Sense and nonsense of corticosteroid administration in the treatment of ocular toxoplasmosis

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1998;82;858-860 Br. J. Ophthalmol.
E H BOSCH-DRIESSEN and A ROTHOVA
toxoplasmosis administration in the treatment of ocular Sense and nonsense of corticosteroid
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Commentary
Sense and nonsense of corticosteroid administration in the treatment of ocular toxoplasmosis
There is no consensus about the use of corticosteroids for the treatment of ocular toxoplasmosis. In clinical practice, corticosteroids are usually given in combination with antiparasitic drugs to reduce the inflammatory reaction during active chorioretinitis and to minimise tissue damage.1 Specifically, in the case of pericentral location, this presumed eVect might help to retain central visual acuity and limit scotomas. However, the use of corticoster- oids can lead to progression of the underlying infectious disease, as repeatedly demonstrated by the occurrence of fulminant ocular toxoplasmosis following both systemic and periocular administration (Fig 1).2–8 On the other hand, low dose corticosteroid monotherapy has been administered without severe side eVects.1 To our know- ledge, a well defined study of the eVect of corticosteroid monotherapy in ocular toxoplasmosis as well as the additional value of corticosteroids as adjuvant therapy has not been performed. Thus, the use of corticosteroids for the treatment of ocular toxoplasmosis is controversial, and the timing and dosages during the course of the disease are not well defined.
During an acute infection with Toxoplasma gondii, oocysts ingested by the host give rise to the extracellular forms (tachyzoites), which actively penetrate host cells and replicate; subsequently the disease enters the chronic stage when cysts are formed.9 The signal for formation of cysts is not known; the onset and the quality of the host immune response may be an important factor.9 The mechanism of chronic recurrent ocular toxoplasmosis is unknown; it is presumed that the multiplication of parasites, liberated from the cysts, causes damage to adjacent retinal tissue.9
The hypothesis of autoimmunity, directed against retinal S-antigen, has not been proved unequivocally.10 11 In fact, the interaction between T gondii and the competent immune system does not lead to parasite elimination, but to a reduction in parasite load and changes in morphology and surface antigen expression.
Host response and eVect of corticosteroids on T gondii infection T cell mediated immunity plays a major role in resistance against toxoplasmosis and probably also controls brain cyst formation; B cell mediated humoral immunity is not protective.12 13 CD8+ T cells are the principal mediators of resistance against acute toxoplasmosis by means of their cytotoxic activity and the secretion of cytokines, including interferon ª (IFN-ª), which plays a crucial role in the response to T gondii.13
The eVects of corticosteroids on the immune system are complex, and not completely understood.14 The anti- inflammatory and immunosuppressive eVects of cortico- steroids are linked to changes in cellular immunity and attributed mainly to inhibiton of communication among leucocytes responsible for production and action of cytokines. In low doses, corticosteroids dramatically inhibit exudation of plasma and accumulation of leuco- cytes at sites of inflammation and suppress cellular immune response.15 As a consequence they influence the production of IFN-ª and IL-2 by T cells, the eVect of
IFN-ª on macrophages, and the interaction of IL-2 with its receptor on activated T cells. The eVect on cellular immune response is dose dependent.16 Corticosteroids have a minor eVect on antigen stimulated B cells and plasma cells.14 Higher doses are required to retard the processing and presentation of antigens by monocytes and macrophages, to inhibit natural killer cell function, and to inhibit the release of tumour necrosis factor by activated macrophages. The compromised leucocyte function coun- teracts the intracellular destruction of parasites and may lead to unrestrained replication of parasites.
An inadequate cell mediated immunity (specifically in patients with AIDS and during iatrogenic immunosup- pression) leads to severe, sometimes fatal toxoplasmic infections and is associated with reactivations of latent dis- ease. Although intact tissue cysts were reported not to evoke an inflammatory response, shedding of parasites from tissue cysts was described.17 It might be possible that, in patients with an insuYcient cellular immunity, these escaped parasites may replicate and cause reactivation. Aging is also associated with a decline in cell mediated immunity (especially CD8+ T cells).18 Severe ocular toxo- plasmosis in elderly patients has been attributed to the above mentioned reduction of cell mediated immunity in the elderly.19
EVect of corticosteroids on toxoplasmosis: animal studies A lethal eVect of corticosteroids in acute toxoplasmosis was found in the majority of animal studies (mice and rabbits)20–24; however, the therapy also induced less eVective resistance to subsequent reactivations.22 In contrast with untreated animals, in corticosteroid treated mice with acute toxoplasmosis, persistence of free parasites together with cysts in the brain and lung tissue was observed.20 21 Furthermore, cyst formation in the brain
Figure 1 A 23 year old male patient with fulminant toxoplasmic chorioretinitis following periocular corticosteroid injection. Note the multiple lesions, pronounced vasculitis (arteriitis), and extensive exudation in the macular area.
