Long-term Results of Trimethoprim-Sulfamethoxazole Versus Placebo to Reduce the Risk of Recurrent Toxoplasma gondii Retinochoroiditis.

PURPOSE: To compare the effects of 1 year of treatment with trimethoprim-sulfamethoxazole (TMP-SMZ) vs placebo in reducing the risk of recurrence of toxoplasmic retinochoroiditis during a 6-year follow-up period. DESIGN: Randomized, double-masked clinical trial. METHODS: This cohort included 141 subjects recruited in Campinas, Brazil. The inclusion criterion was unilateral active recurrent toxoplasmic retinochoroiditis. All subjects were treated with 1 dose of TMP-SMZ (160 mg/800 mg) twice daily for 45 days, and all lesions healed after this treatment. After this initial treatment, subjects were randomly assigned to group 1 (1 TMP-SMZ dose every other day for 311 days) or group 2 (1 identical placebo tablet containing starch with no active ingredients every other day for 311 days). Between the second and sixth years of follow-up appointments, none of the subjects received treatment unless a new recurrence episode had occurred. The primary outcomes were recurrent toxoplasmic retinochoroiditis within the first year of follow-up and recurrent toxoplasmic retinochoroiditis in the 6 years of follow-up. RESULTS: The cumulative probability of recurrence 1, 2, 3, 4, 5, and 6 years after the initial infection was, respectively, 13.0% (9/69), 17.4% (12/69), 20.3% (14/69), 23.2% (16/69), 26.1% (18/69), and 27.5% (19/69) in the placebo group and 0%, 0%, 0%, 0%, 0%, and 1.4% (1/72) in the TMP-SMZ group (P < .001; log-rank test). There were 3 cases (3/69; 4.3%) of multiple recurrences in the same individual in the placebo group. No treatment-limiting toxicity or side effects were observed in either group. New recurrences were more frequent among female subjects. CONCLUSIONS: TMP-SMZ may be used safely for prophylaxis of recurrent toxoplasmic retinochoroiditis and may provide long-term benefits.

Failure of systemic oral doxycycline in preventing ocular toxoplasmic retinochoroiditis in French military personnel.

This paper describes two cases of toxoplasmic chorioretinitis presenting in two French soldiers who had been receiving oral doxycycline for malaria prophylaxis. This is despite the proven effectiveness of oral doxycycline in treating Toxoplasma gondii, the most common cause of this infection. The lack of effectiveness of oral doxycycline in these two cases most likely reflected that the ocular concentration of 100 mg daily doxycycline is too low to treat or prevent Toxoplasmic retinochoroiditis (TC). Clinicians should therefore be aware that soldiers taking prophylactic oral doxycycline are still at risk of developing ocular TC with potentially sight-threatening consequences if not treated adequately.

Trimethoprim-Sulfamethoxazole Versus Placebo in Reducing the Risk of Toxoplasmic Retinochoroiditis Recurrences: A Three-Year Follow-up.

PURPOSE: To compare the effects of 1 year of treatment with trimethoprim/sulfamethoxazole (TMP-SMZ) vs a placebo in reducing the risk of toxoplasmic retinochoroiditis recurrences during a 3-year follow-up period. DESIGN: Randomized, double-masked clinical trial. METHODS: This cohort included 141 volunteers recruited in Campinas, Brazil. Inclusion criterion was unilateral active recurrent toxoplasmic retinochoroiditis. All volunteers were treated with 1 tablet of TMP-SMZ (160 mg/800 mg) twice daily for 45 days, and all lesions healed after this treatment. After this initial treatment, the volunteers were randomly assigned to Group 1 (1 TMP-SMZ tablet every 2 days for 311 days) or Group 2 (1 identical placebo tablet containing starch with no active ingredients every 2 days for 311 days). At the second- and third-year follow-up appointments, none of the volunteers received treatment unless a new recurrence episode had occurred. The primary outcomes were recurrent toxoplasmic retinochoroiditis within the first year of follow-up and recurrent toxoplasmic retinochoroiditis within the third year of follow-up. RESULTS: The cumulative probability of recurrence at 1, 2, and 3 years of follow-up were, respectively, 13.0% (9/69), 17.4% (12/69), and 20.3% (14/69) in the placebo group and 0% (0/72) in the TMP-SMZ group (P < .001, log-rank test). There was no case of multiple recurrences in the same individual. No treatment-limiting toxicity or side effects were observed in either group. New recurrences were more frequent among female volunteers. CONCLUSIONS: TMP-SMZ may be used safely for prophylaxis of recurrent toxoplasmic retinochoroiditis, with long-term benefits.

