Fig. 6.22 Same patient as in Fig. 6.13 after four weekly injections of intravitreal clindamycin and dexamethasone. (a) Color fundus photograph demonstrates resolution, and a large decrease in both the size of the lesion along the inferotemporal vascular arcade and vitreous inflammation. (b) Fluorescein angiogram demonstrated a significant

decrease of leakage from toxoplasmic retinochoroiditis. (c) Optical coherence tomography scan shows normalization of the papillomacular anatomy and a decrease in the height of the peripapillary granuloma. The retina map analysis indicates a central macular thickness of 240 mm. His visual acuity improved to 20/40

zone 1 TRC in pregnant patients, in patients with disease progression despite systemic therapy, or in patients with lesions located at or near the fovea and/or optic disc. Such combined therapy is typically effective at controlling TRC and improving both inflammation and vision (Figs. 6.13 and 6.22). Recently, Sobrin et al. [59] reported a case series of six patients who were treated with a single intravitreal injection of clindamycin alone (1 mg/0.1 mL). Complete resolution of vitreous inflammation was noted within 6 weeks in five of six patients.

Photocoagulation and cryotherapy have been proposed for the treatment of TRC and to decrease relapse rates [60, 61]. These procedures cause destruction of the cysts and the tachyzoites in the retina. However, photocoagulation and

cryotherapy of active lesions have been associated with severe complications, including choroidal neovascularization, vitreous hemorrhages, and retinal detachment [62]. Vitreous surgeries should be used if there are vitreal opacities or vitreal membranes that obstruct vision or cause traction on the retina. Vitrectomy should be performed after the inflammatory process is controlled [63].

Controversies and Perspectives

Although serological tests can reliably identify individuals with recent T. gondii infections, there are currently no serological techniques to discriminate between patients with congenital

infections and remote postnatally acquired infections. In addition, clinical characteristics do not always reliably distinguish between patients with congenital and postnatally acquired infections.

Ocular fluid analysis shows that intraocular anti–T. gondii IgG production is more frequently present in patients with recurrent ocular toxoplasmosis, whereas T. gondii DNA is more frequently present in ocular fluid samples from patients with primary OT. The presence of DNA in patients with primary OT and serologic evidence of acute systemic toxoplasmosis is possibly caused by the gradual activation of the intraocular T. gondii–specific immune response, which is not yet capable of clearing the infectious agent in the early stage of the disease. Intraocular anti– T. gondii IgA antibodies could be detected in patients with both acute and chronic stages of systemic infection and in patients with primary OT as well as in patients with recurrent OT. In contrast, serum IgA antibodies have been noted so far only in the acute phase of primary disease. The intraocular presence of IgA is therefore not a marker of acute disease, but it could be caused by the unique environment of the eye, where the cytokine transforming growth factor-b(beta) is present in relatively high levels [48]. We consider that the combination of serum anti–T. gondii IgG, IgM, and IgA to be essential for evaluation of any TRC case. However, most cases are diagnosed clinically.

Proliferating parasites are believed to be responsible for tissue destruction, whereas hypersensitivity reactions to the parasite are responsible for associated inflammatory signs, including retinal vasculitis, anterior uveitis, vitreous inflammatory reactions, and retinal edema. While it has been suggested that intraocular inflammation can occur without necrotizing retinochoroiditis in patients with acquired T. gondii infections, there has been little data provided to support such statements. It is known that retinochoroidal scars can first develop after birth in patients with congenital infections and that tissue cyst can exist in normal-appearing retina [7]. Acquired T. gondii infection should be considered in the differential diagnosis of patients with

the recent onset of nonspecific vitreous humor inflammation and retinal vasculitis, especially in the presence of constitutional symptoms.

