One would think that after studying a disease for 50 years, more progress would have been made in understanding its management. Yet ocular toxoplasmosis continues to puzzle researchers. In their search for answers, American investigators are reaching out beyond U.S. borders in an attempt to unravel what has been a frustrating mystery for decades.
At the Annual Meeting in November,1,2 Gary N. Holland, MD, professor of ophthalmology at the University of California, Los Angeles, stressed a key theme: Many in the field have “accepted an understanding of the disease that is too superficial. Because of variations in the disease, it may not be effective to treat every patient in the same manner. Obtaining greater insight into the variations of the disease will allow us to tailor treatment to each individual.”
In Your Office
Results from a survey of Academy members indicate that active ocular toxoplasmosis leads to at least 15,000 visits to ophthalmologists each year. Yet, said Dr. Holland, treatment practices vary considerably among clinicians, with some general ophthalmologists treating it themselves and others referring cases to specialists.
Regardless of who treats the patient, however, there remains a void in effective treatment options. While new drugs have become available, “nothing prevents recurrences of active disease, which are the hallmark of ocular toxoplasmosis and can lead to a loss of vision,” he said.
What We Know Now
The widely recognized prototype lesion of ocular toxoplasmosis is a focus of retinitis arising from the border of a retinochoroidal scar. Yet, according to Dr. Holland, studies throughout the late 20th century have shown that there is actually a broad spectrum of disease manifestations.
Estimates hold that at least 1 billion people are infected with Toxoplasma gondii worldwide. The seroprevalence varies geographically and is lowest in arid regions, such as the American Southwest, and highest in moist regions, like the Northeast. And although the prevalence of infection in the U.S. general population has fallen in recent decades, there is still a substantial amount of disease. “The risk of congenital infections has been reduced to an even greater degree,” Dr. Holland said, “and thus, the proportion of cases in the general population attributable to postnatal infections is increasing. And, in fact, recognizing that most of the disease we see now is associated with postnatal, rather than congenital, infections obviously has important implications for future prevention efforts.”
The definitive host of T. gondii is the cat. “Millions of infectious oocysts are shed in cat feces during the early period of a feline infection, and these oocysts can remain viable in the environment for months or years,” said Dr. Holland. Yet T. gondii also reproduces itself asexually in intermediate hosts and can be transmitted by ingestion of undercooked meat, including pork and lamb. Contaminated water also can be a source of infection. If a woman is first infected during pregnancy, she can transmit infection to the fetus.
“The parasite exists in different stages during its life cycle,” Dr. Holland said. “The proliferative form, known as a tachyzoite, invades cells, but in the retina, tachyzoites are transformed into metabolically less-active bradyzoites and remain viable for long periods of time without stimulating a host inflammatory response. Eventually, they can break down, releasing parasites that invade new cells and cause disease.”
Ocular toxoplasmosis is associated with a broad spectrum of clinical findings that “must be appreciated by clinicians” if the disease is to be diagnosed accurately, Dr. Holland noted. The spectrum of findings and course of disease are no doubt influenced by a combination of factors, including the patient’s age and immune status, the genotype of the infecting parasite and various environmental factors that influence host-parasite interactions.
In addition to the classic lesion of recurrent ocular toxoplasmosis, patients can have “primary” retinal lesions—those not arising from scars—either at the time a person acquires infection or much later. In most patients, disease is self-limited. Yet in immunocompromised patients (for example, those with AIDS), the lesions will continue to enlarge. Persistently active disease results in broad areas of retinal necrosis, which can be mistaken for other infections such as cytomegalovirus retinitis.
“Nothing illustrates the limitations of our knowledge about ocular toxoplasmosis better than the lack of consensus regarding treatment,” Dr. Holland pointed out, adding that a recent survey of American Uveitis Society members showed that 16 different drugs are used to treat patients in 24 different combinations as regimens of choice. The most common regimen consists of pyrimethamine-sulfadiazine-prednisone.
Dr. Holland said that short of biologic studies to identify new drug targets, a better understanding of the clinical features of disease will help clinicians individualize treatments based on lesion characteristics. “A new approach is long-term antimicrobial treatment as secondary prophylaxis to prevent recurrences, which has been tested in Brazil” using trimethoprim-sulfamethoxazole.
Other parts of the world have yielded valuable information regarding both characteristics of the disease and possible treatment alternatives. Rubens Belfort Jr., MD, head professor of the Vision Institute, Federal University of São Paulo, Brazil, first met Dr. Holland as a fellow at the Proctor Foundation in San Francisco. Drs. Holland and Belfort, along with other researchers, currently are conducting extensive research in two different sites—São Paulo and Erexim in the south of Brazil.
“Brazil is the world capital of ocular toxoplasmosis,” Dr. Belfort said. “There you will find up to one-third of the general population with toxoplasmosis scars in the retina, and many siblings blind in both eyes by this infection.”
Dr. Belfort added that Brazil is intriguing in that the disease is more severe in his country and in many Latin American countries, vs. the United States. “Its ocular complications are also much more frequent in spite of the fact that the general prevalence of infected individuals in the population is similar.”
Dr. Holland pointed out that in one review of the medical literature,3 the authors identified “only three well-designed, placebo-controlled studies of treatment for ocular toxoplasmosis, and none of them confirmed a benefit of short-term therapy. Yet I think the real problem is that the issue has not been studied correctly.
“Drugs do appear to work in some people and we have to understand why they don’t work better in everyone,” he said. “And this raises the question that hasn’t been answered: What is going on with the parasite during an active episode of the disease? Without a doubt, we need a more sophisticated understanding of disease mechanisms.”
1 LX Edward Jackson Memorial Lecture, Nov. 16, 2003, Anaheim, Calif. Am J Ophthalmol 2003;136:973–988.
2 Ibid. Am J Ophthalmol (in press).
3 Stanford, M. R. et al. Ophthalmology 2003;110(5):926–931.
More to Look For
The challenge of managing ocular toxoplasmosis has another layer of complexity: atypical presentations. Emmett T. Cunningham Jr., MD, PhD, MPH, professor of ophthalmology at New York University and vice president of clinical development at EyeTech Pharmaceuticals, identified so many atypical presentations that he published a paper on the subject with colleague Justine R. Smith, MBBS, PhD.1
For instance, patients who are immunocompromised or elderly may present with large, multiple and/or bilateral lesions. Other presentations to consider include a unilateral pigmentary retinopathy mimicking retinitis pigmentosa; neuroretinitis; optic neuropathy; and scleritis. Dr. Holland agreed that ocular toxoplasmosis can present with a variety of clinical lesions and complications, but he suggested in his Jackson Memorial Lecture at the Annual Meeting that patients not be labeled as having “typical” or “atypical” disease, lest clinicians think that T. gondii causes multiple unique disorders. Instead, he emphasized that despite variations in ocular toxoplasmosis, all result from only one basic disease process: retinal infection with an associated immune response. The spectrum of findings is caused by variable durations of infection and severity of inflammation.
1 Curr Opin Ophthalmol 2002;13:387–392.