Risk of reactivation of toxoplasmic retinitis following intraocular procedures without the use of prophylactic therapy.

BACKGROUND/AIMS: Toxoplasmic retinochoroiditis is the commonest known cause of posterior uveitis worldwide and reactivation is unpredictable. Based on results from one study, the authors proposed that antitoxoplasmic therapy should be initiated as prophylaxis for intraocular surgery in patients with toxoplasmic scars. The aim of this study is to analyse the risk of toxoplasmic retinochoroiditis reactivation following intraocular procedures. METHODS: Retrospective analysis of the medical records of a total of 69 patients who underwent intraocular surgery and presented with toxoplasmic retinochoroiditis scars. RESULTS: No patient received prophylactic antitoxoplasmic therapy. Reactivation following the surgical procedure occurred in four cases, with one at 3 months and the others respectively at 13, 14 and 17 months. CONCLUSIONS: Our study shows that intraocular surgery did not result in a significant reactivation rate of toxoplasmic retinochoroiditis in the absence of preoperative prophylactic antitoxoplasmic therapy.

Trimethoprim-sulfamethoxazole versus placebo to reduce the risk of recurrences of Toxoplasma gondii retinochoroiditis: randomized controlled clinical trial.

PURPOSE: To compare the effects of trimethoprim-sulfamethoxazole vs placebo in reducing the risk of recurrences of Toxoplasma gondii retinochoroiditis. DESIGN: Single-center, prospective randomized double-masked clinical trial. METHODS: A total of 95 patients from Campinas, Brazil, with active recurrent Toxoplasma gondii retinochoroiditis were included. The initially active toxoplasmosis lesions were successfully treated in all cases using trimethoprim-sulfamethoxazole (800 mg/160 mg) twice daily for 45 days. Subsequently, 5 patients dropped out of the study. The remaining patients were randomized to Group 1 (trimethoprim/sulfamethoxazole tablet every 2 days) or Group 2 (identical placebo tablet every 2 days). Randomization was 1:1, was stratified by sex, and used block sizes of 4. The primary outcome was recurrent toxoplasmosis retinochoroiditis within 1 year, and the secondary outcome was a 1-year change in best-corrected visual acuity (BCVA) (ETDRS chart). RESULTS: The incidence of recurrent toxoplasmosis retinochoroiditis within 12 months was 0 of 46 (0%) and 6 of 47 (12.80%) in the trimethoprim-sulfamethoxazole and placebo groups, respectively (P = .026). Visual acuity improvements in the 2 groups were similar. No treatment-limiting toxicity was observed. CONCLUSIONS: Trimethoprim/sulfamethoxazole therapy resulted in a 100% reduction in the recurrence of Toxoplasma gondii retinochoroiditis over 1 year of treatment.

