Ординатура / Офтальмология / Учебные материалы / Uveitis Text and Imaging Text and Imaging Text and Imaging 2009

INTRODUCTION

Although Reid et al1 were the first to describe ocular abnormalities in a patient suffering from disseminated histoplasmosis, Woods et al2 were the first to report a series of young, otherwise healthy adults who had a consistent pattern of discrete atrophic peripheral choroidal scars along with cystic macular lesions. These patients were also noted to be more likely to react to histoplasmin skin testing. In the mid-1960s, atrophic peripapillary scarring was added to the clinical picture.3 Despite these early clinical associations, controversy regarding the true pathophysiology of this ocular syndrome still exists, and thus the term ‘presumed’ remains part of the moniker.

HISTORICAL BACKGROUND

Histoplasma capsulatum is a dimorphic soil fungus endemic to the Ohio and Mississippi River valleys of the United States. The earliest theory, based upon patients suffering from systemic histoplasmosis infection, held that active infection with the fungus lead to the development of ocular histoplasmosis syndrome.1 As additional reports described a similar constellation of fundus lesions in asymptomatic adults, the theory of ocular involvement shifted to one in which prior disseminated H. capsulatum infection resulted in choroidal invasion and scarring, leading to the accepted term presumed ocular histoplasmosis syndrome (POHS). Despite over 50 years of research, a direct relationship has been difficult to prove.

Older studies showed a correlation between a histoplasmin skin test and ocular histoplasmosis,4 but

serologic confirmation has been difficult, as antibodies decline to low or undetectable levels 2 to 5 years after systemic infection.5 Although precious few reports exist showing true histologic evidence linking the choroidal scars to past infection with H. capsulatum, a recent case of a patient with chronic bilateral ocular histoplasmosis found products of H. capsulatum DNA in the choroidal lesions of an enucleated eye.6 The majority of evidence linking the clinical characteristics of ocular histoplasmosis and the organism H. capsulatum, however, is largely based on epidemiologic observations, with endemic regions showing the highest incidence of ocular lesions.7

EPIDEMIOLOGY

Epidemiologic studies from the 1960s and 1970s estimated the prevalence of POHS to be between 1.6 to 5.3%.8 Presumed ocular histoplasmosis was found to be most prevalent in the endemic areas of North America, where over 60% of the adult population was estimated to react positively to histoplasmin skin testing.9 A study conducted in the mid-Atlantic United States found that, while 100% of patients with fundus findings consistent with POHS had a positive histoplasmin skin antigen test, only 4.4% of people with a positive skin test exhibited POHS-like lesions.9 In a larger study involving an institutionalized population consisting of both men and women, whites and blacks in Ohio, the prevalence of ocular lesions was found to be 1.6%.5 New reports have described a POHS-like syndrome in non-endemic regions such as the northwest United States,10 the United Kingdom11, the Netherlands,12,14 and Brazil,13 challenging the classic

epidemiologic linkage between H. capsulatum and POHS. Without definite serologic confirmation, it is not clear whether these cases represent POHS or another uveitis condition such as multifocal choroiditis.

The visual sequelae of POHS occur most frequently during the adult working years, from the second to fifth decade of life. A definite gender predilection has never been found, but some studies have found a higher prevalence in women.14 Atrophic peripheral scars are seen equally in blacks and whites, however disciform macular lesions are primarily described in whites.15,16

As evidence mounts, it is becoming clear that an immune reaction plays a key role in the development of choroidal neovascularization found in POHS. The most common histocompatibility antigens associated with POHS are HLA-DRw2, -B7, and –DR15, although others have been described.

CLINICAL CHARACTERISTICS

Presumed Ocular Histoplasmosis is a clinical diagnosis based on the observation of discrete, atrophic (so-called “punched-out”) choroidal scars in the macula or periphery, peripapillary atrophy, and the absence of active inflammation in the anterior chamber or vitreous cavity2 (Figure 1). Patients with nonexudative POHS are typically asymptomatic, with discovery of typical lesions found incidentally on routine examination. The atrophic scars are considered to be the earliest stage in the disease,17 and represent focal

Figure 1: Typical punched-out, atrophic lesions of POHS seen in the periphery

defects in Bruch membrane. The peripapillary atrophy may, in some cases, represent a spontaneously regressed choroidal neovascular membrane (CNVM).

