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Diagnostic approaches to severe, atypical toxoplasmosis mimicking acute retinal necrosis
Diagnostic Approaches to Severe, Atypical Toxoplasmosis Mimicking Acute Retinal Necrosis Darius M. Moshfeghi, MD,1 Emilio M. Dodds, MD,3 Cristo´bal A. Couto, MD,4 Carmen I. Santos, MD,5 Donald H. Nicholson, MD,6 Careen Y. Lowder, MD, PhD,2 Janet L. Davis, MD6 Purpose: To describe the means of diagnosis and clinical features of atypical toxoplasmic chorioretinitis mimicking acute retinal necrosis. Design: Observational case series. Participants: Twenty-two patients (25 eyes) with widespread chorioretinitis resulting from toxoplasmosis examined between 1990 and 2001. Testing: Patients were diagnosed by various techniques, including polymerase chain reaction (PCR) of aqueous and vitreous, serum and intraocular antibody determination, culture of intraocular fluid, retinal biopsy, histopathologic examination, therapeutic trial of antibiotics active against toxoplasmosis, or a combination thereof. Main Outcome Measures: The primary outcome measure was diagnosis of disseminated toxoplasmic chorioretinitis by any combination of tests or by empiric use of specific antibiotics. The secondary outcome measure was visual and anatomic outcome of treatment. Results: Mean age was 53.5 years (range, 19 –77 years), with a median of 59.5 years. There were 9 women and 13 men. Six patients were infected with HIV, and 3 patients, 1 with HIV, had bilateral disease. Mean initial vision was 20/110 (median, 20/400; range, 20/20 to no light perception [NLP]). Sixteen patients (73%) had received oral or injectable corticosteroids and 11 (50%) had received antiviral therapy before the diagnosis of toxoplasmosis. Diagnosis was made solely by clinical response to antitoxoplasmosis medications in 4 patients. Sixteen patients were diagnosed based on evaluation of intraocular fluids and tissue by antibody determinations, culture, PCR, histopathologic examination, or a combination thereof. Visual acuity improved after treatment in 7 of 25 eyes (28%). Mean final visual acuity was 20/156 (median, 20/2500; range, 20/30 to NLP). Anatomically, 18 of 23 eyes with follow-up had healed or improved chorioretinitis. Retinitis was progressive in 1 eye, 2 eyes were enucleated, and 2 were phthisical. Conclusions: Diagnosis of atypical toxoplasmic chorioretinitis that mimics viral retinitis can be accomplished by several means. Prompt diagnosis may help avoid poor visual and anatomic outcomes after prolonged initial treatment with oral prednisone or antiviral medications. Ophthalmology 2004;111:716 –725 © 2004 by the American Academy of Ophthalmology.
Toxoplasma gondii is a ubiquitous protozoan with worldwide distribution that can infect multiple tissues, including
Originally received: October 10, 2002. Accepted: July 30, 2003.
Manuscript no. 220823.
1
Stanford University School of Medicine, Palo Alto, California. 2 Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio. 3 Consultores Oftalmolo´gicos, Buenos Aires, Argentina. 4 University of Buenos Aires, Buenos Aires, Argentina. 5 Hyde Park Ophthalmology Group, San Juan, Puerto Rico. 6 Bascom Palmer Eye Institute, Miami, Florida. Supported by Heed Ophthalmic Foundation, Cleveland, Ohio (DMM), and the Ronald G. Michels Fellowship Foundation, Baltimore, Maryland (DMM). The authors have no commercial interests in this study. Correspondence to Janet L. Davis, MD, Bascom Palmer Eye Institute, 900 Northwest 17th Street, Miami FL 33136. E-mail: [email protected].
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© 2004 by the American Academy of Ophthalmology Published by Elsevier Inc.
the posterior segment of the eye.1 The diagnosis of toxoplasmic chorioretinitis in immunocompetent adults usually is made by ophthalmoscopic detection of a solitary focus of active chorioretinitis adjacent to a chorioretinal scar.2,3 Atypical presentations, such as bilateral, extensive, or multifocal disease, have been reported in immunocompromised patients with HIV infection, iatrogenic immunosuppression, or advanced age.4 –19 Lack of visible chorioretinal scars and extensive areas of retinal involvement may lead to a diagnosis of necrotizing herpetic retinitis and treatment with antivirals.17–25 Alternatively, severe posterior uveitis may be diagnosed initially, leading to treatment with corticosteroids that may either induce or worsen immunocompromise. Delay in diagnosis and treatment may worsen outcome despite later institution of specific therapy for toxoplasmic infection. We report 22 patients with atypical toxoplasmic chorioretinitis mimicking acute retinal necrosis syndrome and ISSN 0161-6420/04/$–see front matter doi:10.1016/j.ophtha.2003.07.004
Moshfeghi et al 䡠 Diagnosis of Atypical Toxoplasmosis describe the strategies used to reach the diagnosis. We make recommendations regarding diagnosis based on our experience and further describe the clinical features of this rare presentation of toxoplasmic chorioretinitis.
Patients and Methods Design This was a retrospective, observational case series of 22 patients with severe, atypical toxoplasmic chorioretinitis resembling acute retinal necrosis syndrome.
Participants Patients were identified in 2 university and 3 practice-based uveitis referral clinics in the United States, Argentina, and Puerto Rico between 1990 and 2001. Patients were accrued by review of patient lists in the various uveitis clinics. Patients were included if there was a final diagnosis of toxoplasmic chorioretinitis and the lesions were atypical because they were very large, multifocal, bilateral, or associated with diffuse retinal involvement or panophthalmitis. The differential diagnosis in each case included either panuveitis or necrotizing herpetic retinitis. Patients were excluded if the diagnosis of toxoplasmosis had not been satisfactorily confirmed by at least 1 of the following: response to antitoxoplasmosis medications (usually after previous treatment with corticosteroids, antivirals, or both); intraocular diagnostic studies such as polymerase chain reaction (PCR), intraocular antibodies, culture of intraocular fluid, or histopathologic examination showing T. gondii in necrotic retinal tissue. A retrospective review of the medical records of the 22 eligible patients then was conducted. Data collected included age; gender; systemic diseases; duration of symptoms; prior treatment and its duration; extent of ocular involvement; anterior chamber cell and flare graded on a scale of 0 to 4; vitreous inflammation graded as mild, moderate, or dense; preexisting healed chorioretinal scars; retinal detachment; diagnostic studies performed and results; treatment after diagnosis; initial and final Snellen visual acuity; and anatomic status at last follow-up. Response to antitoxoplasmosis medications was assessed by serial fundus examination. Conversion of active chorioretinitis to an inactive scar or clear improvement in disease activity before last follow-up was considered to be evidence of a positive response to specific therapy. Intraocular and serum antibody determinations were performed in reference laboratories and expressed as either enzyme-linked immunosorbent assay units or serum dilutions. In some cases, intraocular production of antibody was calculated by the Goldmann-Witmer (GW) coefficient according to the following formula26,27: GW coefficient ⫽ (Intraocular anti-Toxoplasma IgG / Intraocular IgG) / (Serum anti-Toxoplasma IgG / Serum IgG) Polymerase chain reaction was performed either by reference clinical laboratories, research laboratories at Washington University (Dr. Russell Van Gelder), or by the University of Miami Ocular Microbiology Laboratory, using primers for the B1 gene of T. gondii as previously described28 or using multiplex PCR (Dr. Van Gelder).29 Culture of intraocular fluid, when performed, was on media supporting viral, bacterial, or fungal growth, or a combination thereof. A specific protocol to support
the growth of toxoplasmosis on viral media was used for some cases.28 Histopathologic examination of retinal biopsies and enucleated globes was performed according to standard techniques. Review of data without linkage to unique patient identifiers was conducted according to applicable regulations of the Human Subjects Research Committees at the University of Miami and The Cleveland Clinic by physicians who were aware of the final clinical diagnosis of toxoplasmic chorioretinitis. Standardized intervals of follow-up were not specified. Regular reexamination during the period of treatment was encouraged for all patients as clinically indicated. Because the main emphasis was on diagnosis, no minimum amount of follow-up was required beyond confirmation of the diagnosis, and there was no determination of an adequate sample size.
Main Outcome Measures The primary outcome variable was the means by which diagnosis was made. The secondary outcome variable was final visual and anatomic status of involved eyes.