Guía de la Sociedad Española de Infectología Pediátrica para el diagnóstico y tratamiento de la toxoplasmosis congénita / The Spanish Society of Pediatric Infectious Diseases Guidelines for the diagnosis and treatment of congenital toxoplasmosis

La toxoplasmosis congénita es la consecuencia de la transmisión fetal por vía transplacentaria de Toxoplasma gondii tras la primoinfección materna. El riesgo de infección fetal es bajo en infecciones en el primer trimestre y va aumentando con la edad gestacional, mientras que la gravedad de la infección disminuye con esta. El diagnóstico de infección materna se realiza mediante la demostración de seroconversión o ante la presencia de IgM positiva con anticuerpos IgG de baja avidez. Las gestantes con infección demostrada deben recibir espiramicina para intentar evitar su transmisión al feto. El diagnóstico de infección fetal se realiza mediante reacción en cadena de la polimerasa (PCR) en líquido amniótico obtenido a partir de la semana 18 de gestación. Si esta prueba resulta positiva, debe iniciarse tratamiento a la embarazada con pirimetamina, sulfadiazina y ácido folínico. La mayoría de los niños infectados nacen asintomáticos pero hasta el 80% desarrolla secuelas visuales o neurológicas durante su infancia y adolescencia. El diagnóstico neonatal es complicado porque los anticuerpos IgM e IgA y la PCR en sangre y líquido cefalorraquídeo pueden ser falsamente negativos. En estos casos, el diagnóstico puede realizarse mediante la constatación de un ascenso significativo de los anticuerpos IgG o la persistencia de los mismos después del año de vida. El tratamiento neonatal con pirimetamina y sulfadiazina disminuye la posibilidad de secuelas a largo plazo. La toxoplasmosis congénita es una enfermedad prevenible mediante el cribado pregestacional y la adopción de medidas de profilaxis primaria en las gestantes seronegativas (AU)

Congenital toxoplasmosis is the result of transplacental fetal infection by Toxoplasma gondii after the primary maternal infection. The severity of the disease depends on the gestational age at transmission. First trimester infections are more severe, but less frequent, than third trimester infections. Acute maternal infection is diagnosed by seroconversion or by the detection of IgM antibodies and a low IgG avidity test. In these cases, spiramycin should be initiated to prevent transmission to the fetus. For identification of fetal infection, polymerase chain reaction (PCR) testing of amniotic fluid after 18 weeks gestation should be performed. If fetal infection is confirmed, the mothers should be treated with pyrimethamine, sulfadiazine and folinic acid. Most infants infected in utero are born with no obvious signs of toxoplasmosis, but up to 80% developed learning and visual disabilities later in life. Neonatal diagnosis with IgM/IgA antibodies or blood/cerebrospinal fluid PCR may be difficult because false-negative results frequently occur. In these cases diagnosis is possible by demonstrating a rise in IgG titers during follow-up or by the detection of antibodies beyond one year of age. Early treatment with pyrimethamine and sulfadiazine may improve the ophthalmologic and neurological outcome. Congenital toxoplasmosis is a preventable disease. Pre-pregnancy screening and appropriate counseling regarding prevention measures in seronegative women may prevent fetal infection (AU)

Treating ocular toxoplasmosis: current evidence.

The current treatment of ocular toxoplasmosis is controversial. The mainstay of treatment has been pyrimethamine and sulphonamides with or without systemic corticosteroids, but the actual evidence that antibiotics have a beneficial effect in recurrent toxoplasmic retinochoroiditis is unsupported by randomised placebo controlled trials. Thus far there have only been three studies looking at the efficacy of antibiotic treatment, all of which were methodologically weak and two of which were perfomed more than 30 years ago. All studies reported adverse effects from treatment. There is an urgent need for further randomised, double blind, placebo controlled studies for lesions in all parts of the retina and to test the efficacy of adjunctive corticosteroid treatment.

[Ophthalmoscopic surveillance in treated patients with invasive Candida disease]. / Importancia de la vigilancia oftalmológica durante el tratamiento de la enfermedad invasora por Candida.