As mentioned previously, choroidal scars remain largely asymptomatic. There are cases of patients developing new lesions or reactivation of old ones (Figures 2A-C).18,19 However, it is usually not until a CNVM compromises central vision that patients seek ophthalmic attention. As in other conditions with macular choroidal neovascularization, patients with exudative ocular histoplasmosis typically describe a painless, gradual blurring of central vision with metamorphopsia. POHS affects people between their second and fifth decades of life, when their retinal pigment epithelium cells still have a firm attachment to Bruch membrane. Thus, POHS-associated CNVMs take the path of least resistance, and subretinal neovascularization is seen much more commonly than sub-RPE neovascularization.18 On angiography, active leakage is generally seen at the edge of a scar, with a classic lacy pattern found more commonly in POHS than in other causes of choroidal neovascularization.

NATURAL HISTORY

Since the majority of patients with POHS are not identified until a central scar develops neovascularization, most natural history studies of POHS are based on findings from the fellow eye once follow-up for the affected eye has been established.15,17 When the affected eye has a CNVM or disciform scar, the risk of visual loss in the fellow eye is 1% if no lesions are found. The risk increases to 4% if peripapillary atrophy is present, and to 25% if macular choroidal scars are noted.20 During routine follow-up, 20% of patients will develop new choroidal scars, which can develop in either the peripheral or macular region; however less than 4% will progress to neovascularization.17 If subfoveal neovascular maculopathy remains untreated, over 50% of patients will ultimately have vision worse than 20/200.15,17,21 The average time elapsed for the development of symptoms between the first and second eye is 4 years.17

TREATMENT

Antifungals It has long been known that the development of ocular histoplasmosis does not occur

Figures 2A-C: New inflammatory lesion in POHS (A) New active inflammatory lesion of POHS in the macula (B) Angiogram of lesion showing hypofluorescence in the center and a slight ring of hyperfluorescence, and (C) Involution of the same lesion 5 weeks later showing a slightly pigmented, atrophic scar

concurrently with an active infection with H. capsulatum. Thus it is not surprising that early attempts at treating the disease with antifungal medications failed and were abandoned decades ago.22 Their mention here is for historical purposes only. The majority of POHS lesions remain dormant; therefore treatment is only indicated for and aimed at neovascular complications of macular choroidal scars.

Thermal laser photocoagulation The goal of thermal laser photocoagulation is the complete destruction of the neovascular complex. In large randomized trials, the Macular Photocoagulation Study showed that both argon and krypton laser photocoagulation are effective in treating well-defined, classic juxtafoveal, extrafoveal, and peripapillary neovascular membranes due to ocular histoplasmosis. In the juxtafoveal CNVM arm, 28% of control eyes experienced severe visual loss, defined as loss of six or more lines, at five years, compared to 12% of eyes treated with krypton laser. In eyes with extrafoveal choroidal neovascularization, 42% of control patients suffered severe visual loss, compared to 12% in the treated group at the five-year point.23-26

Although a visual benefit was demonstrated at sixty months, the MPS also showed a high rate of persistence (leakage within 6 weeks of treatment) and recurrence (leakage after 6 weeks from treatment). Of the eyes assigned to the Ocular HistoplasmosisKrypton Laser arm, the persistence rate was found to be 23% of treated patients, while recurrence was observed among an additional 8%.24 Additional drawbacks to thermal laser treatment include absolute central scotoma caused by irreversible destruction of the retina and underlying RPE, as well as the potential for incomplete treatment at the edge of the lesion near the fovea. These treatment effects limit the usefulness of photocoagulation of CNVMs under the fovea.

Photodynamic therapy (PDT). Verteporfin (Visudyne) is a liposome-encapsulated modified porphyrin, which is thought to complex with low-density lipoprotein, whose receptors are found in high numbers on the endothelial cells of actively proliferating neovascular tissue. Following intravenous infusion, the drug effectively concentrates within choroidal neovascular membranes, where a low energy laser can stimulate the drug to destroy neovascular tissue through the creation of reactive oxygen species. The theoretic

advantage of PDT is its ability to target CNVMs without damaging the overlying retina.27 In 2001, the United States Food and Drug Administration approved PDT for the treatment of POHS after the publication of the Verteporfin in Ocular Histoplasmosis study.28