Results There were 22 patients: 9 women and 13 men. Three patients had bilateral disease, for a total of 25 affected eyes. Mean age was 53.5 years (range, 19 –77 years), with a median of 59.5 years. Five patients (23%) were more than 70 years of age. Six patients (27%; patients 17–22) were infected with HIV, with a median CD4⫹ T-lymphocyte count of 168 (range, 18 – 683). A variety of other systemic illnesses were present that might have affected immune competency (Table 1). Three patients underwent uncomplicated cataract extraction with intraocular lens placement within 6 months before the development of chorioretinitis, possibly stimulating recurrence (patients 2, 7, and 11).30 Mean initial Snellen visual acuity was 20/110 (median, 20/400; range, 20/20 to no light perception). There was a wide range of anterior chamber cellular reaction; vitreous reaction usually was graded as “dense” (Table 1). The chorioretinitis involved from 1 to 12 clock hours of the fundus (mean, 6.4⫾3.9 clock hours; median, 6 clock hours). In 6 cases, there was a single, well-defined large lesion. In 9 cases, there was diffuse involvement with poorly defined borders, and in 6 of these, there was more than 1 focus of disease. Six cases were classified as panophthalmitis because of the severity of the inflammatory response with diffuse ocular involvement; 3 of these also had multifocal lesions. In 4 of 23 eyes in which the fundus was visible, healed chorioretinal scars were present (17.4%). Eight of 25 eyes (32%) had retinal detachments. Clinical details are presented in Table 1. Symptoms had been present for an average of 10.3⫾10 weeks and for a median of 7 weeks (Table 1). Twelve patients (54%) had received oral, intramuscular, or periocular corticosteroids before diagnosis for an average of 13.8⫾11.5 weeks (median, 10 weeks; range, 1– 40 weeks). Eleven (50%) had received antiviral therapy for an average of 3.2⫾3.5 weeks (median, 2 weeks; range, 1 day–13 weeks). Seven patients (21.8%) received both antiviral therapy and oral or injectable corticosteroids. A total of 16 of 22 patients (73%) therefore received therapy directed at severe endogenous uveitis, necrotizing herpetic retinitis, or both before diagnosis of toxoplasmosis (Table 1). Intraocular diagnostic specimens consisted of 5 aqueous humors, 13 vitreous humors, 3 retinal biopsies, and 2 whole globes (Table 2). Four patients (18%) received no diagnostic testing, and 2 (9%) were tested for serum antibodies only. In these patients, diagnosis was confirmed by response to antitoxoplasmosis medi-
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Ophthalmology Volume 111, Number 4, April 2004 Table 1. Patient Characteristics and Ocular Findings at Presentation Systemic Disease
Initial Visual Symptoms Acuity (wks)
Patient No.
Age (yrs)
Corticosteroids (wks)
Antivirals (wks)
Gender
1 2
19 71
F F
None None
Left Left
HM HM
12 4
12 16
LP
10
8
Right
3/200
4
12
None Oral acyclovir (1) IV acyclovir (13), IV foscarnet (3), intravitreal ganciclovir ⫻1 None
3
76
M
None
Right
4
44
M
None
5 6 7 8
65 60 77 60
F M F M
None None NIDDM Chronic active hepatitis Thoracic zoster
Left Left Left Right
20/100 20/100 20/400 20/40
24 6 4 8
24 None None None
None None None IV ganciclovir
9
50
M
Left
20/70
16
4
Alzheimer’s, thymoma None
Right
HM
40
40
Oral acyclovir (4) None
10
75
F
11
77
M
Left
HM
3
None
None
12 13
68 40
F F
None Autoimmune hepatitis
Right Right
20/200 20/20
6 1
None 4
None IV acyclovir (3)
Left
20/60 CF
28
28*
20/50
12
8
Eye
14
68
M
Alcoholism
Left
15
61
F
Hypogammaglobulinemia, abnormal CD4:CD8 ratio of 0.88
Right
Left
4/200
16 17
29 35
M F
None HIV CD4 41
Left Left
HM NLP
12 8
8 None
18
36
M
HIV CD4 240
Right
HM
4
None
19
59
M
HIV CD4 400
Left
20/50
2
None
20 21 22
42 35 30
M M M
HIV CD4 294 HIV CD4 18 HIV CD4 23
Right Left Right
20/80 20/300 CF
3 3 2
None None 1
Left
20/400
Oral acyclovir (4) IV acyclovir (1)
None Oral acyclovir (2) Intravitreal and IV foscarnet and ganciclovir (4) IV acyclovir (2) None None IV ganciclovir (1 day)
Active Retinal Lesions (Clock Hours)
Healed Retinal Scars Detachment
Focal (4) Panophthalmitis, multifocal (8) Multifocal, peripheral (12)
Y N
N N
N
N
Multifocal, peripheral (6) Focal (4) Multifocal (12) Diffuse (6) Multifocal (3)
N
N
N N N N
N N N Y
Diffuse (3)
Y
Y
Diffuse (12)
Y
N
Diffuse, multifocal (8) Diffuse (5) Focal (⬍1)
N
N
N N
N N
N
N
N
N
N
N
N
Y
Y No view N
Y Y
N
N
N N N
Y Y N
No view
Y
Diffuse multifocal, peripheral (9) Panophthalmitis, multifocal (12) Diffuse, multifocal (2)
Diffuse, multifocal (3) Focal (3) Panophthalmitis (12) Panophthalmitis (12)
Panophthalmitis (9) Focal (2) Focal (1) Diffuse, multifocal (3) Diffuse, multifocal (6)
N
CD4 ⫽ CD4⫹ T lymphocyte count; CF ⫽ counting fingers; F ⫽ female; HM ⫽ hand motions; LP ⫽ light perception; M ⫽ male; N ⫽ no; NIDDM ⫽ non–insulin-dependent diabetes mellitus; NLP ⫽ no light perception; Y ⫽ yes. *Also treated briefly with antitoxoplasmosis medications early in the course of disease, then switched to prednisone for inadequate response.
cations. Ten patients (45%) were tested with 1 intraocular specimen only (8 vitreous and 2 aqueous humor specimens), and 6 (27%) were tested with 2 or more intraocular specimens. Specimens were collected in 6 eyes (27%) during repair of retinal
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detachment with pars plana vitrectomy, 4 eyes had diagnostic anterior chamber paracentesis, and 4 eyes had vitrectomy for diagnostic purposes. Diagnostic tests used in each case are listed in Table 2.
Moshfeghi et al 䡠 Diagnosis of Atypical Toxoplasmosis Table 2. Diagnostic Testing and Outcomes of Treatment Patient No.
Specimen
Diagnostic Testing and Results
1 2
None Serum
Not carried out Toxoplasmosis IgG high positive
3
Vitreous Serum Vitreous
4
Vitreous
Culture negative for virus, fungi, and bacteria Toxoplasmosis IgG positive Toxoplasmosis IgG high positive, culture negative for virus Toxoplasmosis IgG titers positive
5 6 7
None Serum None
8
Antitoxoplasmosis Therapy*
Final Visual Acuity
Retinal Appearance at Last Follow-up
PY, CL, TS, P PY, TS, CL
HM CF
Inactive retinitis Inactive retinitis, macular scar
PY, TS, CL
NLP
Improving
PY, TS, CL, P
20/200
Not carried out Toxoplasmosis IgG titers 1:1280 Not carried out
PY, S, PCL PY, S, PCL, P PY, CL, DX, P
20/100 20/100 HM
Serum
Toxoplasmosis IgG high positive
PY, S, CL, TS, M
20/70
Vitreous Retinal biopsy Aqueous
Toxoplasmosis IgG high positive, PCR and cultures negative for VZV, HSV, and CMV Necrotic tissue negative for bacterial and fungal stains Toxoplasmosis IgG titers positive
PY, CL, S, P
20/50
10
Vitreous None
Toxoplasmosis IgG titers positive Not carried out
PY, S, P
HM
11
Vitreous
PCR positive for toxoplasmosis, negative for VZV, HSV
PY, S, CL, P
HM
12 13
Serum Aqueous
PY, S, CL, P PY, S, CL, P
14
Serum Aqueous
20/100 20/60 right eye NLP left eye NLP
15
Serum Aqueous
Toxoplasmosis IgG titer 1:512 Multiplex PCR positive for toxoplasmosis, negative for HSV, VZV, and CMV Toxoplasmosis IgG titer ⬎ 1:1024 GW toxoplasmosis, 2.32; CMV, 2.00; VZV, 2.08; HSV, 1.5 Toxoplasmosis IgG low positive GW toxoplasmosis, 66; CMV, 19; VZV, 34; HSV negative Toxoplasmosis IgG high positive, culture negative for bacteria and fungi Histologic results positive for toxoplasmic tissue cysts Toxoplasmosis IgG high positive, culture negative for toxoplasmosis and virus PCR positive for toxoplasmosis, culture positive for toxoplasmosis, culture negative for virus, fungi, and bacteria Histologic results positive for toxoplasmic tissue cysts, PCR positive for toxoplasmosis
Improving active retinitis Inactive retinitis, macular scar Improving retinitis Improving retinitis Improving retinitis Phthisis
20/30 right eye 3/200 left eye
Unknown Unknown
9
Vitreous 16
Retinal biopsy Vitreous
17
Vitreous
18
Whole globe histologic examination Vitreous
19 20
Whole globe histologic examination Serum Aqueous Serum Vitreous
21
Serum Vitreous
PY, CL, TS PY, SSS, M
None
—
Toxoplasmosis IgG high positive, PCR positive for toxoplasmosis, culture positive for toxoplasmosis, culture negative for virus Histologic results positive for toxoplasmic tissue cysts
PY, CL
—
Enucleation
Toxoplasmosis IgG high positive GW toxoplasmosis, 20.3; CMV, 15.4 Toxoplasmosis IgG high positive
PY, S
LP
Progressive retinitis
PY, S
6/200
PY, S
20/400
Inactive retinitis, attached
Inactive retinitis, attached Enucleation
Toxoplasmosis IgG high positive, PCR positive for toxoplasmosis, culture positive for toxoplasmosis, culture negative for virus, flow cytometry and cytologic results negative for lymphoma Negative
DX
Inactive retinitis, macular scar Inactive retinitis Inactive retinitis Inactive retinitis, macular scar Inactive retinitis, attached
20/30
Inactive retinitis, attached
Inactive retinitis, attached
PCR positive for toxoplasmosis, culture positive for toxoplasmosis, culture negative for virus (continued)
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Ophthalmology Volume 111, Number 4, April 2004 Table 2. (Continued.) Patient No. 22
Specimen
Diagnostic Testing and Results
Serum
Toxoplasmosis IgM titer negative
Vitreous
PCR positive for toxoplasmosis, culture negative for virus, fungi, and bacteria PCR positive for toxoplasmosis, culture positive for toxoplasmosis
Retinal biopsy
Antitoxoplasmosis Therapy*
Final Visual Acuity
Retinal Appearance at Last Follow-up
PY,S
20/400 right eye NLP left eye
Inactive retinitis, macular scar Phthisis
CF ⫽ counting fingers; CL ⫽ clindamycin; CMV ⫽ cytomegalovirus; DX ⫽ doxycycline; GW ⫽ Goldmann-Witmer coefficient; HM ⫽ hand motions only; HSV ⫽ herpes simplex virus; IgG ⫽ immunoglobulin G; IgM ⫽ immunoglobulin M; LP ⫽ light perception only; M ⫽ minocycline; NLP ⫽ no light perception; P ⫽ prednisone; PCL ⫽ periocular clindamycin; PCR ⫽ polymerase chain reaction; PY ⫽ pyrimethamine; S ⫽ sulfadiazine; SSS ⫽ triple sulfa; TS ⫽ trimethoprim-sulfamethoxazole; VZV ⫽ varicella zoster virus. *Chronic therapy was recommended for the HIV-positive patients. In 15 of the 16 non-HIV patients, treatment was continued for a median of 2 months (range, 1–24 months).
