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An Analysis of Recent Studies On the Etiology of Trachoma
A N ANALYSIS OF RECENT STUDIES ON T H E ETIOLOGY OF TRACHOMA P H I L L I P S THYGESON, M.D. IOWA CITY, IOWA
Pertinent trachoma studies of the past few years have been analyzed and the following conclusions as to etiology have been drawn: (1) Trachoma is a specific communicable disease. (2) It is not caused by a specific bacterium nor by repeated infection with or dinary conjunctival bacteria. (3) The etiologic agent belongs to the group of filtrable viruses. (4) The particle size of the virus is probably relatively large. (5) The virus may be identical with the elementary body of Prowazek and Halberstaedter. From the De partment of Ophthalmology, College of Medicine, University of Iowa. Read before the Chicago Ophthalmological Society, December 16, 1935.
Trachoma has been studied exten sively during the past five years, and in this country systematic programs for determining the etiology of the disease have been undertaken by the University of Iowa and by Washington University. Definite progress has been made and it now seems worth while to analyze available reports and to draw such con clusions as the evidence warrants. In this survey no attempt is made to re view the entire literature, only pertinent reports of recent date being cited.
contributing factor seems to have been definitely ruled out by the studies of Hetler and James 8 who found that mon keys (M. rhesus) on deficient diets were not more susceptible to trachoma than monkeys on adequate diets. Rice and co-workers, 9 at the United States tra choma hospital at Rolla, Missouri, failed to find clinical improvement in patients fed on adequate diets reinforced with vitamin A. Abundant clinical records are available to show that trachoma oc curs in individuals on adequate diets; for example, trachoma in wrestlers.
Trachoma is a specific communicable disease Trachoma is not a specific bacterial disease The communicability of trachoma has been confirmed by the inoculation ex No specific bacterium has been dem periments of Michail and Vancea, 1 and onstrated as the cause of trachoma. 2 of Thygeson, in which trachomatous While Bacterium granulosis (Nogumaterials were transferred directly to chi 10 ) has been shown 11 to produce in normal human conjunctivae, and by the monkeys a follicular disease resembling experiment of Thygeson, Proctor, and trachomatous infection, it has been Richards 3 in which filtered material pro eliminated as a causal factor for the fol duced trachoma in a human volunteer. lowing reasons: (1) it has not been The susceptibility of the monkey con found with sufficient constancy in the junctiva to trachoma has been demon lesions of the disease, by either bacstrated by Julianelle and Harrison 4 and terioscopic or cultural methods, to in by Stewart. 5 dicate etiologic significance (Julianelle 12 Bengtson, 13 Wilson, 1 * The specificity of the disease is in and Harrison, 15 dicated by the fact that the human in Thygeson, and others) ; (2) it has not oculations have resulted in typical clin produced trachoma when inoculated in 16 ical trachoma. No conclusions as to the human conjunctiva (Wilson, Proc 17 specificity are derivable from monkey tor and co-workers, Proctor, Finnoff, 18 Thygeson, 19 Nicolle inoculations since the induced infection and Thygeson, 20 and many others) ; lacks the diagnostic signs of pannus and and Lumbroso, scarring; experimental trachoma in (3) tissue transfer from Bacterium monkeys is a granular conjunctivitis granulosis conjunctivitis of the M. and cannot be differentiated with cer rhesus to the human conjunctiva did 19 (4) trachoma tainty from Bacterium granulosis con not induce trachoma; 6 7 has been induced with material not con junctivitis, inclusion conjunctivitis, or taining Bacterium granulosis (testicuspontaneous folliculosis. Dietary deficiency as an etiologic or lar passages of Julianelle and Harri649
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son, 21 nitration experiments of Thygeson and Proctor, 22 and of Thygeson, Proctor, and Richards 3 ). Other bacteria occurring on the trachomatous conjunctiva have been eliminated as causal agents by inocula tions of pure and pooled cultures on the human conjunctiva (Thygeson 15 ) and on the monkey conjunctiva (Julianelle and Harrison, 21 Stewart 5 ).
indicate that a noncultivable bacterium* or protozoon is concerned in the etiolo gy of the disease. 2. Evidence obtained from filtration experiments. Filtration experiments in trachoma have for the most part been negative. In 1913, however, Nicolle, Cuenod, and Blaizot 24 reported positive results in two experiments with modi fied Berkefeld-V filters. Of particular significance was the fact that, in one experiment, the infection in the chim Trachoma is not due to repeated panzee inoculated with filtrate was infection with nonspecific proved to be trachomatous by transfer bacteria to a blind human eye. In recent years Whereas trachoma has been trans negative filtrations have been reported mitted to monkeys, attempts to trans by Lumbroso and Thygeson, 25 Candimit ordinary bacterial conjunctivitis an,26 and Stewart. 5 Julianelle and Har have failed (Stewart 5 ). Trachoma has rison 27 obtained infection with Berke been seen to start and to progress feld-V filtrates in three of 44 animals, a through its usual course with pannus in result which they considered unimpor the absence of pathogenic bacteria tant in view of the large proportion of (Thygeson, Proctor, and Richards 3 ). negative results. They concluded that Over a three-year period no clinical the agent of trachoma was generally evidence was found to indicate that not filterable. nonspecific chronic conjunctivitis is ca The varied results from filtration ex pable of developing into trachoma. 23 periments led Thygeson, Proctor, and Richards 3 to examine the technique Trachoma is a virus disease used by Nicolle and co-workers in their Evidence obtained from three differ sharply positive filtrations. In order to ent methods of attack on the problem reduce loss of active agent in the filter, now indicates that trachoma belongs to the French workers had employed a disc of Berkefeld-V substance cemented the group of virus diseases. 1. Evidence obtained through a proc into the end of a glass tube. It seemed ess of elimination. Julianelle and Harri reasonable, therefore, that the inactivity son 21 made extensive inoculations in of filtrates might be due primarily to the conjunctiva of the M. rhesus, using adsorption of the agent rather than to pure cultures or cultures of bacteria large particle size. Experiments were pooled in the proportions found on the conducted, therefore, in which a high trachomatous conjunctiva, without re virus content of the suspension was sult. Stewart 5 inoculated 30 baboons insured by the use of pooled epithelial with various conjunctival bacteria in scrapings from selected cases in Indian cluding staphylococci, gonococci, strep children with active disease. Loss in the tococci, Koch-Weeks, and influenza ba filter28 was controlled by the use of Elcilli, with negative results. Thygeson 15 ford gradocol membranes which be inoculated all forms of bacteria isolated come saturated with very little virus. from 63 cases of trachoma into the hu In four experiments on baboons, using man conjunctiva without producing the 0.75-micron membranes (membranes of disease. In view of the consistently largest pore size which will retain con negative results of these experiments junctival bacteria), bacteria-free fil and of the many other inoculation ex trates were found to be active. To periments recorded in the literature of eliminate the possibility that inclusionthe past 50 years the negative role of * Rickettsialike bodies have been de the conjunctival bacteria in trachoma scribed by Busacca and by Cuenod and Nataf should be accepted. in follicular material from trachoma. Their There is no morphologic evidence to significance has not yet been established.