In recent years, there have been several case series in the literature exploring the efficacy of PDT in the treatment of ocular histoplasmosis. Busquets, et al29 retrospectively evaluated patients who received PDT for juxtafoveal POHS-related CNVM and found that

69% of patients receiving treatment had stable or improved visual acuity, and that treated patients were twice as likely to have stable or improved vision when compared to a natural history group. Another series examining juxtafoveal CNVM had similar results, with 88% of treated eyes showing stabilization or improvement, and a trend toward therapeutic benefit when compared to published natural history data.30 The Verteporfin in Ocular Histoplasmosis Study Group demonstrated safety and efficacy in the use of PDT for subfoveal neovascular lesions, reporting that nearly

82% of patients had stabilized or improved vision at

24 months when compared to baseline examination, and that leakage from subfoveal CNVMs was absent in the majority of cases.31 Combination therapy with PDT and intravitreal steroids has also been used effectively32 (Figures 3A-D).

Corticosteroids For years, steroid compounds have been known to possess angiostatic properties. These attributes have been due to steroids’ ability to alter extracellular matrix degradation,33 as well as inhibit the inflammatory response, which has been shown to both destroy healthy tissue and participate in the creation of neovascular complexes.34,35 Despite the potential benefits of steroid therapy, there is limited data in the literature.

A series comparing oral Prednisone to sub-Tenon’s triamcinolone found that, although Prednisone showed an initial short-term improvement in acuity, both treatment modalities lead to essentially stable vision at 3 months.36 In a retrospective analysis of ten patients receiving intravitreal triamcinolone for ocular histoplasmosis-related subfoveal and juxtafoveal choroidal neovascularization, eight patients experienced stabilization or improvement in visual acuity; however, there was no change in the mean acuity for the group overall.37 Given the limited data, it seems that monotherapy with steroids at best can lead to stabilization of visual acuity when choroidal neovascularization occurs, but their use should be weighed against potential side effects.

Submacular surgery The submacular surgery Trial included an arm that examined surgical removal of idiopathic or POHS-related subfoveal CNVM versus observation (SST group H).38 The study found that, at 24 months, 46% of eyes in the observation arm and 55% in the surgery arm had a successful outcome, defined as visual acuity better or no more than 1 line worse than at baseline examination. The only subgroup that showed some benefit to surgical intervention were patients whose initial visual acuity was worse than 20/ 100. The SST investigators concluded that surgery may be considered for patients in this particular subgroup, but should be weighed against the risks of retinal break/detachment and cataract formation.

Interestingly, despite minimal benefit in visual acuity in the majority of patients, those in the surgi-

cally treated group reported a better vision-targeted quality of life than those in the observation arm.39 Patients showed the greatest improvement in the “role difficulties” and “dependency” subscales of the National Eye Institute Visual Function Questionnaire. The group concluded that the potential psychologic benefit of submacular surgery should also be considered when the decision for surgical intervention is being made.

A long-term retrospective review of patients undergoing surgical removal of peripapillary choroidal neovascular membranes found that 78% of eyes with subfoveal extension of peripapillary neovascularization achieved stable or improved best-corrected visual acuity, while 88% of eyes in which choroidal neovascularization remained extrafoveal had stable or improved acuity when compared to baseline.40 The authors felt that surgical removal of selected peripapillary CNVMs may be preferable to potentially multiple treatments with PDT or anti-VEGF medications.

Anti-vascular endothelial growth factor antibody compounds Vascular endothelial growth factor (VEGF) is a glycoprotein that functions as an angiogenic and vasopermeability factor. There are currently five known naturally occurring isoforms of VEGF, and three tyrosine-kinase receptors that permit signal transduction. Both hypoxia and animal models of choroidal neovascularization have been shown to stimulate VEGF expression. Thus, it seems intuitive that the use of anti-VEGF antibodies would be useful to directly target choroidal neovascular membranes.

Bevacizumab (Avastin®) is a recombinant, humanized, anti-VEGF antibody similar to ranibizumab (Lucentis®) that binds all VEGF isoforms. Full-thick- ness retinal penetration in a rabbit model was shown following intravitreal injection,41 and numerous clinical series have shown its effectiveness in treating choroidal neovascularization from various etiologies. To date, few reviews of the use of intravitreal Bevacizumab to specifically treat POHS-related choroidal neovascularization exist. One report revealed that 86% of eyes stabilized or improved in visual acuity following an average of 1.8 injections.42 There is no doubt that, as the indications for intravitreal anti-VEGF compounds expand, they will become an integral part of the armamentarium against POHS-related choroidal neovascularization.

