24 Ocular toxoplasmosis

Background

Toxoplasmic retinochoroiditis is the most frequent form of posterior uveitis, accounting for 20–60% of the cases.1–3 It is caused by the protozoan, Toxoplasma gondii, and can be acquired congenitally, most frequently during late stages of pregnancy, or during postnatal life, due to exposure to contaminated water, food, direct exposure to cats’ faeces, or inhalation of spores. Ocular toxoplasmosis is commonly attributed to congenital infection, but the role of acquired infection appears to be more important than previously thought. Lesions seen in the retina may actually be more frequently the result of a remote acquired infection rather than a late manifestation of a congenital transmission.4 The evidence available suggests that at least two-thirds of ocular toxoplasmosis is caused by postnatal infection.5

Primary ocular disease occurs more frequently during acute systemic infection, but may also occur during the course of the chronic phase of systemic disease.6,7 Case reports show that new lesions can appear for the first time as early as two months after onset of infection,8 or as late as five years.9 Recurrences are typical of both the congenital form and of the chronic phase of postnatally acquired disease.10,11 The risk of recurrence of lesions in cohorts of prenatally infected children and case series of patients with postnatal disease appear to be similar (8–40%), but are based on small numbers.5

Many theories have been proposed to explain the typical recurrences, but it seems that active invasion of retinal cells by organisms released by a ruptured retinal cyst is the most likely explanation.

Severe morbidity and visual loss is frequently associated with congenital infection. More than 82% of congenitally infected individuals not treated as infants develop retinal lesions by adolescence, many with loss of vision. Information regarding visual loss in postnatal infection is limited.

Ability to control or eradicate the disease will depend on the use of treatment that can destroy the intracellular, cystic form, of the parasite. Also, limitation of retinal damage may be achieved by more effective control of the infection after initial clinical presentation of an active focus of retinitis.

Several different anti-toxoplasma drug therapy regimes can be used to treat this condition, with most of the information derived from uncontrolled series or reports. The

real impact of treatment on the natural history of active disease, or on the risk of recurrences is currently unknown.

Questions

1What is the evidence that current medical therapy is effective in controlling active disease?

2What is the evidence that recurrences can be reduced or eliminated by the use of currently available drugs?

The evidence

We found six randomised controlled trials and one systematic review on the medical treatment of ocular toxoplasmosis. Three studies compared some form of intervention with controls.12–14 In two of them the controls received placebo,12,13 and in the third one, a study on prophylactic therapy,14 only patients with inactive disease were included and treatment was compared with no treatment, without a placebo.

The study by Perkins et al.,12 used Daraprim as therapy for four weeks in 113 patients presenting with active uveitis, regardless of having a typical retinal lesion or not. The outcome was defined as improved or not improved inflammation, and this finding was correlated with treatment given and toxoplasma serologic reaction. The cases were analysed also on the basis of the anatomic distribution of the uveitis (anterior, posterior, or pan-uveitis). For the patients who were serologically negative for toxoplasma there was no difference between the Daraprim and the placebo group. The toxoplasma positive patients treated with placebo showed a similar response to the toxoplasma negative patients (50% improvement). The toxoplasma positive patients treated with Daraprim showed 76% improvement, which was found to be significant. More details about this study can be found in the systematic review recently published.15

At the time this paper was written there was a feeling that ocular toxoplasmosis could not be diagnosed on clinical grounds and the patients included did not necessarily have the typical retinal lesion, which today is considered diagnostic in the immunocompetent individual. The presence of positive

serology in the absence of a retinal lesion does not establish a causal relationship, but only represents exposure of this patient to toxoplasma. Analysis of the data by anatomic distribution of the uveitis is confronted with the problem of small numbers, and does not achieve significance. No clear information is provided about the use of cortisone. Even though the proportion of patients receiving this drug did not differ significantly between the toxoplasma positive and negative, treated and untreated groups, the information on its use in posterior or pan-uveitis is not provided, and it is possible that the improvement seen was more related to the use of cortisone than to Daraprim. There is no information about visual impairment or recurrence rate.

