begun immediately with clindamycin (300 mg every 6hours) and prednisone (40 mg daily). Over the next month, thevisual acuity in the right eye returned to 20/50, and the medi­cations were well tolerated (Fig 12).Clindamycin was stoppedafter 6 weeks, and then prednisone was tapered over the next 2weeks. The toxoplasma titer was reported as I:512, and thelesion regressed to a scarred area beneath the lower vasculararcade (Fig 13). Final visual acuity is 20/25-.

Case 5. A 31-year-old white woman presented with a l-dayhistory of blurred vision in the right eye. She noted the visualdisturbance acutely because a macular scar in the left eyecaused poor central vision, and she preferred the right eye forvision. This macular scar had been noted on an examination 5years previously. Her medical history was negative, and shedenied joint pain or gastrointestinal disorders. She took nomedications.

Best-corrected visual acuity was 20/30 in the right eye and20/40 in the left. The pupils were equally reactive to lightwithout an afferent defect. Extraocular movements were in­tact. In the right eye, many fine keratic precipitates were seenon the inner corneal surface, and there was a 2+ cellular reac­tion in the anterior chamber. The anterior segment of the lefteye was unremarkable. The intraocular pressure with Gold-

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Fig 9. Case 4. Top left. pre­treatment. Retinitis extend­ing from focus on lower ar­cade to central fovea. Fig10. Case 4. Top right, earlyphase angiogram. Blockageof choroidal fluorescence bythe inflamed retina. Noticevascular occlusion. Fig 11.Case 4. Center left, late an­giogram. Leakageoffluores­cein from area of retinitis.Fig 12. Case 4. Center right,partial resolution after Imonth of treatment. Noticeoriginal focus of retinitis.Fig 13. Case 4. Bottom.complete resolution after 10weeks of treatment.

mann applanation tonometry was 32 mmHg in the right eyeand 13 mmHg in the left. The right posterior pole containedtwo lesions on the temporal side ofthe macula. One lesion wasI DD in size and hypopigmented centrally, with a hyperpig­mented edge. The second lesion was cream colored, I DD insize, and had a blurred, indistinct margin. By stereo biomicro­scopic examination, the lesion was located at the level of thedeep retina . A few vitreous cells overlay the area, and no otherlesions were seen. The retinal vessels and optic nerve werenormal.

The left eye showed a central macular hyperpigmented scarwith several satellite lesions. The retinal vessels and optic nervewere normal . On fluorescein angiographic examination, theright eye showed early hyperfluorescence of the edge andcenter of the pigmented discrete lesion and early blockage of

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the choroidal fluorescence by the active fuzzy lesion with theindistinct margins. Both lesions leaked dye in the late-phaseangiogram.

A clinical diagnosis of acute toxoplasma retinochoroiditiswas made, and serum was sent for acute toxoplasma titer ,serum lysozyme, and angiotensin-converting enzyme. The pa­tient reported that results of a recent tuberculosis skin test werenegative. Treatment was begun with clindamycin (300 mgevery 6 hours), prednisone (60 mg daily), prednisolone acetate(every 2 hours), and homatropine (5% every 8 hours). A weeklater, the toxoplasma titer was I:128, and the other test find­ings were normal. Symptoms had improved. Topical medica­tions were stopped, and systemic medications were continuedfor 6 weeks and then tapered. At final examination, the visualacuity in the affected eye was 20/20-, the anterior segment

MATTHEWS AND WElTER • TOXOPLASMOSIS

and vitreous were quiet, and pigmentation was forming in thefuzzy lesion.

Table 1. Ocular Toxoplasmosis Versus Deep Retinal Toxoplasmosis

Table 2. Summary of Cases

Typical Ocular Deep RetinalCharacteristics Toxoplasmosis Toxoplasmosis

Tissue involved Choroid, full th ickness Deep retina, retinalretina, vitreous pigment

epitheliumVitreous reaction "Headlight-in-fog" Little or none

vitreous membranesLesion location Posterior to equator Macular regionPatient age Any age Primarily youngLes ion size Large, more than 1 disc Small, 50-1000 ILm

diameterTreatment response Lesion becomes Quiescent Growth of lesion

possibly haltedby earlytreatment

retina and is associated with minimal vitreous reaction.Our cases all had positive toxoplasmosis titers, thusmaking the diagnosis more secure. The differentialdiagnosis of acute, multifocal, gray-white lesions thatappear at the level of the photoreceptors and retina in­cludes recurrent multifocal choroiditis," acute posteriormultifocal placoid pigment epitheliopathy.!" serpigi­nous choroidopathy, diffuse unilateral subacute neuro­retinitis, birdshot retinochoroidopathy, and sarcoidosis.In patients with systemic illness or those being immuno­suppressed, other disorders such as Candida retinitisand septic multifocal choroiditis should be considered.

Is outer retinal toxoplasmosis a true subset of oculartoxoplasmosis, or does it represent the earliest stage ofacute recurrent retinitis (Table I)? Outer retinal toxo­plasmosis usually is located in the macular region, andthus the inflammation usually is symptomatic when thelesions are relatively small, do not necessarily involvefull-thickness retina, and have not yet resulted in anoverlying vitritis. Thus, it could be argued that becausethe lesions are close to the macula, earl y visual symp­toms and the possibility of evaluation before full-thick­ness retinal involvement result, and if the lesions werelocated farther from the macula they would progress to atypical toxoplasmosis pattern before presentation. In-

CF = counting fingers.