REFERENCES

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2.Woods AC, Wahlen HE. The probable role of benign histoplasmosis in the etiology of granulomatous uveitis. Trans Am Ophthalmol Soc 1959;57:318-43.

3.Schlaegel TF, Kenney D. Changes around the optic nerve head in presumed ocular histoplasmosis. Am J Ophthalmol 1966;62:454-8.

4.Khalil MK. Histopathology of presumed ocular histoplasmosis. Am J Ophthalmol 1982;94:369-76.

5.Asbury T. The status of presumed ocular histoplasmosis: including a report of a survey. Trans Am Ophthalmol Soc 1966;64:371-400.

6.Spencer WH, Chan C, Shen DF, Rao NA. Detection of Histoplasma capsulatum DNA in lesions of chronic ocular histoplasmosis syndrome. Arch Ophthalmol 2003; 121:1551-5.

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8.Hawkins BS, Alexander J, Schachat AP. Ocular histoplasmosis. In: Ryan, SJ, Schahchat AP, (Eds): Retina. St. Louis, MO: Mosby; 2001.

9.Brown DM, Weingeist TA, Smith RE. Histoplasmosis. In: Pepose, JS, Holland GN, Wilhelmus KR, (Eds): Ocular infection and immunity. St. Louis, MO: Mosby; 1996.

10.Watzke RC, Klein ML, Wener MH. Histoplasmosis-like choroiditis in a non-endemic area: the northwest United States. Retina 1998;18:204-12.

11.Braunstein RA, Rosen DA, Bird AC. Ocular histoplasmosis syndrome in the United Kingdom. Br J Ophtalmol 1974; 58:893-8.

12.Ongkosuwito JV, Kortbeek LM, Van der Lelij A, et al. Aetiological study of the presumed ocular histoplasmosis syndrome in the Netherlands. Br J Ophthallmol 1999; 83:535-9.

13.Amaro MH, Muccioli C, Abreu MT. Ocular histoplasmo- sis-like syndrome: a report from a nonendemic area. Arq Bras Oftalmol 2007;70:577-80.

14.Suttorp-Schulten MSA, Bollemeijer JG, Bos PJM, et al. Presumed ocular histoplasmosis in the Netherlands: an area without histoplasmosis. Br J Ophthalmol 1997;81: 7-11.

15.Gass JD, Wilkinson CP. Follow-up study of presumed ocular histoplasmosis. Trans Am Acad Ophthalmol Otolaryngol 1972;76:672-94.

16.Baskin MA, Jampol LM, Huamonte FU, et al. Macular lesions in blacks with the presumed ocular histoplasmosis syndrome. Am J Ophthalmol 1980;89:77-83.

17.Lewis ML, van Newkirk MR, Gass JDM. Follow-up study of presumed ocular histoplasmosis syndrome. Ophthalmology 1980;87:390-9.

18.Gass JD. Pathophysiologic and histopathologic bases for interpretation of fluorescein angiography. In Stereoscopic Atlas of Macular Diseases: Diagnosis and Treatment. St. Louis: Mosby-Year Book, Inc.; 1997;2-49.

19.Callanan D, Fish GE, Anand R. Reactivation of inflammatory lesions in ocular histoplasmosis. Arch Ophthalmol 1998;116:470-4.

20.Regillo C, Chang TS, Johnson MW, et al (Eds). Ocular Histoplasmosis Syndrome. American Academy of Ophthalmology Basic and Clinical Science Course. San Francisco, CA: AAO; 2004.

21.Olk RJ, Burgess DB, McCormick PA. Subfoveal and juxtafoveal subretinal neovascularization in the presumed ocular histoplasmosis syndrome: visual prognosis. Ophthalmology 1984;91:1592-1602.

22.Giles CL, Falls HF. Further evaluation of amphotericin B therapy in presumptive histoplasmosis chorioretinitis. Am J Ophthalmol 1961;51:588-98.

23.Macular Photocoagulation Study Group: Krypton laser photocoagulation for neovascular lesions of ocular histoplasmosis: results of a randomized clinical trial. Arch Ophthalmol 1987;105:1499-1507.

