Retinal Insider
Edited by Jay S. Duker, MD, and Carl Regillo, MD
Some long-held truths about "toxo" are facing new scrutiny.
Russell N. Van Gelder, MD, PhD St. Louis
Historically, the diagnosis of ocular toxoplasmosis seemed straightforward. Toxo was common, and the retinitis lesions were typically full-thickness, often with adjacent or nearby retinochoroidal scars. Testing for anti-toxoplasmosis. gondii IgG serum antibodies was rarely indicated, and most patients could be reassured that they had contracted their infection in utero. Standard therapy, decades old, consisted of a combination of sulfadiazene, pyrimethamine and leukovorin.
Recent research has shown that the parasite causes a wider range of disease, is acquired in different ways and is more diverse than had been previously appreciated. New insights into the biology of T. gondii also offer hope for better treatments.
A 15-year macular toxoplasmosis patient treated with clindamycin and prednisone. Day 1: 20/80, no therapy; Day 5: 20/200, prednisone 40 mg q.d., clindamycin 300 mg q.i.d.; Day 18 : 20/80, prednisone 40 mg q.d., clindamycin 300 mg q.i.d.
Congenital vs. Acquired
Toxoplasma gondii is an intracellular parasite that
infects many vertebrates. The cat is the definitive host for sexual
reproduction of the organism, and ingestion of cat feces, either
directly or indirectly, is certainly one route of infection. The
parasite also exists in two other forms, the asexually dividing
trophozoite and the encysted bradyzoite. Both forms are found
in meat (particularly pork, lamb and poultry), and ingestion of
undercooked, contaminated meat is another, perhaps more common
route of infection.
Ocular disease can occur from either congenital infection or from acquired disease. Cysts are thought to lodge in the retina, and unknown signals prompt them to emerge and cause marked chorioretinal inflammation.
The dogma that the vast majority of ocular toxoplasmosis represents reactivated diseases comes from the seminal 1973 review.1 Dr. E. Perkins noted that the peak prevalence of ocular toxoplasmosis occurred during the second and third decades of life, and he reasoned from this observation that if the disease were acquired, one would expect to see an increasing prevalence with age. He also noted he rarely saw toxo in multiple siblings from a single family and inferred from this that maternal antibodies were probably protective.
More recent work challenges both assumptions. Multiple sibling pairs with the disease have been identified, and the incidence of the disease does appear to increase with age in this population. Individuals demonstrating seroconversion, followed by development of classic, toxo-like chorioretinal scars, have been documented.
Additional epidemiologic evidence that acquired toxoplasmosis leads to eye disease comes from analysis of an outbreak following contamination of a water supply in Victoria, B.C. Of about 100 serologically confirmed cases of infection, 20 percent subsequently showed ocular disease.
Acquired disease may be more variable in its presentation than congenitally reactivated disease.2 Findings can include anterior uveitis, vitritis and vasculitis, even in the absence of the classic retinochoroiditis. The diagnosis of acquired toxoplasmosis requires serologic evidence of active infection, manifest by either the presence of positive IgM or IgA anti-toxoplasma titers, or a documented four-fold rise in serum IgG anti-toxoplasma titers.3 The natural history of acquired disease is not fully known, although in a small study of patients with serologic evidence of primary ocular toxoplasmosis, over half had recurrences within the first two years.4 The true prevalence of anterior and posterior uveitis due to acquired toxoplasmosis is unknown. Since T. gondii is potentially treatable, it is reasonable to order toxoplasma IgM and IgA titers in anterior and atypical posterior uveitis. I order these as "second line" tests (i.e., after negative HLA B-27 in non-granulomatous disease, and after negative FTA-Abs/VDRL/PPD/ACE/CXR in granulomatous uveitis).
Day 32: 20/40, prednisone 40 mg, clindamycin 300 mg q.i.d.; Day 46: 20/40, prednisone 30 mg, clindamycin 300 mg q.i.d.; Day 56: 20/30, prednisone 20 mg, clindamycin 300 mg q.i.d.
New Diagnostic Modalities
Although diagnosis of reactivated, "classic" congenital
toxoplasmosis remains a straightforward clinical task, diagnosis
of acquired ocular toxoplasmosis can be more problematic.
Serologic tests are useful because of their high specificity, but negative IgM and IgA titers do not rule out ocular toxoplasmosis (though negative IgG titers effectively do). Early attempts at polymerase chain reaction (PCR) diagnosis of ocular toxoplasmosis had only limited success, but more recent assays based on detection of highly repetitive gene sequences have been more successful.
Recent assays have achieved a sensitivity of detection of a single tachyzoite;5 when applied clinically to vitreous biopsies, these assays now have sensitivities better than 50-60 percent.6 The sensitivity for detection may be even higher when PCR is combined with intraocular antibody testing.3 A recent report suggested that PCR of blood samples taken during active disease could yield sensitivities comparable to those of an aqueous tap.7
Besides providing another tool for diagnosis, PCR has also opened a new window onto the biology of T. gondii. By serology, all T. gondii appears identical; there are no serologically defined strain types as there are for, say, adenovirus. At the DNA level, however, at least three strains of T. gondii have been identified8 and these strains can be distinguished by PCR.