Clinicians are cautioned against corticosteroid injections in patients of acquired T. gondii infections if there is evidence to suggest systemic toxoplasmosis because the inflammatory reactions may be in response to parasites within the eye and treatment may facilitate proliferation of organisms, leading to necrosis that would otherwise have been prevented by host defenses. On the other hand, low-dose corticosteroid monotherapy has been administered without severe side effects in some reports. However, a welldefined study of the effect of corticosteroid monotherapy in OT as well as the additional value of corticosteroids as adjuvant therapy has not been performed. Thus, the use of corticosteroids for the treatment of OT is controversial, and the timing and dosages during the course of the disease are not well defined [64]. Basically, topical and half-dose (0.5 mg/kg/day) corticosteroids are fine with antimicrobial cover. Depot corticosteroids, both periocular and intraocular, are contraindicated. Intravitreal dexamethasone is fine with antimicrobial cover because it only lasts a day or two. Ocular toxoplasmosis in immunocompromised patients is often treated without the use of corticosteroids, thereby reducing the risk of further suppression of host defenses; clinical series have shown that the signs of OT, including inflammatory signs, can respond rapidly to antiparasitic therapy alone in immunocompromised patients.

A variety of observations suggest that clinical features of OT are related to age of the host. The distribution of active TRC episodes in relation to patient age has been remarkably similar in many reports. Ocular involvement during the acute phase of postnatal toxoplasmosis occurs predominantly in elderly patients [65]. In addition, it has been described a relationship between older age and larger lesions. A relationship between age and scar size could be explained by a history of progressive enlargement in older patients with long-standing disease and multiple reactivations, but this explanation would not account for a relationship to the area of the active recurrence.

The latter relationship may reflect waning immunity with a decreased ability to limit the proliferation of parasites among elderly patients.

Ocular toxoplasmosis is one of the few forms of uveitis in which intraocular pressure (IOP) is elevated during the initial phase of inflammation; others include herpetic anterior uveitis (HSV, VZV, CMV), sarcoidosis, Posner–Schlossman syndrome, and syphilitic uveitis. The cause of elevated IOP in eyes with OT is unknown [26]. Westfall et al. identified a possible relationship between elevated IOP and increased anterior chamber cells, but the relationship was not statistically significant [26, 66].

The source of the original infection in patients with OT has been a subject of debate. For many years, it has been widely accepted that nearly all scars are the residua of congenital infections and that ingestion of undercooked meat is the major source of primary, acquired infection in pregnant women and others. Recent observations have challenged these traditional beliefs [24]. A better understanding of the source of initial infection in patients with recurrent TRC has important implications for prevention of disease transmission and possibly for treatment. If establishment of retinal infections with acquired disease is more common than heretofore believed, it is important to reconsider sources of infection. Ingestion of tissue cysts has traditionally been assumed to be the major route by which infection occurs [17, 24].

Evidence that strain type does indeed affect disease outcome in humans is increasing. We need a more detailed understanding of the population structure for this ubiquitous parasite. Most of the existing information is from a few regions (principally Europe, Brazil, and North America) and a limited number of animals and people with severe disease. Although certain strains appear to dominate in these groups, the numbers analyzed in detail remain small. The use of SAG2 for genotyping T. gondii strains is capable of distinguishing all three clonal genotypes at a single locus. This approach works well in North America and Europe where the three major lineages predominate because of extreme linkage disequilibrium. Current findings indicate that most strains from

Brazil as well as many other countries do not fit the clonal pattern seen in North America. Consequently, studies that rely solely on SAG2 typing will necessarily under represent the true genetic divergence in many regions [45].

Further research is required to determine whether virulence factors are associated with prolongation of the tachyzoite phase, which could create a longer therapeutic window before tissue cyst formation when anti-toxoplasmic treatment might be effective [40].

Finally, the factors that affect the epidemiology of ocular toxoplasmosis include endogenous factors such as age, sex, medical history, and immunogenetic background, as well as exogenous factors such as climate, public health, dietary habits, and causative strands. Primary preventive strategies should include children and adults at risk of ocular disease as a result of postnatal infection and should not be confined to pregnant women. Additionally, prophylaxis to prevent recurrence of OT in immunocompetent individuals has been advocated by some groups and is in continual discussion.