24.Macular Photocoagulation Study Group: Persistent and recurrent neovascularization after krypton laser photocoagulation for neovascular lesions of ocular histoplasmosis. Arch Ophthalmol 1989;107:344-352.

25.Macular Photocoagulation Study Group: Recurrent choroidal neovascularization after argon laser photocoagulation for neovascular maculopathy. Arch Ophthalmol 1986;104:503-12.

26.Macular Photocoagulation Study Group: Argon laser photocoagulation for ocular histoplasmosis: results of a randomized clinical trial. Arch Ophthalmol 1983;101:134757.

27.Kramer M, Miller JW, Michaud N, et al. Liposomal benzoporphyrin derivative verteporfin photodynamic therapy: selective treatment of choroidal neovascularization in monkeys. Ophthalmology 1996;103:427-38.

28.Saperstein DA, Rosenfeld PJ, Bressler NM, et al. Photodynamic therapy of subfoveal choroidal neovascularization with verteporfin in the ocular histoplasmosis syndrome: one-year results of an uncontrolled, prospective case series. Ophthalmology 2002;109:1499-505.

29.Busquets MA, Shah GK, Wickens J, et al. Ocular photodynamic therapy with verteporfin for choroidal neovascularization secondary to ocular histoplasmosis syndrome. Retina 2003;23:299-306.

30.Shah GK, Blinder KJ, Hariprasad SM, et al. Photodynamic therapy for juxtafoveal choroidal neovascularization due to ocular histoplasmosis syndrome. Retina 2005;25:26-32.

31.Rosenfeld PJ, Saperstein DA, Bressler NM, et al. Photodynamic therapy with verteporfin in ocular histoplasmosis: Uncontrolled, open-label 2-year study. Ophthalmology 2004;111:1725-33.

32.Augustin AJ, Offermann I. Combination therapy for choroidal neovascularisation. Drugs Aging 2007;24: 979-90.

33.Folkman J, Ingber DE. Angiostatic steroids. Ann Surg 1987; 206:374-83.

34.Proja A, Hirakata A, McInnes JS, et al. The effect of angiostatic steroids and beta-cyclodextrin tetradecasulfate on corneal neovascularization in the rat. Exp Eye Res 1993; 57:693-8.

35.Okhuma H, Ryan SJ. Vascular casts of experimental subretinal neovascularization in monkeys. Invest Ophthalmol Vis Sci 1983;24:481-90.

36.Martidis A, Miller D, Ciulla TA, et al. Corticosteroids as an antiangiogenic agent for Histoplasmosis-Related

Subfoveal Choroidal Neovascularization. Journal of Ocular

Pharmacology and Therapeutics 1999;15:425-8.

37.Rechtman E, Allen VD, Danis RP, et al. Intravitreal triamcinolone for choroidal neovascularization in ocular histoplasmosis syndrome. Am J Ophthalmol 2003;136:73941.

38.Submacular Surgery Trials Research Group. Surgical removal vs observation for subfoveal choroidal neovascularization, either associated with the ocular histoplasmosis syndrome or idiopathic. I. Ophthalmic findings from a randomized clinical trial: Submacular surgery trials (SST) group H trial: SST report no. 9. Arch Ophthalmol 2004; 122:1597-1611.

39.Submacular Surgery Trials Research Group. Surgical removal vs observation for subfoveal choroidal neovascu-

larization, either associated with the ocular histoplasmosis syndrome or idiopathic: II. Quality-of-life findings from a randomized clinical trial: SST group H trial: SST report no. 10. Arch Ophthalmol 2004;122:1616-28.

40.Almony A, Thomas MA, Atebara NH, et al. Long-term Follow-up of Surgical Removal of Extensive Peripapillary Choroidal Neovascularization in Presumed Ocular Histoplasmosis Syndrome. Ophthalmology 2008;115:540-5.

41.Shahar J, Avery RL, Heilweil G, et al. Electrophysiologic and retinal penetration studies following intravitreal injection of bevacizumab (Avastin). Retina 2006;26:262-9.

42.Schadlu R, Blinder KJ, Shah GK, et al. Intravitreal Bevacizumab for Choroidal Neovascularization in Ocular Histoplasmosis. Am J Ophthalmol 2008;145:875-8.