BACKGROUND: Invasive Candida disease (ICD) is the most common cause of endogenous endophthalmitis. There are two characteristic ocular signs: Candida chorioretinitis defined as retina and choroid lesions without vitreal involvement, and Candida endophthalmitis defined as chorioretinitis with extension into the vitreous with characteristic fluffy balls. The most common visual symptoms are blurred vision and floaters. AIMS: To define in which patients with ICD a surveillance ophthalmoscopic examination should be done. METHODS: We searched the PubMed/Medline data base Candida endophthalmitis in adult and paediatric patients with ICD. RESULTS AND CONCLUSIONS: The need of ophthalmoscopic examination in patients with ICD is controversial, partly due to the fact that early antifungal treatment leads to a significant decrease of endogenous Candida endophthalmitis. Routine ophthalmoscopic examination seems of little value in patients with positive blood culture, with early implementation of antifungal treatment, without symptoms of ocular infection and without impairment of the level of consciousness during the episode. However, ophthalmoscopic examination should be performed in children with candidemia and critically ill patients with documented ICD, in the second week of treatment, especially in echinocandin treatment.

Importancia de la vigilancia oftalmológica durante el tratamiento de la enfermedad invasora por Candida / Ophthalmoscopic surveillance in treated patients with invasive Candida disease

Antecedentes: La enfermedad invasora debida a Candida (EIC) es la causa más común de endoftalmitis endógena. Las 2 formas características de presentación son la coriorretinitis candidiásica, que afecta a coroides y retina sin afectar al vítreo, y la endoftalmitis candidiásica, con presencia de lesiones vítreas redondeadas. Los síntomas visuales más habituales son la visión borrosa y las miodesopsias. Objetivos: Valorar en qué paciente con EIC debe realizarse una exploración oftalmológica y el momento más apropiado. Métodos: Revisión bibliográfica en la base de datos PubMed/Medline sobre endoftalmitis asociadas a EIC en población pediátrica y adulta. Resultados y conclusiones: Hay controversia en cuanto a la necesidad de realizar una exploración de fondo de ojo a todos los pacientes con EIC, debido a que la generalización del tratamiento temprano en estos pacientes ha supuesto una disminución marcada del número de infecciones oculares y de su gravedad. En un paciente con EIC tratado de forma temprana, sin síntomas oftalmológicos y sin alteración del grado de con- ciencia que le impida referir síntomas visuales durante el seguimiento, es muy dudosa la utilidad del estudio oftalmológico sistemático. Sin embargo, en pacientes sin posibilidad de referir ninguna alteración visual en la fase inicial de la infección ocular, como son los pacientes pediátricos con candidemia o los pacientes críticos con EIC, la exploración oftalmológica es obligada entre la primera y la segunda semanas de tratamiento, especialmente en los tratados con equinocandinas, por su baja penetración ocular (AU)

Background: Invasive Candida disease (ICD) is the most common cause of endogenous endophthalmitis. There are two characteristic ocular signs: Candida chorioretinitis defined as retina and choroid lesions without vitreal involvement, and Candida endophthalmitis defined as chorioretinitis with extension into the vitreous with characteristic fluffy balls. The most common visual symptoms are blurred vision and floaters. Aims: To define in which patients with ICD a surveillance ophthalmoscopic examination should be done. Methods: We searched the PubMed/Medline data base Candida endophthalmitis in adult and paediatric patients with ICD. Results and conclusions: The need of ophthalmoscopic examination in patients with ICD is controversial, partly due to the fact that early antifungal treatment leads to a significant decrease of endogenous Candida endophthalmitis. Routine ophthalmoscopic examination seems of little value in patients with positive blood culture, with early implementation of antifungal treatment, without symptoms of ocular infection and without impairment of the level of consciousness during the episode. However, ophthalmoscopic examination should be performed in children with candidemia and critically ill patients with documented ICD, in the second week of treatment, especially in echinocandin treatment (AU)

Treating ocular toxoplasmosis: current evidence

The current treatment of ocular toxoplasmosis is controversial. The mainstay of treatment has been pyrimethamine and sulphonamides with or without systemic corticosteroids, but the actual evidence that antibiotics have a beneficial effect in recurrent toxoplasmic retinochoroiditis is unsupported by randomised placebo controlled trials. Thus far there have only been three studies looking at the efficacy of antibiotic treatment, all of which were methodologically weak and two of which were perfomed more than 30 years ago. All studies reported adverse effects from treatment. There is an urgent need for further randomised, double blind, placebo controlled studies for lesions in all parts of the retina and to test the efficacy of adjunctive corticosteroid treatment.

