Phillips Thygeson

The ocular manifestations of herpes zoster, varicella, infectious mononucleosis, and cytomegalovirus disease

Herpes zoster, caused by varicella-zoster (V-Z) virus which also causes varicella (chickenpox), is usually a benign self-limited disease. However, when the ophthalmic division of the trigeminal nerve is affected, the ocular disease (ophthalmic zoster), although also usually mild and self-limited, may have severe complications (corneal scarring, glaucoma, iris atrophy, posterior synechiae, scleritis, motor disturbances, optic neuritis, retinitis, anterior segment necrosis, and phthisis bulbi and servere postherpetic neuralgia). Varicella affects the eye rarely (except for the typical lid lesions), but associated conjunctival and corneal lesions, iridocyclitis, glaucoma, chorioretinitis, and optic nerve lesions have been described. Infectious mononucleosis may involve the eye either by direct involvement or from a remote focus such as the central nervous system. Ocular manifestations of cytomegalovirus disease is usually limited to the choroid and retina unless involvement of the developing embryo occurs prior to the development of the eye.

Elementary-Body Virus isolated from Clinical Trachoma in California.

From an adult white resident of California with clinically typical early trachoma a virus was isolated by growth in embryonated eggs. Morphologically and serologically the virus belongs in the psittacosis-lymphogranuloma group. When it is instilled into monkey eyes it produces acute follicular conjunctivitis with typical inclusion bodies.

The Etiology of Inclusion Blennorrhea

From an experimental study of eleven cases, the author concludes that inclusion blennorrhea is a distinct clinical entity, unassociated with any pathogenic conjunctival bacteria. It is not identical with trachoma, lacking the tendency to form pannus and scars. It is transferred to the conjunctiva of Macacus rhesus with difficulty, to the baboon more easily and with the induction of more acute symptoms. Other laboratory animals are resistant. Microorganisms are seen in Giemsa-stained films of the secretion, decolorized in alcohol, in numbers in direct proportion to the clinical severity of the disease. The predominating forms are small and are known as elementary bodies, the larger as initial bodies; division forms of both are observable. Their staining reactions, alcohol fast but not acid fast and staining poorly with aniline dyes, constitute a differential point from ordinary conjunctival bacteria, being essentially those of rickettsiae, and of the elementary bodies of vaccinia, fowl-pox, and molluscum contagiosum. The identity of these organisms with the etiologic agent of the disease has been proved. They are intracellular colonies of the virus in various stages of development, the initial body being the early stage, the elementary body the later phase. The life cycle comprises 48 hours. The source of infection is genital, inclusion bodies having been found in vaginal secretion from the mothers of infected infants, and having from that source infected the eyes of monkeys. From the Department of Ophthalmology, College of Medicine, State University of Iowa. Aided by a grant from the American Medical Association. Read before the Association for Research in Ophthalmology, in Cleveland, June 12, 1934.

TRACHOMA VIRUS: HISTORICAL BACKGROUND AND REVIEW OF ISOLATES

Trachoma was one of the first diseases of mankind to be recognized as a distinct clinical entity. The Ebers papyrus (1500 B.C.) mentions its exudative and cicatricial features and its treatment with copper salts. It is known to have been widespread in ancient Greece and Rome and is believed to have afflicted Paul of Tarsus, Cicero, Horace, and Pliny the Younger. The name “trachoma” was first used by a Sicilian physician, Pedanius Dioscorides, in 60 A.D., and a century later the four stages of the disease were delineated by Galen. From the Middle East, which has been heavily infected since antiquity, trachoma was spread over Europe during the Crusades by the returning knights and their followers. A fresh wave followed Napoleon’s campaign in Egypt where a high percentage of French and English troops contracted “Egyptian ophthalmia.” For this reason, in Europe the disease was often referred to as “military ophthalmia.” Over the last century it has gradually disappeared from northern Europe but has prevailed in southern Europe and in all the countries bordering the Mediterranean. First orally administered sulfonamides (introduced that year), and later topically administered medium spectrum and broad spectrum antibiotics, proved curative. In spite of intensive treatment programs, however, the disease has persisted in southern Europe, North Africa, the Middle East, and Asia, and in certain areas of South America and Mexico. In the United States and Canada it is largely confined to American Indians. Current estimates suggest that more than 400,000,000 of the world’s population still suffer from trachoma. Failure of treatment programs to influence materially its prevalence can be blamed on (1) the long treatment time required, with consequent lack of patient cooperation, and (2) the frequency of reinfection in trachoma-endemic areas.

Antibodies to APC Virus Type 8 in Epidemic Keratoconjunctivitis.

Summary The sera from patients with epidemic keratoconjunctivitis (EKC) in Japan, Italy, Switzerland, and North America regularly contain neutralizing antibodies to APC virus type 8, whereas such antibodies are absent from the general population in these areas. Paired sera from patients with EKC show a significant rise in neutralizing antibodies to APC virus type 8. These antibodies persist for only a limited period after the onset of the disease. The constant association of clinical EKC and antibodies to APC virus type 8 suggests that this agent (or antigenically related virus) may play a role in the etiology of this disease.

Trachoma Viruses Isolated in United States.∗ 1. Growth in Embryonated Eggs

Summary From 6 active trachoma cases in the United States strains of“trachoma virus”have been isolated. Conjunctival scrapings suspended in broth-saline containing 1-10 μg/ml streptomycin were inoculated into yolk sac of embryonated eggs. From 1 to 6 blind passages were required for establishment of strains which subsequently reached titers of 106.3-107.4 egg LD50/ml. The essential nature of ill-defined egg“quality”for isolation of“trachoma viruses”is discussed. The isolated agents produced unequivocal eye infections in M. Cynomolgus and in a human volunteer.