Carlos Pavesio

HISTORY

In 1908, Charles Nicolle and Louis Manceaux,1 in Tunis, observed a parasite in mononuclear cells of the spleen and liver of a north African rodent, the gondi (Ctenodactylus gondii). The proposed name was Toxoplasma gondii due to the arch-shaped (from the Greek Toxon) appearance of the organism on light microscopy. Independently, Alfonse Splendore in Sao Paulo, Brazil, during the same year of 1908 describes a parasite which had killed a rabbit and names it

Toxoplasma cuniculli.2

The first case of ocular involvement was described by Janku in Prague in 1923, in a child who presented with hydrocephalus, microphthalmia and a macular coloboma. Actually the identification of Toxoplasma gondii as the cause of this child’s problem occurred only years later, in 1928, by Levaditi.3

The Sabin-Feldman test for serological diagnosis was only introduced in 1948.4 After 1960, toxoplasmosis was recognised as the most important cause of posterior uveitis in the world.

The life cycle of the parasite, with the discovery of the cat as the definitive host, was described only in 1970 by both Frenkel and Hutchison.5,6

EPIDEMIOLOGY

Toxoplasmic retinochoroiditis is the most common identifiable cause of posterior uveitis in many parts of

the world,7 including northern Europe, North America8- 10 and South America.11 It accounts for about 30 to 50% of all cases of posterior uveitis.12 Positive serology increases with age but most cases of active retinal disease are seen in children and young adults, even though it still remains an important cause of posterior uveitis after the fifth decade of life.13 The prevalence of positive serology for toxoplasmosis varies significantly with geographic location and ranges from zero per cent, in esquimos, to levels of over 80% in Brazil and France.14 The estimated incidence of symptomatic active toxoplasmic retinochoroiditis among people in London who were born in the United Kingdom15 is 0.4 cases/ 100,000 population/year. In the USA toxoplasmic retinitis accounts for 25% of posterior uveitis,16 while in southern Brazil it accounts for nearly 85% of all cases of posterior uveitis.17

AETIOLOGY AND TRANSMISSION

This disease is caused by the protozoan Toxoplasma gondii, an obligatory intracellular parasite, which has as its definitive host the Felidae. The organism exists in three forms: (1) oocyst, the products of sexual reproduction which occurs in the epithelial cells of the cats’ gut, and is eliminated in large number in cats’ faeces; (2) tachyzoite, a rapidly multiplying form, responsive for cell invasion; (3) bradyzoites, a resting form inside tissue cysts. Tissue cysts reside inside the cytoplasm of host’s cells and do not elicit an inflam-

matory response since they are well hidden from the eyes of the immune system. It is this cystic form which is believed to be responsible for the recurrent nature of this condition.

It can be transmitted congenitally, when the disease is acquired during pregnancy, or it can be acquired after birth, usually by ingestion of oocysts by handmouth mechanism or contaminated water, or ingestion of tissue cysts in undercooked meat. Ingestion of oocyts, excreted in cat faeces, will result in disease after they have sporulated, which usually happens after 48 hours following elimination in the faeces.

Ingestion of contaminated water is a mechanism more recently described which seems to be quite important especially in rural areas, even though an outbreak of toxoplasmosis was reported due to contamination of municipal water system.18

In congenital disease transmission to the foetus occurs in about 45% of the cases, and will occur only for that pregnancy, with subsequent ones being protected by neutralising antibodies. Most of the cases of congenital transmission occur towards the end of pregnancy, when a more senile placenta is less effective as a barrier. It is less common in the early stages (first trimester) when it will produce severe disease mostly resulting in death of the foetus, while in the later stages it will lead to children born with retinal scars, or entirely normal, but with the potential for developing ocular and brain lesions over the years.19

Following ingestion, the organisms will spread by haematogenous dissemination and will establish themselves especially in tissues with stable cells, such as muscles, brain and retina. They will eventually lead to the formation of tissue cysts, which represents a resting stage of the parasite and one that does not elicit an inflammatory reaction. These cysts are packed with bradyzoites, which will transform into tachyzoites upon cyst rupture and will actively invade new cells to restart the cycle.

Other less frequent forms of transmission include blood transfusion, organ transplant and laboratory accidents.20,21 One epidemic has been linked to inhalation of oocysts from infected cats living in a riding stable,22 but this is certainly a rare occurrence.