The three strains show markedly different virulence in mice and different response to antibiotics. Researchers are now testing intraocular fluid samples from ocular toxoplasmosis patients for the strain of parasite present. It is possible that the strain type of T. gondii will predict its response to therapy, and thus may become an important part of the diagnosis of the disease.
Expanding Therapeutic Options
No one knows if anti-parasitic therapy actually works for toxoplasmosis.
An important paper in 1989 compared treatment of central toxoplasmosis
lesions with established medical therapy to observation of peripheral
lesions.9 The result: no difference in the duration of disease,
and only small differences in the size of the residual scar.
Still, anecdotal evidence abounds that individual cases respond to treatment, and the armamentarium of medications for this condition has been steadily increasing in the recent years. In addition to the "standard" regimen of pyrimethamine/sulfadiazene/leukovoran, clindamycin and trimethoprim/sulfamethoxasole have been advocated.
Two recent additions to the group are azithromycin and atovaquone. Atovaquone is particularly interesting, as it has in vitro activity against the bradyzoite cysts. Theoretically, this could decrease the number and severity of recurrent inflammatory episodes. In a Phase I trial of atovaquone therapy for ocular toxoplasmosis, 17 patients received theoral agent,10 16 were able to tolerate the therapy, and all showed stabilization or improvement of vision. Additionally, in animal studies, atovaquone and clindamycin seem to have a synergistic effect. For my patients, I use either Bactrim DS or clindamycin monotherapy for patients with mild reactivations not impinging on the fovea; for more severe cases, I still use sulfadiazene/pyrimethamine/leukovoran, though hard data to support these practices is lacking.
Day 88: 20/40, no medication; Day 150: 20/25-2, no medication; Day 334: 20/30, no medication. Photos: M. Gil Grand, MD, Barnes Retina Institute. Composite: Humeyra Dabil, MD.
Future Therapies
Besides strain typing, molecular biology has afforded another
insight into the biology of T. gondii: it is evolutionarily
derived from a plant! The parasite has a rudimentary chloroplast.
Clodinafop is an herbicide that targets the plastid acetyl-CoA
carboxylase. In in vitro studies, this agent eliminated
T. gondii infection in fibroblasts in two to four days.11
Preliminary animal work has just begun (and clinical trials are in the distant future), but a parasite-specific therapy may offer a much wider therapeutic window for treatment. Emerging approaches to decreasing the morbidity of systemic treatment for ocular toxoplasmosis include local therapy with intravitreal clindamycin and dexamethasone; this was tried successfully in pregnant patients.12 Work is progressing on livestock and human vaccines for toxoplasmosis. Ultimately, preventive treatment may offer the best hope to limit visual morbidity from ocular toxoplasmosis.
Dr. Van Gelder is an assistant professor in the Department of Ophthalmology and Visual Sciences, and in the Department of Molecular Biology and Pharmacology, Washington University Medical School. Phone: 314 747- 4251, e-mail: vangelder@vision.wustl.edu
1. Perkins E. Ocular toxoplasmosis. Br J Ophthalmol 1973;57:1-17.
2. Holland G, Mmuccioli C, Silveira C, et al. Intraocular inflammatory
reactions without focal necrotizing retinochoroiditis in patients
with acquired systemic toxoplasmosis. Am J Ophthalmol 1999;128:413-420.
3. Ongkosuwito J, Bosch-Driessen E, Kijlstra A, Rothova A. Serologic
evaluation of patients with primary and recurrent ocular toxoplasmosis
for evidence of recurrent infection. Am J Ophthalmol 1999;128:407-412.
4. Bosch-Driessen E, Rothova A. Recurrent ocular disease in postnatally
acquired toxoplasmosis. Am J Ophthalmol 1999;128:421-425.
5. Jones CD, Okhravi N, Adamson P, et al. Comparison of PCR detection
methods for B1, P30, and 18S rDNA genes of T. gondii in aqueous
humor. Invest Ophthalmol Vis Sci 2000;41:634-44.
6. Montoya JG, Parmley S, Liesenfeld O, et al. Use of the polymerase
chain reaction for diagnosis of ocular toxoplasmosis. Ophthalmology
1999;106:1554-63.
7. Bou G, Figueroa MS, Marti-Belda P, et al. Value of PCR for
detection of T. gondii in aqueous humor and blood samples from
immunocompetent patients with ocular toxoplasmosis. J Clin Microbiol
1999;37:3465-8.
8. Howe D, Honore S, et al. Determination of genotypes of T. gondii
isolated from patients with toxoplasmosis. J Clin Microbiol 1997;35:1411-1414.
9. Rothova A, Buitenhuis HJ, et al. Therapy of ocular toxoplasmosis.
Int Ophthalmol 1989;13:415-9.
10. Pearson PA, Piracha AR, et al. Atovaquone for the treatment
of toxoplasma retinochoroiditis in immunocompetent patients. Ophthalmology
1999;106:148-53.
11. Zuther E. Johnson JJ., et al. Growth of T. gondii is inhibited
by aryloxyphenoxypropionate herbicides targeting acetyl-CoA carboxylase.
Proc Nat Acad Sci USA 1999;96:13387-92
12. Martinez C, Zhang D, et al. Successful management of ocular
toxoplasmosis during pregnancy using combined intraocular clindamycin
and dexamethasone with systemic sulfadiazene. Int Ophthalmol 1998;22:85-8.