Intraocular inflammatory reactions without focal necrotizing retinochoroiditis in patients with acquired systemic toxoplasmosis.

PURPOSE: To describe the occurrence of intraocular inflammatory reactions as the sole ophthalmic manifestation of acquired systemic toxoplasmosis. METHODS: Review of medical records for 10 patients with uveitis and evidence of recent Toxoplasma gondii infection. RESULTS: Patient ages ranged from 3 to 51 years. Ocular symptoms were present in each of eight adult patients. Inflammation was unilateral in nine patients; it manifested as vitreous humor cells and haze (10 patients), anterior chamber cells (seven patients), and retinal vasculitis (seven patients). No patient had necrotizing retinochoroiditis upon initial examination. Inflammation resolved in each of nine patients who had follow-up examinations. Foci of retinitis or inactive retinochoroidal scars were seen in four of these nine patients during follow-up examinations, at intervals of 2.0 weeks to 2.5 years after initial examination. CONCLUSIONS: Retinal vasculitis and associated inflammatory reactions may be the only ophthalmic disorder during the early stages of a newly acquired T. gondii infection. Later development of retinitis or scars consistent with toxoplasmic retinochoroiditis in the same eyes suggests that the initial, isolated inflammation may be caused by the presence of parasites in retinal tissue. These cases may have implications for understanding the original source of retinal infection in patients who have recurrent toxoplasmic retinochoroiditis and for treatment of newly acquired T gondii infection.

The Francis I. Proctor Foundation: the first fifty years.

September 15, 1997 marked the golden anniversary of the Francis I. Proctor Foundation, which was established in affiliation with the University of California in San Francisco. Over 50 years, 182 fellows from 27 countries have been trained in programs focusing on the study of infectious and inflammatory eye disease, and the prevention of blindness worldwide. Many of the people and events that have contributed to the success of the Proctor Foundation are presented in this brief essay.

Ocular toxoplasmosis in immunosuppressed nonhuman primates.

To investigate the role of cellular immunodeficiency in recurrent toxoplasmic retinochoroiditis, six Cynomolgus monkeys (Macaca fascicularis) with healed toxoplasmic lesions of the retina were immunosuppressed by total lymphoid irradiation. Three months prior to irradiation 30,000 Toxoplasma gondii organisms of the Beverley strain had been inoculated onto the macula of eye in each monkey via a pars plana approach. Toxoplasmic retinochoroiditis developed in each animal, and lesions were allowed to heal without treatment. During total lymphoid irradiation animals received 2000 centigrays (cGy) over a 7-week period. Irradiation resulted in an immediate drop in total lymphocyte counts and decreased ability to stimulate lymphocytes by phytohemagglutinin. Weekly ophthalmoscopic examinations following irradiation failed to show evidence of recurrent ocular disease despite persistent immunodeficiency. Four months after irradiation live organisms were reinoculated onto the nasal retina of the same eye in each animal. Retinochoroidal lesions identical to those seen in primary disease developed in five of six animals. Toxoplasma organisms therefore were able to proliferate in ocular tissue following the administration of immunosuppressive therapy. This study fails to support the hypothesis that cellular immunodeficiency alone will initiate recurrent toxoplasmic retinochoroiditis. Results suggest that reactivation of disease from encysted organisms involves factors other than suppression of Toxoplasma proliferation. If reactivation occurs by other mechanisms, however, cellular immunodeficiency then may allow development of extensive disease.

Doyne lecture. Heterochromic iridocyclitis.

Fuchs' heterochromic iridocyclitis is a rare but significant cause of visual impairment. This form of uveitis is misdiagnosed more than any other in the entire field of uveitis. This is particularly true among brown-eyed individuals in whom gross heterochromia may not be diagnosed for many years. The clinical presentation of Fuchs' heterochromic iridocyclitis may include a number of generally unrecognised variants among which are Koeppe nodules, transient synechia formations, and blood-filled cysts. Recently the relationship of heterochromic iridocyclitis to posterior inflammatory lesions, such as those of toxoplasmosis, has been explored. Although the disease was once thought to be a degenerative or trophic disorder, current investigations reveal that it is a true inflammation of immunologic origin. The disorder may be related to a depression of suppressor T-cell activity. The aetiology of the disease is still obscure, but in some cases an association with simple heterochromia has been found among families in whom multiple members are affected by either simple heterochromia or Fuchs' heterochromic iridocyclitis. Corticosteroid treatment of Fuchs' heterochromic iridocyclitis is not effective and should be reserved for those patients in whom inflammatory products obstruct the visual axis. Most patients should be treated by observation alone. Cataract and glaucoma are the most important complications. Treatment of the glaucoma is particularly difficult and often unsuccessful.

Scanning electron microscopy of Toxoplasma gondii: parasite torsion and host-cell responses during invasion.

Scanning electron microscopy confirmed our previous finding that toxoplasmas actively invade mouse peritoneal cells that are inhibited from phagocytosis. The parasites entered cells with the conoid end first and sometimes showed a counter-clockwise torsion of the body during invasion. Counter-clockwise torsion was also noted in free toxoplasmas. Host-cell responses to active invasion varied with experimental conditions and with the type of host cell. Under adverse culture conditions for phagocytosis, normal macrophages formed rudimentary filopodia or lamellipodia around the tips of invading toxoplasmas; macrophages subjected to hyperthermia before similar incubation with toxoplasmas showed little or no response to invasion. Normal and heat-treated lymphocytes showed little surface reaction to invasion, but occasionally a flocculent collar was seen around the tip of an invading toxoplasma. Scanning electron microscopy provides clues to possible mechanisms of toxoplasma locomotion and host-cell invasion.