Nine of 11 serum antibody titers were positive. The 2 negative cases occurred in HIV-positive patients (Table 2). All 5 aqueous humor specimens were positive for toxoplasmosis, 4 by immunoglobulin G antibody determinations (3 with GW coefficients) and 1 by PCR. There were 13 vitreous specimens. All 8 vitreous specimens tested for intraocular antibody against toxoplasmosis were positive, as were all 6 PCR determinations and 4 of 5 vitreous cultures. There were 3 retinal biopsy specimens. One retinal biopsy was positive by PCR and culture, 1 by histologic examination (Figs 1, 2), and 1 showed only necrotic tissue with negative fungal and bacterial stains. Both enucleated globes showed toxoplasmic tissue cysts on histologic examination (Fig 3). Vitreous specimens in these 2 cases were positive by PCR and culture. Follow-up of 1 month or more was available in 16 patients (73%) and of 4 months or more in 9 patients (41%). For the 16 patients with at least 1 month of follow-up, the mean follow-up was 19.1⫾25.8 months (range, 1–74.4 months; median, 6.0 months). For the 9 patients with at least 4 months of follow-up, the mean follow-up was 32.2⫾28.3 months (range, 6 –74.4 months; median, 15 months). In 15 of the 16 non-HIV patients, treatment was continued for a median of 2 months (range, 1–24 months). One elderly, non-HIV patient had multiple relapses when medication was discontinued (Fig 4). Thirteen of the 19 evaluable eyes (68%) healed with treatment by the final follow-up, 5 were improving, and 1 was progressing. Eyes considered nonevaluable were enucleated (n ⫽ 2), were phthisical (n ⫽ 2), or were without follow-up (n ⫽ 2). Mean final visual acuity was 20/156 (median, 20/2500; range, 20/30 to no light perception). Only 5 of 25 eyes (20%) had a final visual acuity of ⬎20/80. Seven of 25 eyes (28%) had improved visual acuity at last follow-up compared with initial visual acuity.
Five of 7 eyes with retinal detachment were attached at the final follow-up; 1 eye with no light perception could not be evaluated because of lack of fundus view and retained silicone oil.
Discussion Toxoplasmic chorioretinitis that presents without a typical small to moderate focus of active chorioretinitis adjacent to a healed chorioretinal scar can be difficult to diagnose ophthalmoscopically. Extensive, bilateral, or multifocal toxoplasmic chorioretinitis similar to the cases in this series has been reported previously and is considered rare.4 –19 Differential diagnosis of such lesions includes acute retinal necrosis syndrome, other necrotizing herpetic retinopathy, cytomegalovirus retinitis,31 severe panuveitis, fungal infection, and intraocular lymphoma.32 An initially incorrect diagnosis with prolonged empiric treatment may be harmful by delaying diagnosis. Use of corticosteroids without concomitant treatment with antitoxoplasmosis medication may allow the chorioretinitis to progress at a more rapid rate. Early use of invasive diagnostic procedures in patients with sight-threatening chorioretinitis that cannot be satisfactorily diagnosed by ophthalmoscopy, or in patients without response to a chosen empiric therapy, may result in better visual and anatomic outcomes for this devastating ocular infection. Laboratory evaluation of intraocular fluid and tissue as used in 16 patients in this series can be an effective means of diagnosing toxoplasmic chorioretinitis.23,33–36 Direct de-
Figure 1. A, Right eye of a woman treated with corticosteroids for 2 months before referral (patient 15; see Tables 1, 2). Acyclovir treatment was begun for presumed necrotizing herpetic retinitis. Corticosteroids were continued. Arteriolitis is present. B, The left eye also displayed large areas of confluent necrotizing retinitis with arteriolitis. Macular involvement with severe vision loss to 4/200 is present. C, Right eye. After 13 days, the retinitis is seen to have progressed. Large satellite lesions are present at the edge of the lesion. Vitreous haze has increased. D, Left eye. Similar worsening is noted. Retinal biopsy was elected. Figure 2. A, Retinal biopsy of the patient in Figure 1. Toxoplasmic cysts are present in retinal tissue (stain, hematoxylin– eosin; original magnification, ⫻10). B, Electron microscopy depicting toxoplasmic cysts (same patient as in Figs 1 and 2A). Figure 3. A, Panophthalmitis. At presentation, this 35-year-old woman (patient 17; see Tables 1, 2) had vision of no light perception, necrotizing retinitis, retinal detachment, and marked intraocular inflammation. Oral acyclovir was begun as prophylaxis for the fellow eye after declining intravenous treatment. She was then lost to follow-up for 6 weeks, returning with severe ocular pain. Enucleation was recommended. HIV infection with a CD4 count of 41 was diagnosed on that admission. B, Biopsy from the enucleated globe showing toxoplasmic tissue cysts (stain, hematoxylin– eosin; original magnification, ⫻40).
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Ophthalmology Volume 111, Number 4, April 2004
Figure 4. A, This 77-year-old woman with diabetes mellitus (patient 7; see Tables 1, 2) had a small focus of active chorioretinitis after cataract surgery that seemed to improve spontaneously. Six months later, diffuse chorioretinitis, vitreous inflammation, and reduced vision of 20/400 were noted. Pyrimethamine, clindamycin, and low-dose corticosteroids were begun. She was intolerant to clindamycin. After 6 weeks, treatment was changed to doxycycline 100 mg orally twice daily. B, Three and one-half months later, the lesion showed evidence of healing at the border with reduction in vitreous inflammation. The doxycycline was stopped. C, Six weeks later, there was recurrent chorioretinitis and vitreous inflammation with vision of 20/400. She was administered doxycycline again with stabilization of the infection. Despite arrest of the progression of the lesion, the final outcome was poor, with optic nerve pallor and vision of hand motions.
