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Choroidal neovascular membranes (CNVMs) rarely complicate toxoplasmic chorioretinitis1-5and are managed by observation; antiparasitic, anti-inflammatory medication; laser photocoagulation; surgical excision; or photodynamic therapy, with variable outcomes. As occurs with CNVMs secondary to age-related macular degeneration, Toxoplasma gondiiincreases expression of hypoxia-inducible factor–1α in tissue cultures along with vascular endothelial growth factor (VEGF).6
Two patients with prior ocular toxoplasmosis had active CNVMs with subretinal blood and fluid on clinical examination and ocular coherence tomography (OCT) and hyperfluorescence with leakage documented on fluorescein angiogram (FA). Each was treated with off-label intravitreal injections of ranibizumab (Genentech, Inc, South San Francisco, California) and antiparasitic treatment, with responses documented with measurements of visual acuity, full fundus photographs, FA, and OCT. We reviewed courses and photographs of 187 persons with toxoplasmosis, 175 definitely congenitally acquired, followed up in the National Collaborative Chicago-based Congenital Toxoplasmosis Study to identify those who had recognized ocular neovascular disease. Three persons had a CNVM and 1 had a retinal angioma with exudation.
Institutional review board approval was obtained for this study. Written informed consent was obtained from parents or legal guardians of participating children and directly from patients (if legal adult age). This study is in compliance with Health Insurance Portability and Accountability Act of 1996 regulations.
Unless otherwise specified, reported visual acuities are best-corrected visual acuity.
A 25-year-old man was seen with a complaint of abrupt onset of decreased vision of the left eye for 1 week. He reported that he could not distinguish faces, see television, distinguish numbers on the face of a clock or on the dashboard of his car or fingers held up in an examination room, or distinguish the lines on an Amsler grid. He had a history of decreased vision in the right eye since age 12 years secondary to a macular scar attributed to ocular toxoplasmosis, and he said that in the prior week his vision in his left eye had become as severely impaired as the vision in his right eye. Results of a Toxoplasmadye test with undiluted serum in the US reference laboratory were positive and serology results were negative for antibody to Histoplasma. A brain computed tomographic scan showed no abnormalities. His visual acuity at the initial visit was 20/400 OD and 20/50 OS; his visual acuity had been 20/20 OS. Results of tonometry and anterior segment examination were within normal limits in each eye. There was no anterior chamber inflammation or vitritis in either eye.
Fundus examination of the right eye revealed an inactive macular chorioretinal scar along with peripapillary and peripheral scars. The left fundus similarly showed peripapillary and peripheral chorioretinal scars. There was subretinal fluid with retinal striae, and subretinal hemorrhage was evident within the macula tracking toward the fovea. An FA and OCT demonstrated a peripapillary CNVM with hemorrhage (Figure 1).
Patient 1 fundus photographs, fluorescein angiography, and optical coherence tomography at the initial visit and 1, 2, and 5 months after the first ranibizumab injection.
After extensive discussions and consideration of all options, we and the patient decided to perform an off-label intravitreal injection of 0.5 mg of ranibizumab in the left eye with concurrent systemic administration of oral pyrimethamine, sulfadiazine, and leukovorin. One month following initial injection and initiation of medical treatment, visual acuity improved to 20/20 OS. There was resolution of a significant portion of the subretinal hemorrhage and subretinal fluid, and degree of hyperfluorescence of the CNVM had decreased (Figure 1). One more ranibizumab treatment was administered at this visit. One month later there was a small amount of residual subretinal hemorrhage without leakage of fluorescein or presence of subretinal fluid noted clinically or with OCT (Figure 1). Complete involution of the CNVM, resolution of the subretinal fluid and hemorrhage, and maintenance of 20/20 acuity were documented by the second month after treatment. Visual acuity remained between 20/20 and 20/15, and examination documented that the CVNM was no longer present 6 months after the initial ranibizumab injection (Figure 1). Clearing subretinal hemorrhage revealed a lesion superior to the optic disc with initially soft blurred edges and eventually sharply demarcated edges with pigment around the perimeter (Figure 1). Anti-Toxoplasmamedicines were continued until 2 weeks after the edges of the scar became sharply demarcated and pigmented.
A 7-year-old boy had a CNVM with hemorrhage 1 month prior to his initial visit with us for this problem. At this visit with us, he described complete loss of vision and had a visual acuity of hand motion OD. He was treated 1 year prior to this examination for active toxoplasmic chorioretinitis and had a right macular chorioretinal scar. He had a visual acuity of 20/40 OD following treatment of the acute episode and visual acuity of 20/20 OS. He had progressive visual loss in the right eye during the subsequent year. He had undergone unilateral strabismus surgery in the right eye for esotropia, with perioperative use of topical steroids without antiparasitic treatment 5 months prior to his initial visit with us for this problem. He reported gradual worsening of vision and, by the week prior to his initial visit with us for this problem, he reported that he could not see with this eye at all. Results of tonometry and anterior segment examination were within normal limits in each eye. There was no aqueous or vitreous inflammation in either eye. Subretinal hemorrhage surrounded a macular scar in the right eye (Figure 2). There was leakage recorded by FA. Optical coherence tomography revealed cystic spaces overlying the area of increased transmission through the atrophic lesion, with the CNVM adjacent to this area elevating the overlying retina (Figure 2).