Immunopathological basis of lymphocytic choriomeningitis virus-induced chorioretinitis and keratitis.

The infection of humans with the rodent-borne lymphocytic choriomeningitis virus (LCMV) can lead to central nervous system disease in adults or severe neurological disease with hydrocephalus and chorioretinitis in children infected congenitally. Although LCMV-induced meningitis and encephalitis have been studied extensively, the immunopathological mechanisms underlying LCMV infection-associated ocular disease remain elusive. We report here that the intraocular administration of the neurotropic LCMV strain Armstrong (Arm) elicited pronounced chorioretinitis and keratitis and that infection with the more viscerotropic strains WE and Docile precipitated less severe immunopathological ocular disease. Time course analyses revealed that LCMV Arm infection of the uvea and neuroretina led to monophasic chorioretinitis which peaked between days 7 and 12 after infection. Analyses of T-cell-deficient mouse strains showed that LCMV-mediated ocular disease was strictly dependent on the presence of virus-specific CD8(+) T cells and that the contribution of CD4(+) T cells was negligible. Whereas the topical application of immunosuppressive agents did not prevent the development of chorioretinitis, passive immunization with hyperimmune sera partially prevented retinal and corneal damage. Likewise, mice displaying preexisting LCMV-specific T-cell responses were protected against LCMV-induced ocular disease. Thus, antibody- and/or T-cell-based vaccination protocols could be employed as preventive strategies against LCMV-mediated chorioretinitis.

Predictors of retinochoroiditis in children with congenital toxoplasmosis: European, prospective cohort study.

OBJECTIVE: By school age, 20% of children infected with congenital toxoplasmosis will have > or = 1 retinochoroidal lesion. We determined which children are most at risk and whether prenatal treatment reduces the risk of retinochoroiditis to help clinicians decide about treatment and follow-up. PATIENTS AND METHODS: We prospectively studied a cohort of children with congenital toxoplasmosis identified by prenatal or neonatal screening in 6 European countries. We determined the effects of prenatal treatment and prognostic markers soon after birth on the age at first detection of retinochoroiditis. RESULTS: Of 281 children with congenital toxoplasmosis, 50 developed ocular disease, and 17 had recurrent retinochoroiditis during a median follow-up of 4.1 years. Prenatal treatment had no significant effect on the age at first or subsequent lesions. Delayed start of postnatal treatment did not increase retinochoroiditis, but the analysis lacked power. Older gestational age at maternal seroconversion was weakly associated with a reduced risk of retinochoroiditis. The presence of nonocular clinical manifestations of congenital toxoplasmosis at birth strongly predicted retinochoroiditis. For 92% (230 of 249) of children with no retinochoroiditis detected before 4 months of age, the probability of retinochoroiditis by 4 years was low, whether clinical manifestations were present or not 8.0%. CONCLUSIONS: Prenatal treatment did not significantly reduce the risk of retinochoroiditis in this European cohort. If children have no retinochoroiditis in early infancy, the low risk of subsequent ocular disease may not justify postnatal treatment and repeated ophthalmic assessments during childhood. Controlled trials are needed to address the lack of evidence for the effectiveness of postnatal treatment.

Effect of Fas and Fas ligand deficiency in resistance of C57BL/6 mice to HSV-1 keratitis and chorioretinitis.