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started earlier and was more prolific in corticosteroid treated mice.22 However, corticosteroid treated rabbits with ocular toxoplasmosis had localised retinal lesions with preservation of normal tissue in contrast with non-treated animals in which retinal destruction was considerably more massive and areas of normal retina were not encountered.23
In studies assessing the eVect of corticosteroids in chronic toxoplasmosis, the majority of the corticosteroid treated animals died while untreated animals survived.21 22 24 25 Administration of corticosteroids to animals with chronic toxoplasmosis resulted in reactivation of the disease, generally leading to fatal encephalitis or pneumonia; the latter was characterised by the absence of an inflammatory reaction on histological examination.24 26
Frequent relapses of toxoplasmic chorioretinitis were reported in corticosteroid treated hamsters with chronic disease.24 It was suggested that corticosteroids, because of their eVect on the immune system, trigger rupture of the cysts followed by dissemination of parasites to adjacent tis- sues and other organs, thus causing chronic relapsing disease.25 27 In contrast, small numbers of animals treated with corticosteroids exhibited no changes in their ocular or systemic symptoms.23
EVect of corticosteroids on toxoplasmosis: human studies Various case reports provide information on the eVects of corticosteroids in human ocular toxoplasmosis. In the past, duration and the number of recurrences were not diVerent for 10 patients with presumed toxoplasmic chorioretinitis treated with low dose systemic corticosteroids compared with 10 patients treated with antiparasitic drugs together with corticosteroids.28 In contrast, destructive and dissemi- nated ocular toxoplasmosis was repeatedly demonstrated in case reports of presumably immunocompetent patients (n=16) after administration of corticosteroids without a shield of antiparasitic drugs (Table 1).2–8 We examined 10 additional patients with fulminant ocular toxoplasmosis following monotherapy with corticosteroids (Table 1).
Many of corticosteroid treated patients were initially not recognised as having toxoplasmosis (recent series 4/10; lit- erature 8/16; total 12/26); in 4/26 patients (2/10 in the present series) corticosteroid therapy was given for an unrelated systemic disease. The remaining patients (10/26) were known to have toxoplasmic retinitis but received cor- ticosteroids without an antiparasitic shield anyway.
Legal blindness (visual acuity less than 0.1) in at least one eye developed in 19 of 26 reported patients (73%). Recurrent disease occurred subsequently in four of our 10 patients (40%); the number of recurrences among the pre- viously reported 16 patients is unknown. The dosages of administered corticosteroids varied between 20 mg and 150 mg per day (or were not specified). The eventual rela- tion of ocular disease to the dosage of corticosteroids used cannot be assesed and therefore it is not possible to define something as a “safe dose”.
Laboratory evidence of primary infection was found in the present series for six of 10 patients (60%): four with positive IgM titres, two additional patients had an initial serum IgG titre <1:512 which increased within 4 weeks to 1:4096 in both cases. It was not possible to evaluate the frequency of primary infection for previously reported patients. An absence of retinal scars, suggesting a primary infection, was noted however for 9/16 of these patients (61%).