Retinal vasculitis in ocular toxoplasmosis in nonhuman primates.

Six monkeys had prior systemic immunization followed by intraretinal challenge to each eye with Toxoplasma antigens. All eyes developed iridocyclitis, vitritis, and retinal edema, but no necrotizing retinochoroiditis. One-half of the eyes were then challenged with living organisms and the other one-half with Toxoplasma antigens. All eyes developed iridocyclitis, vitritis, and retinal edema, but no necrotizing retinochoroiditis. Four months later, the right eye of each monkey was challenged with living Toxoplasma organisms injected intraretinally. Each injected eye developed iridocyclitis, vitritis, and retinal edema 24 hours after injection, and all developed a retinal vasculitis 6 days after injection. One injected eye developed a papillitis. A subcutaneous booster of living Toxoplasma organisms in four of the monkeys failed to produce a reactivation of the iridocyclitis, vitritis, and vasculitis. These findings suggest that hyperimmunization provides protection against the development of a necrotizing toxoplasmic retinochoroiditis in nonhuman primates and that it may lead to retinal vasculitis and iridocyclitis. This study also serves as an animal model of retinal vasculitis in ocular toxoplasmosis.

Atypical syphilitic chorioretinitis and vasculitis.

Although syphilis is frequently overlooked as a cause of ocular disease, it remains an endemic disease and its incidence is increasing. This article reports on four recent cases of ocular syphilis, including pseudoretinitis pigmentosa, chorioretinitis, and a rare presentation of an isolated retinal vasculitis involving both the arteries and the veins. Fundus photography, fluorescein angiography, and electrophysiologic testing are included. These cases show the diverse manifestations of ocular syphilis, which may involve any structure in the eye, and they demonstrate that atypical presentations are often encountered.

Factors related to the initiation and recurrence of uveitis. XL Edward Jackson memorial lecture.

Uveitis comprises a complex group of diseases in which morbidity may depend on the nature of the initial inflammation as well as on the genetic, hormonal, and emotional background of the patient. Uveitis is initiated in every instance by some form of tissue injury. This may occur as an attack on individual cells by organisms such as Toxoplasma gondii or Herpesvirus hominis. Autoimmune disease may be produced as a late result of microbe-induced injury. The development of specific forms of autoimmunity seems to be dependent upon genetic as well as hormonal factors, particularly estrogens. Tissue injury of immunologic origin takes several forms, such as cytotoxic damage from sensitized lymphocytes, immune complex-mediated injury, and injury from the oxidative products of inflammatory cells. In some cases, permanent alteration of uveal vascular permeability results. Recurrent uveitis may be attributed in some instances to the reappearance of infectious organisms in the target tissue. In other cases, recurrence of inflammation may be attributed to the localization of immune complexes in the uveal tract. Changes in immunoregulation can be attributed to pregnancy, aging, and emotional factors. Neurohumoral pathways related to stress-mediated changes in immunoregulation have recently been described in laboratory animals. These pathways may be linked with stress-related recurrences of uveitis in humans.

Ocular tissue absorption of minocycline in the rabbit.

After intramuscular (IM) administration of minocycline hydrochloride, concentrations of the drug that would be adequate for the control of sensitive organisms (greater than 0.5 micrograms/g of tissue) were detectable in the cornea, iris, and retinochoroid 3, 6, and 12 hours after a single injection. The concentration of the drug in the aqueous humor was greater than in the vitreous humor. Following a single IM injection of 40 mg/kg, the drug level was found to be significantly higher in the iris and aqueous humor of pigmented rabbits than in the corresponding tissues of albino rabbits. The drug seems to concentrate in the pigmented layers of the ocular tissue.

Secretion from the rhoptries of Toxoplasma gondii during host-cell invasion.

To determine whether the rhoptries of Toxoplasma gondii play a role in the invasion of host cells by this parasite, we inoculated toxoplasmas into the peritoneal cavities of normal mice and into macrophage cultures, fixed the specimens at various intervals thereafter, and analyzed them by electron microscopy. We found that during host-cell invasion, the rhoptry membrane fused with the anterior limiting membrane of the toxoplasma, producing an opening to the exterior. Since such openings were formed when the host-cell membrane was disrupted, it appears that the rhoptries may secrete a lytic product that facilitates invasion through the host-cell membrane. Such a "penetration-enhancing factor" was previously isolated from lysed toxoplasmas (Lycke and Norrby, 1966). Occasionally, when secretion was incomplete, masses of tubules were found in the rhoptries, sometimes as soon as 15 sec after the toxoplasms had been injected into mice. Similar tubules were found in the parasitophorous vacuole that was formed 10-15 min later, and such tubules are typical of vacuoles containing replicating parasites. Because these tubules are in continuity with the vacuolar membrane, it appears to be a hybrid membrane, composed in part of toxoplasma products. We speculate that the hybrid nature of the vacuolar membrane prevents it from fusing with the lysosomes of phagocytes and thereby contributes to the intracellular survival of the parasites.

Detection of toxoplasmal antigen and antibody in ocular fluids in experimental ocular toxoplasmosis.

Enzyme-linked immunosorbent assays were used to detect intraocular toxoplasmal antigen and antitoxoplasmal IgG antibodies in a rabbit model of experimental ocular toxoplasmosis. Toxoplasmal antigen could be detected in the vitreous humor of the infected eye at the height of clinical activity of the lesion. Antitoxoplasmal IgG antibodies were detected in the aqueous and vitreous humors of the infected eyes five weeks following the onset of toxoplasmic retinochoroiditis.