PURPOSE: To investigate the effect of Fas and Fas ligand (FasL) deficiency on the development of herpes stromal keratitis and on the von Szily model of herpes retinitis in C57BL/6 mice, which are ordinarily resistant to development of both of these herpetic diseases. METHODS: Anterior chamber inoculation of the right eye of each mouse with various titers of HSV-1 (KOS strain) was performed. Both eyes of each mouse were enucleated on postinoculation day 15 and processed for histopathologic examination. HSV-1 was inoculated into one cornea of other mice, and the severity of stromal keratitis was scored. RESULTS: Contralateral destructive chorioretinitis developed in susceptible Balb/cByj mice (19/23); ipsilateral chorioretinitis did not occur (0/23). Stromal keratitis developed in susceptible C.AL-20 mice (15/16). None of the C57BL/6 (0/10 for keratitis or 0/20 for retinitis) developed inflammation. Neither did B6.SMN.C3H.gld (FasL deficient; 0/12 or 0/28) or B6.MRL.lpr (Fas deficient; 0/11 or 0/34) mice (keratitis or contralateral chorioretinitis). Minimal scattering of inflammatory cells in the contralateral retina but not destructive chorioretinitis was observed in two C57BL/6, three B6.SMN.C3H.gld, and five B6.MRL.lpr mice. Few inflammatory cells were also found in the ipsilateral vitreous and vitreoretinal interface (but not destructive chorioretinitis) of all C57BL/6, two gld, and three lpr mice. CONCLUSIONS: Immune dysregulation secondary to deficiency in Fas or FasL system does not influence the resistance of the C57BL/6 mice to develop herpes simplex keratitis or destructive herpes simplex chorioretinitis.

[Cytomegalovirus chorioretinitis in a patient with orthotopic liver transplant. Role of virologic diagnosis and of antiviral chemoprophylaxis]. / Corioretinite da cytomegalovirus in paziente sottoposto a trapianto ortotopico di fegato. Ruolo della diagnostica virologica e della chemioprofilassi antivirale.

A case report of cytomegalovirus retinitis in a patient who underwent orthotopic liver transplantation, and suffered from a prior episode of systemic cytomegalovirus disease, is described. Although the diagnosis was obtained only when clinical symptoms prompted ophthalmoscopic evaluation, a successful outcome was attained after ganciclovir treatment. The role of clinical and virologic monitoring of organ transplant recipients, and that of primary and secondary chemoprophylaxis against cytomegalovirus infection are discussed, according to personal observations and to an updated literature review.

[Congenital toxoplasmosis: presentation of a case]. / Toxoplasmose congénitale: à propos d'un cas.

We report a case of a 4 months old boy with esotropia of the left eye with large bilateral chorioretinal toxoplasmic macular scars. Chorioretinal scars are the most common eye finding in congenital toxoplasmosis and are often located in the macular region. Most infants with congenital infection are asymptomatic at birth but will develop retinal and/or neurologic damage later in life with consequent loss of vision. A routine examination of the fundus and computed tomography of the head can be negative. Serologic testing is essential for the diagnosis and the follow-up of the infection. Every infant with evident or suspected congenital infection by Toxoplasma gondii must be treated by Pyrimethamine, Sulphadiazine and Folinic Acid during at least the first year of life with regular serologic testing and ophthalmologic examination. Neurologic outcome is better with treatment and the risk of chorioretinitis seems reduced.

Pharmacomanipulation of HSV-1 induced chorioretinitis in mice.

In the von Szily mouse model, intracameral inoculation of herpes simplex virus type-1 (HSV-1) results in inflammation of the ipsilateral anterior segment with relative chorioretinal sparing and destructive contralateral chorioretinitis. We studied the effect of the systemic antiviral agent acyclovir (ACV) and anti-HSV-1 antibody therapy in this model. Contralateral chorioretinitis developed in none of the 18 mice receiving ACV from post-inoculation day (pid) 1 (p < 0.0001), in 6 of 10 (60%) mice when treatment was delayed until pid 7 (p = 0.40) and in 14 of 18 (77%) controls. Contralateral disease developed in 8 of 16 (50%) mice that received anti-HSV-1 antibody from pid 1 (p = 0.02), in 13 of 16 (81%) treated from pid 5 (p = 0.64), in 7 of 8 (87.5%) treated from pid 7 (p = 1.0) and in 17 of 20 (85%) controls. We conclude that early treatment with ACV or anti-HSV-1 antibody reduces the incidence of contralateral chorioretinitis in mice.