Although toxoplasmic chorioretinitis is more common during the second and third decades of life, 16/26 patients (61%) were older than 50 years. Severe toxoplasmic retini- tis resembling herpetic retinitis was recently described in seven elderly patients.19 29 The authors hypothesised that the susceptibility of older patients to severe toxoplasmic chorioretinitis may be due to the previously mentioned age related decrease in immunological resistance, which might also have played a role in our patients.19 It is noteworthy that the initial diagnosis was acute retinal necrosis in four of the 10 present cases (40%). The advanced age of the patients together with severe and atypical retinitis, may explain why toxoplasmosis was not suspected and initially misdiagnosed. In the past, eight eyes of patients treated with corticosteroids were examined histologically with consistent results—large areas of necrotic tissue with mul- tiple cysts, located between the necrotic retina and remnants of normal tissue. In the necrotic regions were numerous free parasites without an inflammatory reaction.2 3 6–8
Evaluation of the eYcacy of corticosteroids as an adjunct to antiparasitic regimens has never been per- formed. Studies addressing the eYcacy of multiple therapies were not designed for evaluation of the eVects of corticosteroids. However, no adverse eVects of additional corticosteroids were noted.30 31 No diVerences in onset of inactivity were seen between patients treated with py- rimethamine and sulphadiazine with or without added corticosteroids, even at high doses in a study by Fajardo et al.32 In a meta-analysis of three studies, involving 134 patients altogether (antiparasitic therapy without cortico- steroids in 16 cases and with corticosteroids in 118 cases), no striking diVerences were found in the duration of activity.33–35 Although occasionally a poor ocular outcome was reported, this might be explained by the bias of added corticosteroids in a selected group of patients with extremely severe inflammation. Similar visual outcomes were found for patients treated with antiparasitic drugs with and without corticosteroids in a retrospective non-randomised study of 75 patients.36
In conclusion, our results confirm the case report based assumption that in ocular toxoplasmosis corticosteroids, whether given systemically or periocularly, should be administered with a shield of antiparasitic drugs, especially if the patients are elderly or exhibit evidence of a primary infection. Owing to its frequent atypical clinical features, it is important to include the possibility of ocular
Table 1 Administration of corticosteroids without antiparasitic drugs to patients with ocular toxoplasmosis
No of patients
Age at onset >50 years No (%)
Evidence for primary aquired infection Corticosteroid administration
Retinal scars > 3 PD No (%)
Legal blindness of aVected eye No (%)
Laboratory No (%)
Clinical* No (%)
Systemic No (%)
Periocular No (%)
Literature survey† 16 10 (63) NS 9 (56) 15 (94) 6 (38) 11 (69) 12 (75) Present study 10 6 (60) 6(60) 7 (70) 8 (80) 6 (60) 5 (50) 7 (70) Total 26 16 (62) 16 (62) 23 (88) 12 (46) 16 (62) 19 (73)
*Chorioretinitis without associated old scars. †See references 2–8; three patients received additional medication (two azathioprine, one sulphisoxazole respectively); five patients received systemic and periocular steroids. ‡Four patients received systemic and periocular steroids. NS= not specified.
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toxoplasmosis in the diVerential diagnosis for elderly patients. Further research is indicated to evaluate the ben- eficial eVect of corticosteroids in combination therapy.
Supported in part by the Dr F P Fischer Foundation, Netherlands.
E H BOSCH-DRIESSEN A ROTHOVA
Donders Institute of Ophthalmology, University Hospital Utrecht, Utrecht, Netherlands
Correspondence to: E H Bosch-Driessen, Donders Institute of Ophthalmology, University Hospital Utrecht, E-03-136, Heidelberglaan 100, 3584 CX Utrecht, Netherlands.
1 Engstrom RE Jr, Holland GN, Nussenblatt RB, et al. Current practices in the management of ocular toxoplasmosis. Am J Ophthalmol 1991;111:601– 10.
2 Sabates R, Pruett RC, Brockhurst RJ. Fulminant ocular toxoplasmosis. Am J Ophthalmol 1981;92:497–503.
3 PauleikhoV D, Messmer E, Beelen DW, et al. Bone marrow transplantation and toxoplasmic retinochoroiditis. Graefes Arch Clin Exp Ophthalmol 1987; 225:239–43.
4 Gallino A, Maggiorini M, Kiowski W, et al. Toxoplasmosis in heart transplant recipients. Eur J Clin Microbiol Infect Dis 1996;14:389–93.
5 Morhun PJ, Weisz JM, Elias SJ, et al. Recurrent ocular toxoplasmosis in patients treated with systemic corticosteroids. Retina 1996;16:383–7.
6 Nicholson DH, Wolchock EB. Ocular toxoplasmosis in an adult receiving long-term corticosteroid therapy. Arch Ophthalmol 1976;94:248–54.
7 Crawford JB, Bethesda. Toxoplasma retinochoroiditis. Arch Ophthalmol 1966;76:829–32.
8 Benson MT, Parsons MA, Talbot JF, et al. Aggressive toxoplasma retinitis. Acta Ophthalmol 1992;70:795–800.
9 Pavesio CE, Lightman S. Toxoplasma gondii and ocular toxoplasmosis: pathogenesis. Br J Ophthalmol 1996;80:1099–107.
10 Nussenblatt RB, Mittal KK, Fuhrman S, et al. Lymphocyte proliferative responses of patients with ocular toxoplasmosis to parasite and retinal anti- gens. Am J Ophthalmol 1989;107:632–41.