The study by Acers13 was designed to compare the use of pyrimethamine, trisulfapyridines and prednisolone with placebo combined with prednisolone. Only 20 patients matching the criteria of a focus of retinitis, a positive serology and exclusion of other causes were included. No mention is made of the method of randomisation and no distinction as to severity of the inflammatory process, anatomical site, duration, and frequency of recurrences. More details about this study can be found in the recent systematic review.15 All patients showed improvement by three weeks and almost complete clearing after eight weeks. Only patients with macular lesions ended up with poor visual acuity. Two relapses, one in each group, were reported over two years. According to this study steroid therapy is as efficacious as specific antimicrobial therapy with pyrimethamine. No final details on numbers followed up or long-term visual acuity were provided.

The study by Silveira et al.11 had the objective of determining the effect of long-term intermittent therapy with trimethoprim/sulfamethoxazole on recurrences of toxoplasmic retinochoroiditis. Sixty-one patients received the drug therapy and 63 were controls, without placebo. The regime involved the use of one tablet of the combination drug every three days for up to 20 consecutive months. All patients had inactive disease at inclusion, and a new focus of necrotising retinitis defined a recurrence (end-point). Randomisation was done using a computergenerated list (1:1 ratio). Medications were administered in a non-masked fashion and the examining ophthalmologist was also not masked. Recurrences were found in 6·6% of patients in the treatment group and in 23·8% of the patients in the control group, which was statistically significant. There were no qualitative differences in recurrent lesions between groups. There was no statistical difference for the average time for recurrence between groups. No information on vision is available. The non-masking may have introduced bias during examination, and the data, as recognised by the authors, only support the protective effect of active therapy. No data on follow up, after the discontinuation of therapy, are available and no conclusions can be drawn for long lasting effects of this approach.

A recent prospective, randomised multi-center study6 has compared the efficacy, safety and tolerability of two treatment regimens: one combining pyrimethamine and sulfadiazine, and the other combining pyrimethamine and azythromycin, both given for a period of four weeks. Both groups received folinic acid and oral prednisone from day three. The presence of an active focus of toxoplasmic retinitis, within the major temporal vascular arcades, was essential for inclusion in the study. The assignment to one of the treatments was done by a randomisation protocol. A total of 46 patients entered the study, with 24 receiving the regimen with azythromycin and 22 receiving the sulfadiazine. On clinical examination no differences were found between the groups in terms of time needed for resolution of inflammation, in the decrease in size of retinal lesions, and improvement of visual acuity of more than

0·5 logMAR units. There was also no difference in the recurrence rate for those patients followed up for one year. Adverse effects were more frequent, but not statistically significant, in the sulfadiazine group.

The study shows similar efficacy between the two regimens used, with reduced frequency of adverse effects in the azythromycin group. Due to the unmasked nature of the study, bias by the ophthalmologist cannot be excluded when comparing response to therapy between the two groups. Also, the number of patients was too small to detect real differences between the two groups, especially when considering the long follow up and recurrence data.

Two studies compared the use of oral therapy with pyrimethamine and sulfadiazine against sub-conjunctival clindamycin, without a control group.16,17 Both studies used systemic steroids, but in one of them this was only started after 48 hours of specific therapy.17 No randomisation method is reported in these studies.

The inclusion criteria included a typical clinical and angiographic lesion suggestive of toxoplasmosis, exclusion of other causes and a positive serology. All lesions were inducing reduction in vision either because of location or intense vitritis.

The patients were followed up for 20–24 months in one study and up to 19 months in the other. Both studies showed that no significant differences between the groups could be found in terms of subjective improvement, visual acuity recovery, and healing of the retinal lesion. Poor visual outcome was associated with macular lesions. Recurrences occurred in both groups with a higher frequency in the pyrimethamine/sulfadiazine group, but without reaching significance.

The conclusion was that sub-conjunctival clindamycin is as effective as systemic therapy with pyrimethamine and sulfadiazine, with the advantage of avoiding systemic side effects, but was unable to prevent recurrences. Both studies involve a small number of patients and no clear randomisation method is described. This does not exclude

the possibility that the improvement was actually due to the systemic steroid therapy used in both groups. The follow up period is not long enough to allow proper conclusions about recurrences.