Final

20/2020/2520/2020/2520/20-

Visual Acuity

20/2520/8020/20-3CF20/30-

Initial

1:5121:1281:2561:5121:128

ToxoplasmaTiter

159

412931

Age(yrs)

12345

PatientNo.

Toxoplasma gondii is an obligate, intracellular, pro­tozoan parasite with almost universal geographic distri­bution. This organism commonly produces infection inhumans. Serologic surveys have shown that up to 50% ofthe population in the United States has been infectedwith the organism. Most of the infections are asympto­matic and subclinical and are not recognized.

Ocular toxoplasmosis is a leading cause of posterioruveitis.! Two clinical forms of toxoplasma infection arerecognized-congenital and acquired. Acquired toxo­plasmosis rarely causes ocular disease" and is associatedwith very high antibody titers, making diagnosis rela­tively easy. The diagnosis of ocular toxoplasmosis,which is generally thought to be reactivation of the con­genital disease, may be very difficult. Since toxoplasmaorganisms usually cannot be isolated from the eye tissue,ocular toxoplasmosis is a presumptive diagnosis basedon clinical appearance and supported by serologic evi­dence of exposure to the parasite. Most authors agreethat a positive test by any of the accepted serologicmethods is compatible with the diagnosis of oculartoxoplasmosis." A recent study' showed that the defini­tive diagnosis or exclusion of ocular toxoplasmosis byserologic means is not yet feasible , and that the diagnosisstill remains clinical.

The treatment of ocular toxoplasmosis with clinda­mycin and corticosteroids seemed to limit chorioretinaldamage in our cases. This combination or the regimenof triple sulfa, Daraprim (pyrimethamine), and cortico­steroids is usually chosen when lesions are vision threat­ening-involving the macula or optic nerve. Some au­thors have suggested withholding medical therapy innonvision-threatening lesions to strengthen the immuneresponse.

The clinical diagnosis of typical ocular toxoplasmosisis not difficult. The lesions usually occur at or close tothe margins of an old chorioretinal scar, involve theinner retina, and have an associated marked vitritis.These typical , acute, recurrent inflammations areusually solitary.

A recent report emphasized a subset of ocular toxo­plasmosis that involves the outer retina and has little ifany vitreous reaction.' The authors described young pa­tients with acute, recurrent, multifocal retinal lesionsthat slowly resolved over time, resulting in scarring. Thelesions occurred close to each other and were associatedwith serologic evidence of exposure to T gondii. Thesefindings are sufficient to make a presumptive diagnosisof ocular toxoplasmosis.

Our five additional cases of outer retinal toxoplas­mosis confirm the existence of a subset of ocular toxo­plasmosis that initially and primarily affects the outer

DISCUSSION

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deed, these acute, outer-retinal toxoplasmosis lesions, ifuntreated, may evolve into the more familiar and char­acteristic toxoplasmosis chorioretinal scar with satellitechanges. ' On the other hand, the simultaneous appear­ance of multiple lesions is unusual and may indicate atrue subset of ocular toxoplasmosis and not just earlyrecognition.

Awareness of this form of presentation of oculartoxoplasmosis should facilitate early recognition andtreatment and thus preservation of good vision (Table2). Our patients were started on therapy before the re­sults of the toxoplasmosis serology tests were received.Although many of these lesions might have resolvedwithout therapy," the excellent results obtained withtherapy suggests that early treatment is beneficial.

REFERENCES

1. O'Connor GR. Protozoan diseases of the uvea. Int Ophthalmol Clin1977; 17(3):163-76.

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2. Doft BH, Gass JDM. Punctate outer retinal toxoplasmosis. Arch Oph­thalmol 1985; 103:1332-6.

3. Gass JDM. Fluorescein angiography in endog enous intraocular in­flammation. In: Aronson SB, Gamble CN, Goodner EK, O'ConnorGR, eds. Clinical Methods in Uveitis: The Fourth Sloan Symposium onUveitis. St Louis: CV Mosby, 1968; 214.

4. Friedman CT, Knox DL. Variations in recurrent active toxoplasmisretinochoroidit is. Arch Ophthalmol1969; 81:481-93.

5. Vadot E, Barth E, Billet P. Epidemiology of uveitis-preliminary resultsof a prospective study in Savoy. In: Saari KH, ed . Uveitis Update:Proceedings of the First International Symposium on Uveitis held inHanasaari, Espoo , Finland, on May 16-19, 1984. Amsterdam: Ex­cerpta Medica , 1984; 13-6.

6. Scott EH. New concepts in toxoplasmosis . Surv Ophthalmol 1974;18:255-74.

7. O'Connor GR. Ocular toxoplasmosis . Jpn J Ophthalmol 1975 ;19:1-24.

8. Rothova A, van Knapen F, Baarsma GS, et al. Serology in oculartoxoplasmosis. Br J Ophthalmol1986; 70:615-22.

9. Morgan CM, Schatz H. Recurrent multifocal choroiditis. Ophthalmol­ogy 1986; 93:1138-47.

10. Gass JDM. Acute posterior multifocal placoid pigment epitheliopathy.Arch OphthalmoI1968; 80:177-85.