11 Kijlstra A. Humoral and cellular immune reactions. Curr Eye Res (suppl) 1996;9:85–9.
12 Sher A, Denkers EY, Gazzinelli RT. Induction and regulation of host cell-mediated immunity by Toxoplasma gondii. Ciba Found Symp 1995;195:95–104; discussion 104–9.
13 Däubener W, Hadding U. Cellular immune reactions directed against Toxo- plasma gondii with special emphasis on the central nervous system. Med Microbiol Immunol 1997;185:195–206.
14 Goodman-Gilman A. The pharmacological basis of therapeutics. Vol II. Singapore: McGraw-Hill, 1992;1439–57.
15 Boumpas DT, Chrousos GP, Wilder RL, et al. Glucocorticoid therapy for immune-mediated diseases: basic and clinical correlates. Ann Intern Med 1993;119:1198–208.
16 Cupps TR, Fauci AS. Corticosteroid-mediated immunoregulation in man. Immunol Rev 1982;65:133–55.
17 Wong S, Remmington JS. Biology of Toxoplasma gondii. AIDS 1993;7:299– 316.
18 Hirokawa K. Understanding the mechanism of the age related decline in immune function. Nutr Rev 1992;50:361–6.
19 Johnson MW, Greven GM, JaVe GJ, et al. Atypical, severe toxoplasmic retinochoroiditis in elderly patients. Ophthalmology 1997;104:48–57.
20 HoZin JM, Conley FK, Remington JS. Murine model of intracerebral toxo- plasmosis. J Infect Dis 1987;155:550–6.
21 Sumyuen MH, Garin YJF, Derouin F. EVect of immunosuppressive drug regiments on acute and chronic murine toxoplasmosis. Parasitol Res 1996; 82:681–6.
22 Stahl W, Matsubayashi H, Akao S. Modification of subclinical toxoplasmo- sis in mice by cortisone, 6-mercaptopurine and splenectomy. Am J Trop Hyg 1966;15:869–74.
23 Kaufman HE. The eVect of corticosteroids on experimental ocular toxoplasmosis. Am J Ophthalmol 1960;50:919–25.
24 Frenkel JK, Nelson BM, Arias-Stella J. Immunosuppression and toxoplas- mic encephalitis, clinical and experimental aspects. Human Pathol 1975;6: 97–111.
25 Chinchill AM, Guerrero OM, Catarinella G, et al. Natural and induced blood dissemination of toxoplasma gondii: experimental model in white mice and hamsters. Rev Biol Trop 1993;41:197–202.
26 Frenkel JK. Pathogenesis of toxoplasmosis and of infections with organisms resembling toxoplasma. Ann NY Acad Sci 1956;??215–51.
27 Odaert H, Soete M, Fortier B, et al. Stage conversion of Toxoplasma gondii in mouse brain during infection and immunodepression. Parasitol Res 1996;82:28–31.
28 Acers TE. Toxoplasmic retinochoroiditis: a double blind therapeutic study. Arch Ophthalmol 1964;71:58–61.
29 Ronday MJH, Luyendijk L, Baarsma GS, et al. Presumed acquired ocular toxoplasmosis. Arch Ophthalmol 1995;113:1524–9.
30 Lam S, Tessler H.H. Quadruple therapy for ocular toxoplasmosis. Can J Ophthalmol 1993;28:58–61.
31 Rothova A, Meenken C, Buitenhuis HJ, et al. Therapy for ocular toxoplasmosis. Am J Ophthalmol 1993;115:517–23.
32 Fajardo RV, Furgiuelle FP, Leopold IH. Treatment of toxoplasmosis uveitis. Arch Ophthalmol 1962;67:712–20.
33 Ghosh M, Levy PM, Leopold IH. Therapy of toxoplasmosis uveitis. Am J Ophthalmol 1963;55–61.
34 Guldsten H. Clindamycin and sulphonamides in the treatment of ocular toxoplasmosis. Acta Ophthalmol 1983;61:51–7.
35 Lakhanpal V, Schocket SS, Nirankari VS. Clindamycin in the treatment of toxoplasmic retinochoroiditis. Am J Ophthalmol 1983;95:605–13.
36 Damms T, Bohnke M, Behrend-Berdin B. Ergebnisse der therapie bei oku- larer toxoplasmose. Ophthalmologe 1993;90:737–41.
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