OCULAR DISEASE

For many years it was accepted that ocular toxoplasmosis was the result of congenital transmission,

with few cases occurring secondary to post-natal disease. Evidence to the contrary started to be gathered after the identification in Southern Brazil of a very high prevalence of retinal scars in the community and of several families with several siblings showing retinal disease, not explainable on the basis of congenital transmission alone.17 A recent analysis of the incidence and prevalence of the disease in the UK confirms the view that ocular disease is predominantly the result of acquired disease after birth.13

CLINICAL PICTURE

The most accepted explanation for the initial events in the acute disease is the cyst rupture mentioned above, even though other theories, including autoimmunity, have been proposed. In classic congenital disease bilateral macular involvement is present at birth, and it is interesting to note that the vitreous does not reveal signs of inflammation, especially when we consider the size of these scars. This is due to the lack of inflammatory reaction in the presence of an immature immune system.

The typical lesion is a necrotizing retinitis. In primary acquired retinal disease the retinitis is seen in the absence of a previous scar (Figure 1), while in reactivations the lesions will occur adjacent to a previous scar with variable pigmentation (the more pigmented the older the lesion is), and are called satellite lesions (Figure 2). These satellite lesions are typical of the recurrent behaviour of this condition.

Figure 1: Primary toxoplasmic retinitis: Active lesion at superotemporal arcade. Note the absence of a scar in the vicinity of the new lesion

Figure 2: Reactivation of toxoplasmic retinitis: A white focus of retinitis is seen between two pigmented scars superior to the disc. The inflammatory response surrounding the new lesion obscures details of the old lesions. A certain degree of vitritis is also blurring the fundus view

Recurrences are totally unpredictable and may occur years after the original lesion resolved. These acute lesions appear as white focus of retinitis, surrounded by oedema, which makes the margins poorly defined (Figure 3). They may have various sizes, which usually defines severity of the inflammatory reaction, and may be located in the posterior retina or periphery. After a few weeks, the edges start to get better defined, as the oedema resolves, and following that the lesion progressively resolves, from the periphery to the centre, leaving scar tissue in its wake (Figures 4A-D). The end result is a scar, which will progressively

Figure 3: Acute toxoplasmic retinitis: Active focus of retinitis superonasal to the disc, showing central white core representing the necrotising process, surrounded by retinal oedema

pigment, starting at the edges. These lesions are selflimited in the immunocompetent individual, but this progression to resolution may be hastened by treatment (see below). In very aggressive presentations a serous detachment of the retina can develop and it usually resolves fairly quickly after initiation of therapy (Figure 5).

Atypical presentations include papillitis, pseudomultiple retinochoroiditis, intraocular inflammation without retinochoroiditis, unilateral pigmentary retinopathy, Fuchs’-like anterior uveitis, scleritis and multifocal or diffuse necrotising retinitis. Lesions developing in proximity to the optic disc may produce significant morbidity leading to central vision loss or field defects. Some of these presentations will show the typical pattern of neuroretinitis with disc swelling and macular star (Figure 6). Punctate outer retinal toxoplasmosis is a subset of ocular toxoplasmosis that is characterised by multifocal grey-white lesions at the level of deep retina and retinal pigment epithelium and that is associated with little or no overlying vitreous reaction. Acute lesions may resolve to form fine granular white dots24,25 (Figure 7).

Vitritis is commonly seen, especially overlying the active lesion and it may be severe enough to prevent proper visualisation of the lesion, which may appear only as a “headlight in the fog” (Figure 8). Cellular deposits, resembling keratic precipitates (KPs) may be seen on the posterior vitreous face (Figure 9). Vitritis can become quite intense and may represent an indication for therapy (see below).

Rarely, blood vessels crossing over the active retinitis may suffer occlusion, but it is quite common to find sheathing of vessels, more commonly in the proximity of the lesion, but also far from it (Figure 10). These vessels do not suffer the risk of occlusion and the sheathing disappears very quickly with therapy. This vascular response represents an immune mediated reaction. Also in the vicinity of the acute focus arteries may show multiple small deposits on their surface, which are known as Kyrieleis plaques, and even though not pathognomonic, are very suggestive of toxoplasmosis (Figure 11). These vessels do not show leakage on fluorescein angiography and do not suffer occlusion. The pathogenesis of these plaques is unknown.