tection of an infective agent in a diseased eye generally is taken as prima facie evidence of causation; culture and histopathologic examination have been traditional means of detection.37 Recently, isolation of toxoplasmosis organisms from blood or eye fluid has been reported in tissue culture systems developed for viral culture.28 Five patients in this series from a single center had growth of toxoplasmosis organisms on tissue culture media. Although the technique appears sensitive, it was slow, taking 2 to 23 days (average, 12 days) after inoculation to produce visible plaques that then required confirmation by microscopy, fluorescent antibody staining, and PCR.28 Histopathologic analysis is considered the gold standard, but biopsies of the eye are rarely undertaken except in severe disease requiring enucleation (2 patients in this series), when incidental to retinal detachment surgery (2 patients),37 or in bilaterally sight-threatening disease (1 patient). Polymerase chain reaction amplification of toxoplasmic DNA is more rapid than culture and requires only a small amount of intraocular fluid.38 – 40 An intracellular organism
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such as T. gondii ordinarily would not be expected to be floating freely in intraocular fluid.41,42 Widespread chorioretinitis with necrotizing retinitis as in this series presumably increases the chance that organisms or parts of organisms will be present in vitreous fluid. In the report of Montoya et al,43 5 of 7 patients with atypical, severe toxoplasmic chorioretinitis had positive vitreous PCR results. Aqueous humor has been believed to be less satisfactory as a substrate for PCR in toxoplasmic chorioretinitis than in viral retinitis.36,42– 45 The first report of PCR testing for toxoplasmosis in aqueous humor was able to amplify DNA from only 17% of the cases.41 Fardeau et al19 subsequently reported 9 cases of atypical toxoplasmosis characterized by large lesions in elderly or immunocompromised patients, each of which had positive PCR results for toxoplasmosis from aqueous humor. Johnson et al17 also reported 7 elderly patients with atypical toxoplasmic chorioretinitis resembling acute retinal necrosis, in 2 of whom diagnosis was made by PCR testing of aqueous humor. Nine of 15 patients (60%) with lesions larger than 3 disc areas had positive PCR
Moshfeghi et al 䡠 Diagnosis of Atypical Toxoplasmosis
Figure 5. Flow chart depicting an approach to the diagnosis of atypical disseminated chorioretinitis. Useful initial data include history of chorioretinitis or healed scars; risk factors or laboratory evidence for toxoplasmosis infection, human immunodeficiency virus, or other immunocompromise; and clinical features such as duration of symptoms and rapidity of onset, and the location, appearance, and confluency of the retinal infiltrates. Aqueous humor is often an adequate substrate for initial testing (see text). Test results and response to therapy help the clinician determine whether diagnostic vitrectomy is needed. Diagnostic vitrectomy should be as comprehensive as indicated and feasible with polymerase chain reaction (PCR) determinations; antibody determinations; bacterial, fungal, and viral cultures; and consideration of retinal biopsy. Cytologic examination may be appropriate in some cases. IgG ⫽ immunoglobulin G; PPV ⫽ pars plana vitrectomy.
results from aqueous humor versus 3 of 12 patients (25%) with smaller lesions in the study of Labalette et al18; all patients were older than 50 years. Detection of specific antibodies against toxoplasmosis in intraocular fluids is an alternative strategy that complements PCR testing. Both timing and immune status may influence results of antibody testing. Garweg et al36 confirmed ocular toxoplasmosis in 28 of 49 patients (57%) tested for intraocular antitoxoplasmosis immunoglobulin G within 3 weeks of onset of symptoms; sensitivity rose to 70% if a later specimen was tested. In the same series, PCR detected toxoplasmic DNA in only 6 of 39 aqueous humor specimens (15%).36 Fardeau et al19 reported that 7 of their 9 patients with positive aqueous PCR results had negative results for local antibody production; these patients were immunocompromised. Of the 25 patients who did have local antibody production in aqueous humor, only 1 was immunocompromised.19 Labalette et al18 found no difference in the detection of local antibody production in aqueous between groups with different lesion sizes; however, all lesions in their study were less than 10 disc areas in size. Care needs to be taken in the interpretation of intraocular antibodies. Antibodies against toxoplasmosis in intraocular
fluid may be the result of either passive accumulation in a damaged, leaky eye or of local production as part of the specific host response. The GW coefficient26,27 addresses this problem by quantitating the relative excess of specific antibody in the eye. Coefficients higher than 1 theoretically should indicate local antibody production; however, most authors consider coefficients of only 3 or more to be reliable.23,33,34 Even without calculation of a formal GW coefficient, detection of any antibody directed against toxoplasmosis may be a useful, rapid, and inexpensive way of supporting a clinical suspicion of atypical toxoplasmic chorioretinitis.35 If vitreous fluid is taken, dilution by infusion solution must be avoided or the quantitative aspect of the test will be negated. The diagnostic approach to take in any individual patient is influenced by the specific features of the case and the local resources available to make the diagnosis. These factors, and the long interval over which cases were accrued, led to the heterogeneous approach to diagnostic testing in this series. The immune status of the patient and clinical circumstances influence the choice between (1) detection of the organism by PCR, culture, or histologic analysis; (2) detection of the host response with antibodies; or (3) both. The elderly and patients with AIDS are likely to have specific defects in immune response that render them more at risk for atypical, diffuse forms of toxoplasmosis17 and, because of the large burden of organisms, may be better suited to diagnosis by PCR. Immunocompetent individuals may be better candidates for antibody testing of aqueous humor, especially if the testing is performed after the immune response is well established. Local resources also influence the diagnostic test selected. Settings that are resource poor but have experienced clinicians may be more suited to an empiric trial of antitoxoplasmosis drugs before resorting to diagnostic testing. However, if the initial response to any therapy is equivocal, intraocular diagnostic testing is appropriate to avoid delay in instituting proper therapy. Intraocular antibody detection or PCR of aqueous humor avoids the high acquisition costs of vitreous fluid. Centers with virologic laboratories may prefer to culture vitreous fluid for toxoplasmosis on MRC-5 cell lines that also will support growth of common herpetic viruses known to cause necrotizing herpetic retinitis. Any eye undergoing vitrectomy surgery for diagnosis is presumed already to have eluded easier diagnosis by anterior chamber paracentesis or empiric therapy. In such eyes, because the diagnostic specimen will be obtained only once, maximal use of the vitreous specimen with multiple diagnostic tests seems warranted. In addition, eyes with retinal detachment or very unusual presentations may benefit from retinal biopsy of diseased areas.37 In our series, 11 patients (50%) received treatment with antiviral medications for presumed acute retinal necrosis syndrome before diagnosis and antitoxoplasmic therapy. Acute retinal necrosis syndrome is a clinical diagnosis that includes a variety of etiologic agents,46 although herpes class viruses are found in most retinal biopsy specimens47– 49 and in ocular fluids from acute retinal necrosis cases50 –52 and are not found in normal eyes.53 If severe confluent necrotizing retinitis with vascular inflammation
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Ophthalmology Volume 111, Number 4, April 2004 and vitreitis is present, the rapidity with which herpes viruses replicate may necessitate initiation of antiviral therapy to avoid irreversible damage. However, prompt diagnostic evaluation of intraocular fluids at the onset of any severe necrotizing or atypical chorioretinitis can help avoid delays in initiation of proper therapy while waiting for a clinical response. Ideally, anterior chamber paracentesis for PCR for herpes simplex, varicella, and cytomegalovirus would be performed simultaneously with initiation of treatment for a presumptive necrotizing viral retinitis. Polymerase chain reaction also seems to be an efficient means of diagnosis of toxoplasmosis in patients who are immunocompromised, elderly, or have large lesions. If there is uncertainly that PCR will yield a result, toxoplasmosis antibodies also can be obtained from aqueous humor. Rapid diagnosis by these simple means may avoid the extensive and invasive testing performed in many patients in this series after more severe disease developed. Earlier intervention with appropriate diagnostic studies also may improve prognosis. Although patients in this series ultimately were diagnosed with atypical toxoplasmosis and treated, visual results were poor, with improved vision in only 7 of 25 eyes. Figure 5 shows a suggested approach to the diagnosis of atypical, widespread chorioretinitis resulting from T. gondii.
14. 15. 16. 17. 18. 19. 20. 21. 22. 23.