Patient 2 fundus photographs, fluorescein angiography, and optical coherence tomography at the initial visit for this problem and 7 and 11 weeks after the first ranibizumab injection.
When initially diagnosed at 6 years of age, his Sabin-Feldman dye test result was 1:2048 in the US reference laboratory and his mother's serology results were negative for T gondii. He had no IgM, IgA, or IgE antibodies to T gondiiand his differential agglutination (AC/HS) test indicated a chronic infection. A brain computed tomographic scan showed no abnormalities.
After careful consideration by his parents and all physicians caring for the child, off-label intravitreal injection of 0.5 mg of ranibizumab was performed with concurrent oral administration of pyrimethamine, sulfadiazine, and leukovorin. This intravitreal ranibizumab treatment was repeated 4 weeks and 8 weeks after the initial treatment. Because of transient neutropenia during the prodrome of a viral infection, this treatment was changed to a lower dose of pyrimethamine and clarithromycin. Sulfadiazine administration was discontinued. Neutropenia resolved and neither neutropenia nor any other problems were noted at any other time during treatment, including with the subsequent ranibizumab injections. The child was followed up with fundus photographs every 1 to 2 weeks throughout treatment.
Seven weeks after the first ranibizumab injection, fundus photographs and FA recorded resolution of much of the subretinal hemorrhage with a concurrent decrease in the size of the CNVM. Optical coherence tomography documented resorption of cystic fluid and flattening of the CNVM. Eleven weeks after the first ranibizumab injection, fundus photographs and FA showed complete resolution of the subretinal hemorrhage and involution of the CNVM. There was a small amount of cystic fluid accumulation on OCT. Visual acuity improved to 20/100 at distance and 20/40 at near 11 weeks after the initial ranibizumab injection. Treatment was continued for 3 injections and he currently is being followed up. Antiparasitic medications were continued throughout, and 1 week after the last ranibizumab injection, pyrimethamine administration was discontinued followed by an additional week of leukovorin treatment. Clarithromycin administration alone has been continued.
Increased expression of VEGF, in addition to compromise in the Bruch membrane and inflammation secondary to infection with T gondii, may contribute to neovascular disease in ocular toxoplasmosis. Increased expression of hypoxia-inducible factor–1α and VEGF caused by T gondiiin tissue culture provides a rationale for specifically targeting VEGF to treat CNVMs in ocular toxoplasmosis.
Six patients with ocular toxoplasmosis and neovascular disease (Table) (Figures 1, 2, and 3) were diagnosed with ocular toxoplasmosis when younger than 12 years. Neovascularization developed between ages 4 and 25 years. None had been treated with antiparasitic medicines in utero or their first year of life. Two patients were treated with anti-VEGF therapy and anti-Toxoplasmamedicines; 1, with photodynamic therapy only; and 2, with only antiparasitic medicines (Figure 4). One patient with acquired retinal angioma, exudate, and partial serous retinal detachment was treated with anti-VEGF and antiparasitic medicines. She developed a progressive subretinal exudate with frank macular detachment and a drop in visual acuity to 2400. She had a scleral buckle and vitrectomy procedure on the left eye with peeling of posterior membranes, cryopexy to the vasoproliferative lesion, and laser barricade posterior to the buckle. The buckle was placed high and over the areas of significant traction and vasoproliferation. An air-fluid exchange was performed. Antiparasitic medicines were continued until the process resolved. This restored visual acuity to 20/60 at present and there appears to be continuing improvement in visual acuity.
Fundus photographs of patients 3, 4, 5, and 6. Patient 3 before choroidal neovascular membrane (CNVM) (top row) and 4 years after photodynamic therapy (bottom row). Patient 4 with CNVM (top row) and 3 months later (bottom row). Patient 5 with CNVM (top row) and 4 years later (bottom row). Patient 6 before (top row) and after development of angiomatous proliferation (bottom row).