Focal Points

The timing of toxoplasma infection leading to ocular disease is rarely known. However, current evidence suggests that many more people are affected by postnatal than by prenatal toxoplasmosis. This has major public health implications. Considerable expertise and expense is concentrated on screening and health information to reduce the risks of toxoplasmosis due to prenatally acquired infection, principally to reduce the risks of ocular morbidity in the long term.

Initial retinal infection may be subclinical, with development of retinal lesions months or years later. Tissue destruction is probably attributable both to proliferation of T. gondii and to inflammatory reactions, but the relative importance of each factor may vary between hosts. In some cases, the disease may be predictably selflimiting, and so no intervention is needed. In other instances, aggressive treatment may be warranted. These decisions will probably be most

important in the treatment of maternal infection, in which the developing fetus is especially sensitive to drugs, and so the drugs must be used only when absolutely necessary.

Patients can periodically have mild, transient recurrences of inflammation without evidence of active retinochoroiditis. Attention to these various observations may help to understand disease mechanisms, ultimately with implications for choice of therapy. Reinfection with T. gondii might explain some clinical observations and should be investigated with new techniques that can differentiate between parasite types. Disease features are probably more diverse than traditionally taught; yet most, if not all, “atypical” forms of disease appear to be part of a spectrum of the same basic disease process of retinal infection with stimulation of a host immune response.

Although the general approach to management of OT is similar for most uveitis specialists, there is currently no consensus regarding a preferred treatment regimen.

Prognosis of OT is generally good in immunocompetent individuals. Immunosuppressed patients and the elderly may have more chronic disease, and vision loss can occur secondary to macular scar formation, optic nerve involvement, vascular occlusion, retinal detachment, and other potential complications:

•Acquired toxoplasmosis in childhood may lead to severe blinding OT late in life and antitoxoplasma drugs may be indicated when the infection is diagnosed.

•Most cases of OT are acquired, not congenital.

•The classic clinical presentation for OT is retinochoroiditis, but rarely only vasculitis or small areas of retinal thickening/whitening can be seen.

•Pregnant women can rarely transmit the infection to fetus more than once.

•Cats and meat are not the only source of infection; both air and water sources have been recognized.

•Anti-toxoplasma drugs should be given according to the clinical picture and not just for 4–6 weeks.

•Prevention of recurrence is possible and should be used in high-risk patients.

•Recurrences not just related to retinal cysts (persistency of infectious agent).

•PCR and modern molecular biologic techniques still play a minor role in diagnosis.

Acknowledgments The authors have no financial or proprietary interest in any of the products or techniques mentioned in this chapter.

Supported in part by the Arévalo-Coutinho Foundation for Research in Ophthalmology, Caracas, Venezuela; a Research Grant CNPq-Brazil; and the Pacific Vision Foundation, San Francisco, California, USA.

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M. Ibrahim, M.D. • R. Channa, M.D. • M. Shulman, B.A.

• Y.J. Sepah, M.B.B.S. • E. Hatef, M.D. • A.A. Khwaja, M.D.

Retinal Imaging Research and Reading Center, Wilmer Ophthalmological Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Woods 259, Baltimore, MD 21287, USA

e-mail: mibrahi5@jhmi.edu; rchanna3@jhmi.edu; mshulman1@gmail.com; ysepah2@jhmi.edu; afsheenkhwaja@yahoo.com

P. Turkcuoglu, M.D.

Department of Ophthalmology, Inonu University School of Medicine, Malatya 44000, Turkey

e-mail: peykan74@yahoo.com

D.V. Do, M.D.

Diseases of the Retina and Vitreous, Wilmer Ophthalmological Institute, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Maumenee 745, Baltimore, MD 21287, USA e-mail: ddo@jhmi.edu

Q.D. Nguyen, M.D. ( )

Diseases of the Retina and Vitreous, and Uveitis, Wilmer Ophthalmological Institute, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Maumenee 745, Baltimore, MD 21287, USA

e-mail: qnguyen4@jhmi.edu