References 1. Dodds EM. Ocular toxoplasmosis: clinical presentations, diagnosis, and therapy. Focal Points. Clin Modules Ophthalmol 1999;17:1–13. 2. Perkins ES. Ocular toxoplasmosis. Br J Ophthalmol 1973;57: 1–17. 3. Weiner A, BenEzra D. Clinical patterns and associated conditions in chronic uveitis. Am J Ophthalmol 1991;112:151– 8. 4. Nicholson DH, Wolchok EB. Ocular toxoplasmosis in an adult receiving long-term corticosteroid therapy. Arch Ophthalmol 1976;94:248 –54. 5. Hoerni B, Vallat M, Durand M, Pesme D. Ocular toxoplasmosis and Hodgkin’s disease: report of two cases. Arch Ophthalmol 1978;96:62–3. 6. Sabates R, Pruett RC, Brockhurst RJ. Fulminant ocular toxoplasmosis. Am J Ophthalmol 1981;92:497–503. 7. Pass RF, Morris RE, Shaw JF, Diethelm AG. Ocular toxoplasmosis after renal transplantation. South Med J 1981;74: 1033– 4. 8. Holland GN, Pepose JS, Pettit TH, et al. Acquired immune deficiency syndrome. Ocular manifestations. Ophthalmology 1983;90:859 –73. 9. Yeo JH, Jakobiec FA, Iwamoto T, et al. Opportunistic toxoplasmic retinochoroiditis following chemotherapy for systemic lymphoma. A light and electron microscopy study. Ophthalmology 1983;90:885–98. 10. Weiss A, Margo CE, Ledford DK, et al. Toxoplasmic retinochoroiditis as an initial manifestation of the acquired immune deficiency syndrome. Am J Ophthalmol 1986;101:248 –9. 11. Parke DW III, Font RL. Diffuse toxoplasmic retinochoroiditis in a patient with AIDS. Arch Ophthalmol 1986;104:571–5. 12. Heinemann MH, Gold JMW, Maisel J. Bilateral toxoplasma retinochoroiditis in a patient with acquired immune deficiency syndrome. Retina 1986;6:224 –7. 13. Pauleikhoff D, Messmer E, Beelen DW, et al. Bone-marrow
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pretation of intraocular and serum antibody levels in necrotizing retinitis. Retina 1995;15:233– 40. Garweg JG, Jacquier P, Boehnke M. Early aqueous humor analysis in patients with human ocular toxoplasmosis. J Clin Microbiol 2000;38:996 –1001. Freeman WR, Wiley CA, Gross JG, et al. Endoretinal biopsy in immunosuppressed and healthy patients with retinitis. Indications, utility, and techniques. Ophthalmology 1989;96: 1559 – 65. Saiki RK, Gelfand DH, Stoffel S, et al. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 1988;239:487–91. Burg JL, Grover CM, Pouletty P, Boothroyd JC. Direct and sensitive detection of a pathogenic protozoan, Toxoplasma gondii, by polymerase chain reaction. J Clin Microbiol 1989; 27:1787–92. Bre´ zin AP, Egwuagu CE, Burnier M Jr, et al. Identification of Toxoplasma gondii in paraffin-embedded sections by the polymerase chain reaction. Am J Ophthalmol 1990;110:599 – 604. Bre´ zin AP, Silveira C, Egwuagu CE, et al. Analysis of aqueous humor in ocular toxoplasmosis [letter]. N Engl J Med 1991;324:699. Aouizerate F, Cazenave J, Poirier L, et al. Detection of Toxoplasma gondii in aqueous humour by the polymerase chain reaction. Br J Ophthalmol 1993;77:107–9. Montoya JG, Parmley S, Liesenfeld O, et al. Use of the polymerase chain reaction for diagnosis of ocular toxoplasmosis. Ophthalmology 1999;106:1554 – 63. Bou G, Figueroa MS, Martı´-Belda P, et al. Value of PCR for detection of Toxoplasma gondii in aqueous humor and blood samples from immunocompetent patients with ocular toxoplasmosis. J Clin Microbiol 1999;37:3465– 8.
45. Figueroa MS, Bou G, Marti-Belda P, et al. Diagnostic value of polymerase chain reaction in blood and aqueous humor in immunocompetent patients with ocular toxoplasmosis. Retina 2000;20:614 –9. 46. Holland GN, Executive Committee of the American Uveitis Society. Standard diagnostic criteria for the acute retinal necrosis syndrome. Am J Ophthalmol 1994;117:663–7. 47. Culbertson WW, Blumenkranz MS, Pepose JS, et al. Varicella zoster virus is a cause of the acute retinal necrosis syndrome. Ophthalmology 1986;93:559 – 69. 48. Rahhal FM, Siegel LM, Russak V, et al. Clinicopathologic correlations in acute retinal necrosis caused by herpes simplex virus type 2. Arch Ophthalmol 1996;114:1416 –9. 49. Duker JS, Blumenkranz MS. Diagnosis and management of the acute retinal necrosis (ARN) syndrome. Surv Ophthalmol 1991;35:327– 43. 50. Rummelt V, Wenkel H, Rummelt C, et al. Detection of varicella zoster virus DNA and viral antigen in the late stage of bilateral acute retinal necrosis syndrome. Arch Ophthalmol 1992;110:1132– 6. 51. Knox CM, Chandler D, Short GA, Margolis TP. Polymerase chain reaction-based assays of vitreous samples for the diagnosis of viral retinitis. Use in diagnostic dilemmas. Ophthalmology 1998;105:37– 44, discussion 44 –5. 52. Ganatra JB, Chandler D, Santos C, et al. Viral causes of the acute retinal necrosis syndrome. Am J Ophthalmol 2000;129: 166 –72. 53. Pendergast SD, Werner J, Drevon A, Wiedbrauk DL. Absence of herpesvirus DNA by polymerase chain reaction in ocular fluids obtained from immunocompetent patients. Retina 2000; 20:389 –93.
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Toxoplasma gondii is a ubiquitous protozoan with worldwide distribution that can infect multiple tissues, including
Originally received: October 10, 2002. Accepted: July 30, 2003.
Manuscript no. 220823.
1
Stanford University School of Medicine, Palo Alto, California. 2 Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio. 3 Consultores Oftalmolo´gicos, Buenos Aires, Argentina. 4 University of Buenos Aires, Buenos Aires, Argentina. 5 Hyde Park Ophthalmology Group, San Juan, Puerto Rico. 6 Bascom Palmer Eye Institute, Miami, Florida. Supported by Heed Ophthalmic Foundation, Cleveland, Ohio (DMM), and the Ronald G. Michels Fellowship Foundation, Baltimore, Maryland (DMM). The authors have no commercial interests in this study. Correspondence to Janet L. Davis, MD, Bascom Palmer Eye Institute, 900 Northwest 17th Street, Miami FL 33136. E-mail: [email protected].
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© 2004 by the American Academy of Ophthalmology Published by Elsevier Inc.
the posterior segment of the eye.1 The diagnosis of toxoplasmic chorioretinitis in immunocompetent adults usually is made by ophthalmoscopic detection of a solitary focus of active chorioretinitis adjacent to a chorioretinal scar.2,3 Atypical presentations, such as bilateral, extensive, or multifocal disease, have been reported in immunocompromised patients with HIV infection, iatrogenic immunosuppression, or advanced age.4 –19 Lack of visible chorioretinal scars and extensive areas of retinal involvement may lead to a diagnosis of necrotizing herpetic retinitis and treatment with antivirals.17–25 Alternatively, severe posterior uveitis may be diagnosed initially, leading to treatment with corticosteroids that may either induce or worsen immunocompromise. Delay in diagnosis and treatment may worsen outcome despite later institution of specific therapy for toxoplasmic infection. We report 22 patients with atypical toxoplasmic chorioretinitis mimicking acute retinal necrosis syndrome and ISSN 0161-6420/04/$–see front matter doi:10.1016/j.ophtha.2003.07.004
Moshfeghi et al 䡠 Diagnosis of Atypical Toxoplasmosis describe the strategies used to reach the diagnosis. We make recommendations regarding diagnosis based on our experience and further describe the clinical features of this rare presentation of toxoplasmic chorioretinitis.
Patients and Methods Design This was a retrospective, observational case series of 22 patients with severe, atypical toxoplasmic chorioretinitis resembling acute retinal necrosis syndrome.
Participants Patients were identified in 2 university and 3 practice-based uveitis referral clinics in the United States, Argentina, and Puerto Rico between 1990 and 2001. Patients were accrued by review of patient lists in the various uveitis clinics. Patients were included if there was a final diagnosis of toxoplasmic chorioretinitis and the lesions were atypical because they were very large, multifocal, bilateral, or associated with diffuse retinal involvement or panophthalmitis. The differential diagnosis in each case included either panuveitis or necrotizing herpetic retinitis. Patients were excluded if the diagnosis of toxoplasmosis had not been satisfactorily confirmed by at least 1 of the following: response to antitoxoplasmosis medications (usually after previous treatment with corticosteroids, antivirals, or both); intraocular diagnostic studies such as polymerase chain reaction (PCR), intraocular antibodies, culture of intraocular fluid, or histopathologic examination showing T. gondii in necrotic retinal tissue. A retrospective review of the medical records of the 22 eligible patients then was conducted. Data collected included age; gender; systemic diseases; duration of symptoms; prior treatment and its duration; extent of ocular involvement; anterior chamber cell and flare graded on a scale of 0 to 4; vitreous inflammation graded as mild, moderate, or dense; preexisting healed chorioretinal scars; retinal detachment; diagnostic studies performed and results; treatment after diagnosis; initial and final Snellen visual acuity; and anatomic status at last follow-up. Response to antitoxoplasmosis medications was assessed by serial fundus examination. Conversion of active chorioretinitis to an inactive scar or clear improvement in disease activity before last follow-up was considered to be evidence of a positive response to specific therapy. Intraocular and serum antibody determinations were performed in reference laboratories and expressed as either enzyme-linked immunosorbent assay units or serum dilutions. In some cases, intraocular production of antibody was calculated by the Goldmann-Witmer (GW) coefficient according to the following formula26,27: GW coefficient ⫽ (Intraocular anti-Toxoplasma IgG / Intraocular IgG) / (Serum anti-Toxoplasma IgG / Serum IgG) Polymerase chain reaction was performed either by reference clinical laboratories, research laboratories at Washington University (Dr. Russell Van Gelder), or by the University of Miami Ocular Microbiology Laboratory, using primers for the B1 gene of T. gondii as previously described28 or using multiplex PCR (Dr. Van Gelder).29 Culture of intraocular fluid, when performed, was on media supporting viral, bacterial, or fungal growth, or a combination thereof. A specific protocol to support
the growth of toxoplasmosis on viral media was used for some cases.28 Histopathologic examination of retinal biopsies and enucleated globes was performed according to standard techniques. Review of data without linkage to unique patient identifiers was conducted according to applicable regulations of the Human Subjects Research Committees at the University of Miami and The Cleveland Clinic by physicians who were aware of the final clinical diagnosis of toxoplasmic chorioretinitis. Standardized intervals of follow-up were not specified. Regular reexamination during the period of treatment was encouraged for all patients as clinically indicated. Because the main emphasis was on diagnosis, no minimum amount of follow-up was required beyond confirmation of the diagnosis, and there was no determination of an adequate sample size.