Relationship of Agents of Trachoma and Inclusion Conjunctivitis to Those of Lymphogranuloma-Psittacosis Group

While the nature of the etiologic agents of trachoma and inclusion blennorrhea is still not indisputably established, they appear to belong to the group of agents generally known as viruses and the great preponderance of evidence points to a causal relationship for the elementary and initial bodies which are characteristically present in the lesions. 1 That these elementary and initial bodies, and other related structures are similar in morphology and dimension to those found in psittacosis and lymphogranuloma venereum has been pointed out.2, 3 Moreover, with the exception of the glycogen reaction, which is positive for the large plaques in trachoma and inclusion blennorrhea, 4 but negative for those in psittacosis and lymphogranuloma venereum, 3 the tinctorial characteristics of the morphological units in all 4 diseases are similar. A further bond between the two groups lies in the fact that of all the so-called virus diseases only 4, namely trachoma, inclusion blennorrhea, lymphogranuloma venereum, pneumonitis of mice, 5 together with the rickettsial infection of heart-water in sheep, 6 are known to respond to chemotherapy with the sulfonamide drugs. It has recently been demonstrated that a powerful complement fixing antigen can be prepared for lymphogranuloma venereum by the propagation of the agent of this disease in the yolk-sac of the embryonated chick egg. 7 Furthermore, it has been shown that this antigen gives marked cross fixation with sera from individuals infected with other members of this group of agents, i. e., psittacosis or pneumonitis. 8 It seemed of interest, therefore, to test the sera of individuals infected with trachoma or inclusion blennorrhea by the same method to see whether any cross-fixation would occur here. The results are shown in Table I. It was found that in the case of adults suffering from chronic trachoma (Institution EI) our usual routine of fixation at 37 C for 1 ½ hours gave fixation at serum titers comparable to those obtained with some lymphogranulomatous sera.

Trachoma viruses isolated in the United States. 4. Infectivity and immunogenicity for monkeys.

Summary Three strains of trachoma virus and one strain of inclusion conjunctivitis virus isolated in the United States gave reproducible disease upon inoculation into eyes of rhesus or cynomolgus monkeys. Among several clinical criteria follicle scores were most suitable for quantitation of eye disease, and microscopic demonstration of inclusions in conjunctival scrapings served as additional criterion of infection. Significant differences were demonstrated in the infectivity of 2 strains for the monkey eye. Repeated eye infection failed to modify the response to re-infection. Repeated parenteral administration of live virus in large quantities significantly diminished disease from subsequent challenge infection but failed to induce solid immunity.

THE LIMBUS AND CORNEA IN EXPERIMENTAL AND NATURAL HUMAN TRACHOMA AND INCLUSION CONJUNCTIVITIS

There is general agreement among workers with trachoma that trachoma is a keratoconjunctivitis in which, a t onset, limbal and corneal changes in the form of extension of capillary loops, epithelial keratitis, and subepithelial infiltrates occur simultaneously with conjunctival changes, even in disease of low intensity. Recognition of these early corneal signs requires the slit lamp and corneal microscope. In a study of trachoma in Egyptian children, Wilson1 found the early changes of incipient pannus (extension of vascular loops from the limbus), an invariable early feature of the disease, and included excellent illustrations of them in color in his report. Wilson’s observations have been fully confirmed by our studies in the United States. In my opinion a definitive clinical diagnosis of precicatricial trachoma cannot be made unless the characteristic vascular and infiltrative changes are found a t the upper limbus. We have seen children with upper tarsal follicles which on gross examination in mass trachoma surveys would undoubtedly have been diagnosed trachoma; the follicular disease healed spontaneously, however, without pannus or scars, and repeated cytological examinations failed to reveal inclusions or other evidence of trachoma. These cases were in all probability examples of sporadic chronic follicular conjunctivitis, Axenfeld type, which is more commonly seen in epidemics in institutions. This type of pannus-free pseudotrachoma will be the subject of a separate communication. In the first part of the present report will be described the limbus and cornea in trachoma produced by (1) a bacteria-free filtrate, (2) tissue transfer, and (3) natural infection of white adults; in the second part, the limbus and cornea in inclusion conjunctivitis produced by (1) egg-grown virus, (2) bacteria-free filtrates, (3) tissue transfer, and (4) natural infection of newborns and adults.

Infection of rhesus and cynomolgus monkeys with egg-grown viruses of trachoma and inclusion conjunctivitis.

Before the isolation of trachoma virus in embryonated eggs in 1956,l the only way to study the biological characteristics of the agents of trachoma and inclusion conjunctivitis was by producing the diseases experimentally in primates. With cultivated strains now available from many sources, the inoculation of monkeys and apes continues to be a useful tool in the study of these agents and of the host-parasite relationship. The history of inoculating primates with conjunctival scrapings from human cases of both diseases was reviewed in 1938 by Julianelle? and more recently by Thygeson and C r ~ c k e r , ~ and Nataf et aZ.4 In general, primates higher on the phylogenetic scale (for example, orangutans and chimpanzees) have been more susceptible than monkeys, and inclusion conjunctivitis has produced a more severe disease than trachoma in any given species. C ~ l l i e r , ~ Grayston et u Z . , ~ and our group7z8 have shown recently that the conjunctivas of monkeys and baboons are susceptible to cultivated strains of both viruses but that most trachoma strains produce a mild disease a t best. To obtain further information on the response of monkeys to infection with various strains, the following investigations were undertaken. We have been particularly interested in the reaction of the monkey to different strains, and in the modifying effect of parenteral immunization on the experimental disease.