The final study by Mets et al.,18 had the purpose of determining the natural history of treated and untreated congenital toxoplasmosis and the impact on vision. Children were included if they had confirmed infection and were less than 2·5 months in age. Untreated children during the first year of life were historical controls. Children were randomised to treatments A or C (both groups received pyrimethamine and sulfadiazine, the difference being that group A received the pyrimethamine daily for two months followed by three days a week for one year, while group C had the daily treatment prolonged for six months, before reducing to three days a week for the rest of the year). The randomisation was stratified for severity, prior maternal treatment, and certainty of diagnosis at birth, and was based on a random number table, with treatment assigned in blocks of varying size. All patients were evaluated prospectively up to 15 years of age.

The most common eye manifestation was chorioretinal scars, most commonly in the peripheral retina. The severity of eye disease was worse in the historical control group (less severe systemic or neurologic disease), and no statistical difference could be found between the two treatment groups.

Development of active lesions following discontinuation of therapy was seen in 13% of treated patients during 189 patient-years of follow up, and in 44% of the controls during 160 patient-years of follow up. Treatment did not prevent new lesions appearing and the recurrence rate between the two treatment groups was not significant (7% for group A and 4% for group C).

Owing to ethical implications, there were no concomitant untreated controls. No direct comparisons can be made between the treated patients and the historical controls because the difference in severity of disease presentation and different ages would induce bias. The historical patients were comparable to only 20% of the treated patients who had no or mild clinical involvement at birth.

This study, even though including groups not directly comparable, showed a trend towards reduction of reactivation of ocular disease for those children with congenital toxoplasmosis who were offered prolonged therapy in the postnatal period. No differences could be found between the lower and higher dosage regime.

Summary

In spite of the fact that the aetiological agent for toxoplasmosis was identified at the beginning of the

twentieth century and that the drugs currently being used have been in use for several decades, few randomised clinical trials looking into their true efficacy in controlling active disease or preventing recurrences could be found. This is certainly related to the difficulty in performing such studies, which is related to the self-limiting character of this infection, its different clinical presentations, and also factors related to host and parasite. The most frequently used drugs (pyrimethamine, sulfadiazine, other sulfonamides and clindamycin) were tested in these studies, and in one study a new alternative regimen (pyrimethamine combined with azythromycin) was tested.

No clear evidence that the therapeutic regimens had a beneficial effect on the outcome of active lesions could be found. Reduction in the size of the lesions and improvement in vision was certainly shown in the study by BoschDriessen and colleagues,6 but this study had no control group. The study by Silveira and colleagues11 shows a protective prophylactic effect of the drug therapy used, but no follow-up data, after discontinuation of therapy, are available to show long-term protection. The other studies comparing different forms of therapy could not show any significant difference and the improvement demonstrated may have been simply the effect of systemic steroid therapy used.The study by Bosch-Driessen et al.6 shows similar efficacy with less toxicity with the use of azythromycin, and this finding has affected the treatment policy of their group. The only study looking into therapy in congenital disease also shows a trend towards reduction in recurrences, but longer follow-up is needed to confirm this observation. It did not allow for comparisons with the control group since this was a historical control showing different severity of disease and including children of different age groups.

Implications for research

The available data do not allow a conclusive answer to the questions proposed and properly designed studies are clearly necessary.

Implications for practice

Current practice in the management of toxoplasmic retinitis involves the use of courses of anti-toxoplasmic drugs in cases where lesions are threatening critical structures such as the macula and optic nerve, and also in cases of large lesions causing significant vitritis. The combination of pyrimethamine/sulfadiazine and corticosteroids seems to be the most frequently used,19 but discontinuation of therapy occurs in about 25% of the cases because of bone marrow suppression or allergic reactions. The few clinical trials discussed in this review do not show a significant

advantage of one regimen over the other in terms of efficacy during the acute disease or for long-term protection against new relapses. The prolonged use of intermittent therapy was shown to reduce attacks during therapy, but it does not represent a practical solution for most cases since there is no evidence that it can reduce the long-term risk of attacks after discontinuation of therapy. It may be an interesting alternative, as pointed out by the authors, for the management of those individuals with macular lesions in whom a new attack may result in severe visual loss, but long-term toxicity of this regimen needs to be assessed. The introduction of azythromycin as a first line agent, in combination with pyrimethamine, seems to be an interesting alternative. The study by Bosch-Driessen et al.6 has shown similar efficacy with less toxicity of this combination in comparison to the classic regimen. Even though numbers were small this seems to be the best contribution to practical management found in the studies analysed in this review.

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