Main Outcome Measures The primary outcome variable was the means by which diagnosis was made. The secondary outcome variable was final visual and anatomic status of involved eyes.
Results There were 22 patients: 9 women and 13 men. Three patients had bilateral disease, for a total of 25 affected eyes. Mean age was 53.5 years (range, 19 –77 years), with a median of 59.5 years. Five patients (23%) were more than 70 years of age. Six patients (27%; patients 17–22) were infected with HIV, with a median CD4⫹ T-lymphocyte count of 168 (range, 18 – 683). A variety of other systemic illnesses were present that might have affected immune competency (Table 1). Three patients underwent uncomplicated cataract extraction with intraocular lens placement within 6 months before the development of chorioretinitis, possibly stimulating recurrence (patients 2, 7, and 11).30 Mean initial Snellen visual acuity was 20/110 (median, 20/400; range, 20/20 to no light perception). There was a wide range of anterior chamber cellular reaction; vitreous reaction usually was graded as “dense” (Table 1). The chorioretinitis involved from 1 to 12 clock hours of the fundus (mean, 6.4⫾3.9 clock hours; median, 6 clock hours). In 6 cases, there was a single, well-defined large lesion. In 9 cases, there was diffuse involvement with poorly defined borders, and in 6 of these, there was more than 1 focus of disease. Six cases were classified as panophthalmitis because of the severity of the inflammatory response with diffuse ocular involvement; 3 of these also had multifocal lesions. In 4 of 23 eyes in which the fundus was visible, healed chorioretinal scars were present (17.4%). Eight of 25 eyes (32%) had retinal detachments. Clinical details are presented in Table 1. Symptoms had been present for an average of 10.3⫾10 weeks and for a median of 7 weeks (Table 1). Twelve patients (54%) had received oral, intramuscular, or periocular corticosteroids before diagnosis for an average of 13.8⫾11.5 weeks (median, 10 weeks; range, 1– 40 weeks). Eleven (50%) had received antiviral therapy for an average of 3.2⫾3.5 weeks (median, 2 weeks; range, 1 day–13 weeks). Seven patients (21.8%) received both antiviral therapy and oral or injectable corticosteroids. A total of 16 of 22 patients (73%) therefore received therapy directed at severe endogenous uveitis, necrotizing herpetic retinitis, or both before diagnosis of toxoplasmosis (Table 1). Intraocular diagnostic specimens consisted of 5 aqueous humors, 13 vitreous humors, 3 retinal biopsies, and 2 whole globes (Table 2). Four patients (18%) received no diagnostic testing, and 2 (9%) were tested for serum antibodies only. In these patients, diagnosis was confirmed by response to antitoxoplasmosis medi-
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Ophthalmology Volume 111, Number 4, April 2004 Table 1. Patient Characteristics and Ocular Findings at Presentation Systemic Disease
Initial Visual Symptoms Acuity (wks)
Patient No.
Age (yrs)
Corticosteroids (wks)
Antivirals (wks)
Gender
1 2
19 71
F F
None None
Left Left
HM HM
12 4
12 16
LP
10
8
Right
3/200
4
12
None Oral acyclovir (1) IV acyclovir (13), IV foscarnet (3), intravitreal ganciclovir ⫻1 None
3
76
M
None
Right
4
44
M
None
5 6 7 8
65 60 77 60
F M F M
None None NIDDM Chronic active hepatitis Thoracic zoster
Left Left Left Right
20/100 20/100 20/400 20/40
24 6 4 8
24 None None None
None None None IV ganciclovir
9
50
M
Left
20/70
16
4
Alzheimer’s, thymoma None
Right
HM
40
40
Oral acyclovir (4) None
10
75
F
11
77
M
Left
HM
3
None
None
12 13
68 40
F F
None Autoimmune hepatitis
Right Right
20/200 20/20
6 1
None 4
None IV acyclovir (3)
Left
20/60 CF
28
28*
20/50
12
8
Eye
14
68
M
Alcoholism
Left
15
61
F
Hypogammaglobulinemia, abnormal CD4:CD8 ratio of 0.88
Right
Left
4/200
16 17
29 35
M F
None HIV CD4 41
Left Left
HM NLP
12 8
8 None
18
36
M
HIV CD4 240
Right
HM
4
None
19
59
M
HIV CD4 400
Left
20/50
2
None
20 21 22
42 35 30
M M M
HIV CD4 294 HIV CD4 18 HIV CD4 23
Right Left Right
20/80 20/300 CF
3 3 2
None None 1
Left
20/400
Oral acyclovir (4) IV acyclovir (1)
None Oral acyclovir (2) Intravitreal and IV foscarnet and ganciclovir (4) IV acyclovir (2) None None IV ganciclovir (1 day)
Active Retinal Lesions (Clock Hours)
Healed Retinal Scars Detachment
Focal (4) Panophthalmitis, multifocal (8) Multifocal, peripheral (12)
Y N
N N
N
N
Multifocal, peripheral (6) Focal (4) Multifocal (12) Diffuse (6) Multifocal (3)
N
N
N N N N
N N N Y
Diffuse (3)
Y
Y
Diffuse (12)
Y
N
Diffuse, multifocal (8) Diffuse (5) Focal (⬍1)
N
N
N N
N N
N
N
N
N
N
N
N
Y
Y No view N
Y Y
N
N
N N N
Y Y N
No view
Y
Diffuse multifocal, peripheral (9) Panophthalmitis, multifocal (12) Diffuse, multifocal (2)
Diffuse, multifocal (3) Focal (3) Panophthalmitis (12) Panophthalmitis (12)
Panophthalmitis (9) Focal (2) Focal (1) Diffuse, multifocal (3) Diffuse, multifocal (6)
N
CD4 ⫽ CD4⫹ T lymphocyte count; CF ⫽ counting fingers; F ⫽ female; HM ⫽ hand motions; LP ⫽ light perception; M ⫽ male; N ⫽ no; NIDDM ⫽ non–insulin-dependent diabetes mellitus; NLP ⫽ no light perception; Y ⫽ yes. *Also treated briefly with antitoxoplasmosis medications early in the course of disease, then switched to prednisone for inadequate response.
cations. Ten patients (45%) were tested with 1 intraocular specimen only (8 vitreous and 2 aqueous humor specimens), and 6 (27%) were tested with 2 or more intraocular specimens. Specimens were collected in 6 eyes (27%) during repair of retinal
718
detachment with pars plana vitrectomy, 4 eyes had diagnostic anterior chamber paracentesis, and 4 eyes had vitrectomy for diagnostic purposes. Diagnostic tests used in each case are listed in Table 2.
Moshfeghi et al 䡠 Diagnosis of Atypical Toxoplasmosis Table 2. Diagnostic Testing and Outcomes of Treatment Patient No.