Algorithm used to manage toxoplasmic retinal disease and active choroidal neovascular membrane (CNVM) with extravasation of serous fluid or hemorrhage (also see Table). Treatment of active toxoplasmic chorioretinitis (Anti-tg Rx) or when a diagnosis of active toxoplasmic chorioretinitis cannot be excluded or activity might be induced by trauma in the context of an active CNVM: pyrimethamine, 1 mg/kg/d (maximum dose, 50-75 mg/d) following loading dose of 1 mg/kg twice a day for 2 days; leucovorin, 10 mg each Monday, Wednesday, and Friday or adjusted based on absolute neutrophil count, continued 1 week beyond resolution of active infection; sulfadiazine, 100 mg/kg divided twice per day, maximum dose per day, 4 g; clindamycin or clarithromycin have been used in place of sulfadiazine when there is sulfonamide hypersensitivity. Complete blood cell count to monitor neutrophil count is obtained during pyrimethamine therapy twice weekly during and in the week after stopping pyrimethamine therapy. This treatment should be supervised with a pediatrician, an internal medicine physician, or infectious diseases specialist. Additional suggestions concerning treatment of toxoplasmic chorioretinitis can be obtained on request. Anti-VEGF: treatment of active CNVM in our experience has been with 0.5 mg in 0.05 mL of ranizumab once a month. This is continued for at least 1 to 2 treatments beyond resolution of activity of CNVM.
Questions remain about how and when to treat these vascular lesions in ocular toxoplasmosis.7-16Anti-VEGF therapy has potential to provide a more favorable visual outcome than other therapies since it minimizes destruction of the retina and choroid, especially for subfoveal or juxtafoveal CNVM or lesions with edges obscured by subretinal hemorrhage. Because active infectious retinitis may be obscured by hemorrhage or be difficult or impossible to distinguish from CNVM and because injections may reactivate chorioretinitis, concurrent therapy with oral anti-Toxoplasmamedicine and ranibizumab was prescribed for our 2 patients (Table) (Figure 4). The characteristic pattern of resolution of the lesion with visualization of a scar with indistinct borders as hemorrhage first resolved and then healing with well-demarcated pigmentation in patient 1 is consistent with the typical pattern of resolution of active toxoplasmic chorioretinitis with medical treatment. The lesion did not appear to be toxoplasmic chorioretinitis alone because of extensive subretinal fluid and subretinal hemorrhage. Choroidal neovascular membranes also occur in other ocular infections (eg, histoplasmosis), suggesting a similar pathogenesis.
Safety of anti-VEGF therapy in infants, children, and young adults and its longer-term efficacy remain to be established. It appears to have been well-tolerated in our patients and in infants described by Capone.17Favorable outcome in our 2 patients indicates that intravitreal ranibizumab therapy plus anti–T gondiimedicines have potential to be efficacious in treatment of ocular neovascularization secondary to ocular toxoplasmosis.
Correspondence:Dr McLeod, University of Chicago, AMBH S206, 5841 S Maryland Ave, Chicago, IL 60637 (firstname.lastname@example.org).
Author Contributions:Dr McLeod had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Toxoplasmosis Study Group Members:Dianna Bardo, MD, Audrey Cameron, MS, Diana Chamot, BA, Barbara Danis, PhD, Sanjay Gupta, MD, Peter Heydemann, MD, Ellen Holfels, BA, Joyce Hopkins, PhD, Kristen Kasza, MS, Theodore Karrison, PhD, Douglas Mack, PhD, John Marcinak, MD, Paul Meier, PhD, James McAuley, MD, Saeid Mojatahedi, MD, Ernest Mui, BS, Dushyant Patel, MD, Jeanne Perkins, MA, Linda Pfiffner, PhD, Peter Rabiah, MD, James Rago, Jack Remington, MD, Nancy Roizen, MD, Mark Stein, PhD, Andrew Suth, PhD, Marie Weissbourd, PhD, and Shawn Withers, RN.
Financial Disclosure:None reported.
Funding/Support:This study was supported in part by National Institutes of Health grant RO1 AI 1-27530, Research to Prevent Blindness, the Hyatt Hotel Foundation, United Airlines Friendly Skies, Braniff International Airways, Southwest Airlines, American Airlines, Air Canada, and Angel Flight America and the Langel, Morel, Kiewit, Rooney-Alden, Blackman, Rosenstein, Kapnick, Cussen, Samuel, Lipskar, Dunphy, Taub, Rose, and Singer families.
Role of the Sponsor:All sponsors listed provided partial funding for either design or conduct of the study but did not participate directly in any other aspect, with the exception of the National Institutes of Health overseeing the data safety monitoring board.
Additional Contributions:The following physicians allowed us to follow up their patients with them: Richard Lin, MD, Vinod Wadhwa, MD, Michael Struck, MD, Timothy Olsen, MD, Khaled A. Tawansy, MD, Peggy Mei-Chi Liao, MD, Byron M. W. Wong, MD, Michael D. Bennett, MD, Pamela Rath, MD, Hua Gao, MD, Stephen E. Kroczek, MD, Neil Bressler, MD, and James P. Dunn, MD.
Benevento JD, Jager RD, Noble AG, et al. Toxoplasmosis-Associated Neovascular Lesions Treated Successfully With Ranibizumab and Antiparasitic Therapy. Arch Ophthalmol. 2008;126(8):1152–1156. doi:10.1001/archopht.126.8.1152
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