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The challenge in clinical syphilis today is the detection of the disease in the sero-negative patient. The magnitude of this problem is evident when one considers that over 100 cases of ocular syphilis and neurosyphilis have been encountered in this institution within the past year (Smith, 1964; Smith and Moore, 1964; Smith and Taylor, 1965). Of paramount importance is the fact that the majority of these patients were non-reactive to the standard reagin tests for syphilis. Diagnosis was established by the following criteria: (1) history of infection and inadequate treatment; (2) clinical signs of the disease-as optic atrophy, pupillary changes, and the like-and (3) reactive Treponemapallidum immobilization (TPI) and/or fluorescent treponemal antibody absorbed (FTA-ABS) tests on the peripheral blood (Deacon, Falcone, and Harris, 1957; Deacon, Freeman, and Harris, 1960; Deacon and Hunter, 1962). A combined clinical and experimental study was therefore undertaken in collaboration with the

WooDs and Wahlen (1959) proposed Histoplasma capsulatum as a cause for an ophthalmoscopic entity in man. The epidemiological significance of this suggestion is apparent when one considers that over 30 million Americans are histoplasminpositive (Silverman, Schwarz, Lahey, and Carson, 1955). An investigation of ocular histoplasmosis was therefore initiated in this laboratory, and primary ocular infections have been induced to date in the domestic pigeon (Smith and Jones, 1962), rabbit, and two primate species (Smith and Singer, in press) by anterior chamber injections of H. capsulatum. This is the first report of experimental ocular infections from inoculation of Histoplasma capsulatum by the corneal route.Methods and Procedure 1: 10 and 1: 100 dilutions of yeast phase H. capsulatum with normal saline were prepared by techniques outlined in previous reports. Injections were given into the right eye of rabbits, anaesthetized with topical 0'5 per cent. proparacaine hydrochloride, using tuberculin syringes and 30 needles. Control injections of saline were given into the left eye of each animal. Two routes ofcorneal infection were studied. Four rabbits with histoplasminnegative skin-tests were given 0-02 ml. diluted organisms by injection into the corneal stroma. Three other histoplasmin-negative rabbits were given intra-epithelial inoculations of H. capsulatum by placing one drop of 1 :10 yeast phase organisms on the cornea, and then streaking the cornea with a 30 needle as one would a blood agar plate. The left cornea was similarly streaked with saline. Atropine 1 per cent. drops were instilled into each eye daily to facilitate ophthalmoscopy. The eyes were examined daily with focal illumination and serial colour photographs were made. Biomicroscopic and indirect ophthalmoscopic examinations were made at appropriate intervals. Findings Stromal Corneal Histoplasmosis.-Immediately after organisms or sterile saline had been injected into the corneal stroma, a glistening infiltrate could be seen at the injection site which had a fractured or splintered appearance due to interlamellar dissection of fluid. The injected fluid was promptly resorbed, however, and by 48 to 96 hours the corneae appeared perfectly normal and the eyes showed little reaction. By 7 to 14 days, however, slight stromal opacification and beginning vascularization could be seen grossly at the injection site. Injections given close to the limbus produced a lesion which closely resembled a phlycten in man during the first 2 weeks. By 3 weeks, these lesions often developed a daughter lesion of raised, pinkish, vascularized tissue. Vascularization progressed slowly after 3 weeks, and the entire clinical picture was quite different from the fulminating granulomatous iridocyclitis noted in rabbits given the organisms by anterior chamber injection.

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