Specimen
Diagnostic Testing and Results
1 2
None Serum
Not carried out Toxoplasmosis IgG high positive
3
Vitreous Serum Vitreous
4
Vitreous
Culture negative for virus, fungi, and bacteria Toxoplasmosis IgG positive Toxoplasmosis IgG high positive, culture negative for virus Toxoplasmosis IgG titers positive
5 6 7
None Serum None
8
Antitoxoplasmosis Therapy*
Final Visual Acuity
Retinal Appearance at Last Follow-up
PY, CL, TS, P PY, TS, CL
HM CF
Inactive retinitis Inactive retinitis, macular scar
PY, TS, CL
NLP
Improving
PY, TS, CL, P
20/200
Not carried out Toxoplasmosis IgG titers 1:1280 Not carried out
PY, S, PCL PY, S, PCL, P PY, CL, DX, P
20/100 20/100 HM
Serum
Toxoplasmosis IgG high positive
PY, S, CL, TS, M
20/70
Vitreous Retinal biopsy Aqueous
Toxoplasmosis IgG high positive, PCR and cultures negative for VZV, HSV, and CMV Necrotic tissue negative for bacterial and fungal stains Toxoplasmosis IgG titers positive
PY, CL, S, P
20/50
10
Vitreous None
Toxoplasmosis IgG titers positive Not carried out
PY, S, P
HM
11
Vitreous
PCR positive for toxoplasmosis, negative for VZV, HSV
PY, S, CL, P
HM
12 13
Serum Aqueous
PY, S, CL, P PY, S, CL, P
14
Serum Aqueous
20/100 20/60 right eye NLP left eye NLP
15
Serum Aqueous
Toxoplasmosis IgG titer 1:512 Multiplex PCR positive for toxoplasmosis, negative for HSV, VZV, and CMV Toxoplasmosis IgG titer ⬎ 1:1024 GW toxoplasmosis, 2.32; CMV, 2.00; VZV, 2.08; HSV, 1.5 Toxoplasmosis IgG low positive GW toxoplasmosis, 66; CMV, 19; VZV, 34; HSV negative Toxoplasmosis IgG high positive, culture negative for bacteria and fungi Histologic results positive for toxoplasmic tissue cysts Toxoplasmosis IgG high positive, culture negative for toxoplasmosis and virus PCR positive for toxoplasmosis, culture positive for toxoplasmosis, culture negative for virus, fungi, and bacteria Histologic results positive for toxoplasmic tissue cysts, PCR positive for toxoplasmosis
Improving active retinitis Inactive retinitis, macular scar Improving retinitis Improving retinitis Improving retinitis Phthisis
20/30 right eye 3/200 left eye
Unknown Unknown
9
Vitreous 16
Retinal biopsy Vitreous
17
Vitreous
18
Whole globe histologic examination Vitreous
19 20
Whole globe histologic examination Serum Aqueous Serum Vitreous
21
Serum Vitreous
PY, CL, TS PY, SSS, M
None
—
Toxoplasmosis IgG high positive, PCR positive for toxoplasmosis, culture positive for toxoplasmosis, culture negative for virus Histologic results positive for toxoplasmic tissue cysts
PY, CL
—
Enucleation
Toxoplasmosis IgG high positive GW toxoplasmosis, 20.3; CMV, 15.4 Toxoplasmosis IgG high positive
PY, S
LP
Progressive retinitis
PY, S
6/200
PY, S
20/400
Inactive retinitis, attached
Inactive retinitis, attached Enucleation
Toxoplasmosis IgG high positive, PCR positive for toxoplasmosis, culture positive for toxoplasmosis, culture negative for virus, flow cytometry and cytologic results negative for lymphoma Negative
DX
Inactive retinitis, macular scar Inactive retinitis Inactive retinitis Inactive retinitis, macular scar Inactive retinitis, attached
20/30
Inactive retinitis, attached
Inactive retinitis, attached
PCR positive for toxoplasmosis, culture positive for toxoplasmosis, culture negative for virus (continued)
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Ophthalmology Volume 111, Number 4, April 2004 Table 2. (Continued.) Patient No. 22
Specimen
Diagnostic Testing and Results
Serum
Toxoplasmosis IgM titer negative
Vitreous
PCR positive for toxoplasmosis, culture negative for virus, fungi, and bacteria PCR positive for toxoplasmosis, culture positive for toxoplasmosis
Retinal biopsy
Antitoxoplasmosis Therapy*
Final Visual Acuity
Retinal Appearance at Last Follow-up
PY,S
20/400 right eye NLP left eye
Inactive retinitis, macular scar Phthisis
CF ⫽ counting fingers; CL ⫽ clindamycin; CMV ⫽ cytomegalovirus; DX ⫽ doxycycline; GW ⫽ Goldmann-Witmer coefficient; HM ⫽ hand motions only; HSV ⫽ herpes simplex virus; IgG ⫽ immunoglobulin G; IgM ⫽ immunoglobulin M; LP ⫽ light perception only; M ⫽ minocycline; NLP ⫽ no light perception; P ⫽ prednisone; PCL ⫽ periocular clindamycin; PCR ⫽ polymerase chain reaction; PY ⫽ pyrimethamine; S ⫽ sulfadiazine; SSS ⫽ triple sulfa; TS ⫽ trimethoprim-sulfamethoxazole; VZV ⫽ varicella zoster virus. *Chronic therapy was recommended for the HIV-positive patients. In 15 of the 16 non-HIV patients, treatment was continued for a median of 2 months (range, 1–24 months).
Nine of 11 serum antibody titers were positive. The 2 negative cases occurred in HIV-positive patients (Table 2). All 5 aqueous humor specimens were positive for toxoplasmosis, 4 by immunoglobulin G antibody determinations (3 with GW coefficients) and 1 by PCR. There were 13 vitreous specimens. All 8 vitreous specimens tested for intraocular antibody against toxoplasmosis were positive, as were all 6 PCR determinations and 4 of 5 vitreous cultures. There were 3 retinal biopsy specimens. One retinal biopsy was positive by PCR and culture, 1 by histologic examination (Figs 1, 2), and 1 showed only necrotic tissue with negative fungal and bacterial stains. Both enucleated globes showed toxoplasmic tissue cysts on histologic examination (Fig 3). Vitreous specimens in these 2 cases were positive by PCR and culture. Follow-up of 1 month or more was available in 16 patients (73%) and of 4 months or more in 9 patients (41%). For the 16 patients with at least 1 month of follow-up, the mean follow-up was 19.1⫾25.8 months (range, 1–74.4 months; median, 6.0 months). For the 9 patients with at least 4 months of follow-up, the mean follow-up was 32.2⫾28.3 months (range, 6 –74.4 months; median, 15 months). In 15 of the 16 non-HIV patients, treatment was continued for a median of 2 months (range, 1–24 months). One elderly, non-HIV patient had multiple relapses when medication was discontinued (Fig 4). Thirteen of the 19 evaluable eyes (68%) healed with treatment by the final follow-up, 5 were improving, and 1 was progressing. Eyes considered nonevaluable were enucleated (n ⫽ 2), were phthisical (n ⫽ 2), or were without follow-up (n ⫽ 2). Mean final visual acuity was 20/156 (median, 20/2500; range, 20/30 to no light perception). Only 5 of 25 eyes (20%) had a final visual acuity of ⬎20/80. Seven of 25 eyes (28%) had improved visual acuity at last follow-up compared with initial visual acuity.
Five of 7 eyes with retinal detachment were attached at the final follow-up; 1 eye with no light perception could not be evaluated because of lack of fundus view and retained silicone oil.
Discussion Toxoplasmic chorioretinitis that presents without a typical small to moderate focus of active chorioretinitis adjacent to a healed chorioretinal scar can be difficult to diagnose ophthalmoscopically. Extensive, bilateral, or multifocal toxoplasmic chorioretinitis similar to the cases in this series has been reported previously and is considered rare.4 –19 Differential diagnosis of such lesions includes acute retinal necrosis syndrome, other necrotizing herpetic retinopathy, cytomegalovirus retinitis,31 severe panuveitis, fungal infection, and intraocular lymphoma.32 An initially incorrect diagnosis with prolonged empiric treatment may be harmful by delaying diagnosis. Use of corticosteroids without concomitant treatment with antitoxoplasmosis medication may allow the chorioretinitis to progress at a more rapid rate. Early use of invasive diagnostic procedures in patients with sight-threatening chorioretinitis that cannot be satisfactorily diagnosed by ophthalmoscopy, or in patients without response to a chosen empiric therapy, may result in better visual and anatomic outcomes for this devastating ocular infection. Laboratory evaluation of intraocular fluid and tissue as used in 16 patients in this series can be an effective means of diagnosing toxoplasmic chorioretinitis.23,33–36 Direct de-
Figure 1. A, Right eye of a woman treated with corticosteroids for 2 months before referral (patient 15; see Tables 1, 2). Acyclovir treatment was begun for presumed necrotizing herpetic retinitis. Corticosteroids were continued. Arteriolitis is present. B, The left eye also displayed large areas of confluent necrotizing retinitis with arteriolitis. Macular involvement with severe vision loss to 4/200 is present. C, Right eye. After 13 days, the retinitis is seen to have progressed. Large satellite lesions are present at the edge of the lesion. Vitreous haze has increased. D, Left eye. Similar worsening is noted. Retinal biopsy was elected. Figure 2. A, Retinal biopsy of the patient in Figure 1. Toxoplasmic cysts are present in retinal tissue (stain, hematoxylin– eosin; original magnification, ⫻10). B, Electron microscopy depicting toxoplasmic cysts (same patient as in Figs 1 and 2A). Figure 3. A, Panophthalmitis. At presentation, this 35-year-old woman (patient 17; see Tables 1, 2) had vision of no light perception, necrotizing retinitis, retinal detachment, and marked intraocular inflammation. Oral acyclovir was begun as prophylaxis for the fellow eye after declining intravenous treatment. She was then lost to follow-up for 6 weeks, returning with severe ocular pain. Enucleation was recommended. HIV infection with a CD4 count of 41 was diagnosed on that admission. B, Biopsy from the enucleated globe showing toxoplasmic tissue cysts (stain, hematoxylin– eosin; original magnification, ⫻40).
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Figure 4. A, This 77-year-old woman with diabetes mellitus (patient 7; see Tables 1, 2) had a small focus of active chorioretinitis after cataract surgery that seemed to improve spontaneously. Six months later, diffuse chorioretinitis, vitreous inflammation, and reduced vision of 20/400 were noted. Pyrimethamine, clindamycin, and low-dose corticosteroids were begun. She was intolerant to clindamycin. After 6 weeks, treatment was changed to doxycycline 100 mg orally twice daily. B, Three and one-half months later, the lesion showed evidence of healing at the border with reduction in vitreous inflammation. The doxycycline was stopped. C, Six weeks later, there was recurrent chorioretinitis and vitreous inflammation with vision of 20/400. She was administered doxycycline again with stabilization of the infection. Despite arrest of the progression of the lesion, the final outcome was poor, with optic nerve pallor and vision of hand motions.
tection of an infective agent in a diseased eye generally is taken as prima facie evidence of causation; culture and histopathologic examination have been traditional means of detection.37 Recently, isolation of toxoplasmosis organisms from blood or eye fluid has been reported in tissue culture systems developed for viral culture.28 Five patients in this series from a single center had growth of toxoplasmosis organisms on tissue culture media. Although the technique appears sensitive, it was slow, taking 2 to 23 days (average, 12 days) after inoculation to produce visible plaques that then required confirmation by microscopy, fluorescent antibody staining, and PCR.28 Histopathologic analysis is considered the gold standard, but biopsies of the eye are rarely undertaken except in severe disease requiring enucleation (2 patients in this series), when incidental to retinal detachment surgery (2 patients),37 or in bilaterally sight-threatening disease (1 patient). Polymerase chain reaction amplification of toxoplasmic DNA is more rapid than culture and requires only a small amount of intraocular fluid.38 – 40 An intracellular organism
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such as T. gondii ordinarily would not be expected to be floating freely in intraocular fluid.41,42 Widespread chorioretinitis with necrotizing retinitis as in this series presumably increases the chance that organisms or parts of organisms will be present in vitreous fluid. In the report of Montoya et al,43 5 of 7 patients with atypical, severe toxoplasmic chorioretinitis had positive vitreous PCR results. Aqueous humor has been believed to be less satisfactory as a substrate for PCR in toxoplasmic chorioretinitis than in viral retinitis.36,42– 45 The first report of PCR testing for toxoplasmosis in aqueous humor was able to amplify DNA from only 17% of the cases.41 Fardeau et al19 subsequently reported 9 cases of atypical toxoplasmosis characterized by large lesions in elderly or immunocompromised patients, each of which had positive PCR results for toxoplasmosis from aqueous humor. Johnson et al17 also reported 7 elderly patients with atypical toxoplasmic chorioretinitis resembling acute retinal necrosis, in 2 of whom diagnosis was made by PCR testing of aqueous humor. Nine of 15 patients (60%) with lesions larger than 3 disc areas had positive PCR
Moshfeghi et al 䡠 Diagnosis of Atypical Toxoplasmosis
Figure 5. Flow chart depicting an approach to the diagnosis of atypical disseminated chorioretinitis. Useful initial data include history of chorioretinitis or healed scars; risk factors or laboratory evidence for toxoplasmosis infection, human immunodeficiency virus, or other immunocompromise; and clinical features such as duration of symptoms and rapidity of onset, and the location, appearance, and confluency of the retinal infiltrates. Aqueous humor is often an adequate substrate for initial testing (see text). Test results and response to therapy help the clinician determine whether diagnostic vitrectomy is needed. Diagnostic vitrectomy should be as comprehensive as indicated and feasible with polymerase chain reaction (PCR) determinations; antibody determinations; bacterial, fungal, and viral cultures; and consideration of retinal biopsy. Cytologic examination may be appropriate in some cases. IgG ⫽ immunoglobulin G; PPV ⫽ pars plana vitrectomy.
results from aqueous humor versus 3 of 12 patients (25%) with smaller lesions in the study of Labalette et al18; all patients were older than 50 years. Detection of specific antibodies against toxoplasmosis in intraocular fluids is an alternative strategy that complements PCR testing. Both timing and immune status may influence results of antibody testing. Garweg et al36 confirmed ocular toxoplasmosis in 28 of 49 patients (57%) tested for intraocular antitoxoplasmosis immunoglobulin G within 3 weeks of onset of symptoms; sensitivity rose to 70% if a later specimen was tested. In the same series, PCR detected toxoplasmic DNA in only 6 of 39 aqueous humor specimens (15%).36 Fardeau et al19 reported that 7 of their 9 patients with positive aqueous PCR results had negative results for local antibody production; these patients were immunocompromised. Of the 25 patients who did have local antibody production in aqueous humor, only 1 was immunocompromised.19 Labalette et al18 found no difference in the detection of local antibody production in aqueous between groups with different lesion sizes; however, all lesions in their study were less than 10 disc areas in size. Care needs to be taken in the interpretation of intraocular antibodies. Antibodies against toxoplasmosis in intraocular
fluid may be the result of either passive accumulation in a damaged, leaky eye or of local production as part of the specific host response. The GW coefficient26,27 addresses this problem by quantitating the relative excess of specific antibody in the eye. Coefficients higher than 1 theoretically should indicate local antibody production; however, most authors consider coefficients of only 3 or more to be reliable.23,33,34 Even without calculation of a formal GW coefficient, detection of any antibody directed against toxoplasmosis may be a useful, rapid, and inexpensive way of supporting a clinical suspicion of atypical toxoplasmic chorioretinitis.35 If vitreous fluid is taken, dilution by infusion solution must be avoided or the quantitative aspect of the test will be negated. The diagnostic approach to take in any individual patient is influenced by the specific features of the case and the local resources available to make the diagnosis. These factors, and the long interval over which cases were accrued, led to the heterogeneous approach to diagnostic testing in this series. The immune status of the patient and clinical circumstances influence the choice between (1) detection of the organism by PCR, culture, or histologic analysis; (2) detection of the host response with antibodies; or (3) both. The elderly and patients with AIDS are likely to have specific defects in immune response that render them more at risk for atypical, diffuse forms of toxoplasmosis17 and, because of the large burden of organisms, may be better suited to diagnosis by PCR. Immunocompetent individuals may be better candidates for antibody testing of aqueous humor, especially if the testing is performed after the immune response is well established. Local resources also influence the diagnostic test selected. Settings that are resource poor but have experienced clinicians may be more suited to an empiric trial of antitoxoplasmosis drugs before resorting to diagnostic testing. However, if the initial response to any therapy is equivocal, intraocular diagnostic testing is appropriate to avoid delay in instituting proper therapy. Intraocular antibody detection or PCR of aqueous humor avoids the high acquisition costs of vitreous fluid. Centers with virologic laboratories may prefer to culture vitreous fluid for toxoplasmosis on MRC-5 cell lines that also will support growth of common herpetic viruses known to cause necrotizing herpetic retinitis. Any eye undergoing vitrectomy surgery for diagnosis is presumed already to have eluded easier diagnosis by anterior chamber paracentesis or empiric therapy. In such eyes, because the diagnostic specimen will be obtained only once, maximal use of the vitreous specimen with multiple diagnostic tests seems warranted. In addition, eyes with retinal detachment or very unusual presentations may benefit from retinal biopsy of diseased areas.37 In our series, 11 patients (50%) received treatment with antiviral medications for presumed acute retinal necrosis syndrome before diagnosis and antitoxoplasmic therapy. Acute retinal necrosis syndrome is a clinical diagnosis that includes a variety of etiologic agents,46 although herpes class viruses are found in most retinal biopsy specimens47– 49 and in ocular fluids from acute retinal necrosis cases50 –52 and are not found in normal eyes.53 If severe confluent necrotizing retinitis with vascular inflammation
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Ophthalmology Volume 111, Number 4, April 2004 and vitreitis is present, the rapidity with which herpes viruses replicate may necessitate initiation of antiviral therapy to avoid irreversible damage. However, prompt diagnostic evaluation of intraocular fluids at the onset of any severe necrotizing or atypical chorioretinitis can help avoid delays in initiation of proper therapy while waiting for a clinical response. Ideally, anterior chamber paracentesis for PCR for herpes simplex, varicella, and cytomegalovirus would be performed simultaneously with initiation of treatment for a presumptive necrotizing viral retinitis. Polymerase chain reaction also seems to be an efficient means of diagnosis of toxoplasmosis in patients who are immunocompromised, elderly, or have large lesions. If there is uncertainly that PCR will yield a result, toxoplasmosis antibodies also can be obtained from aqueous humor. Rapid diagnosis by these simple means may avoid the extensive and invasive testing performed in many patients in this series after more severe disease developed. Earlier intervention with appropriate diagnostic studies also may improve prognosis. Although patients in this series ultimately were diagnosed with atypical toxoplasmosis and treated, visual results were poor, with improved vision in only 7 of 25 eyes. Figure 5 shows a suggested approach to the diagnosis of atypical, widespread chorioretinitis resulting from T. gondii.
14. 15. 16. 17. 18. 19. 20. 21. 22. 23.
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