ETIOLOGY O F TRACHOMA
conjunctivitis virus was present and had produced the lesions in the mon keys, a single inoculation on a human eye was made with a filtrate which had passed a 0.6-micron membrane. The re sult was positive. 3. Evidence obtained by inoculations with bacteria-free trachomatous mate rial. Julianelle and Harrison, 21 using the method of testicular inoculation which Noguchi developed to rid vaccine virus of contaminating bacteria, were able to obtain active bacteria-free trachomatous material capable of inducing infection in monkeys. Properties of trachoma virus Very little is known concerning the properties of trachoma virus. The ex periments of Stewart 5 indicate that it survives mechanical procedures such as centrifugation and grinding; that it sur vives for at least 24 hours in a mixture of inactivated human serum and Tyrode solution, pH 7.4; but that its activity is quickly destroyed at pH 6.4 either in distilled water or Tyrode solution. Re ports as to the survival of the virus in glycerine are at variance. Nature of trachoma virus Filtration experiments with collodion membranes of graded pore size have shown that viruses vary greatly in par ticle size; some, like foot-and-mouthdisease virus, are very small (8-12[JL[X), and others, like vaccinia virus, are relatively large (125-175^^). In suit ably stained preparations these larger viruses are resolvable under the micro scope as minute coccuslike granules, known as elementary bodies. 29 In the case of vaccinia virus, fowl-pox virus, and certain others, they are about 0.25 microns in diameter when stained. Most of the viruses of large particle size filter with difficulty, whereas small viruses, such as that of foot and mouth disease, readily pass the ordinary bac terial filters. The fact that trachoma virus filters with difficulty suggests that the particle size may be relatively large. Elemen tary bodies, resembling those in other virus diseases, have been known to
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exist in trachoma since their descrip tion by Halberstaedter and Prowazek 30 in 1907. They were noted both free in the secretion and massed together in the cytoplasm of the conjunctival epithelial cells to form the socalled Halberstaedter-Prowazek inclu sion bodies. The presence of these bodies in tra choma has been reported by investi gators from all parts of the world, but no general agreement as to their nature or as to their etiologic relationship to trachoma has been reached. The inves tigations of Stewart, 31 Bengtson, 32 and Julianelle and Harrison 38 have not sup ported the claims of Halberstaedter and Prowazek. In Egypt, Stewart found the bodies only in trachoma com plicated by secondary bacterial infec tion and concluded that they were the granular products of cellular digestion of phagocyted conjunctival bacteria, particularly the Koch-Weeks bacillus. In a later report 34 he suggested that the elementary bodies were a granular virus which had been introduced into the conjunctival epithelial cells by way of phagocyted bacteria. Bengtson* con sidered the bodies of probable etiologic importance but believed them to be of bacterial origin. Julianelle and Harri son found trachomatous material in which they could not demonstrate the bodies to be infective and also noted the apparent absence of the bodies in experimental trachoma of the Macacus rhesus. The investigations of Taborisky 35 and of Thygeson 36 and of Thygeson, Proctor, and Richards 3 have supported the identification of the elementary body with trachoma virus. The findings of the latter observers may be discussed under the following headings: 1. Relative specificity of the Halber staedter-Prowazek elementary body. The elementary body was not found on the normal conjunctiva. A survey of a thousand cases of conjunctivitis indicated that it was to be found only * In a report appearing while this article was in press, Bengtson (Amer. Jour. Ophth., 1936, v. 19, p. 229) concludes that the inclu sion body is concerned etiologically in tra choma.
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P H I L L I P S THYGESON
in trachoma and in the nonbacterial conjunctivitis generally known as in clusion conjunctivitis (inclusion blennorrhea, swimming-pool conjunctivi tis). 2. Nature of the elementary bodies of inclusion conjunctivitis. The abun dance of elementary bodies in inclusion blennorrhea and the harmlessness of the disease offered opportunities for study not possible in trachoma. It was shown 7 : (1) that the elementary bodies were constantly associated with the disease; (2) that they were absent in conjunctivitis of known bacterial ori gin; (3) that the occasional sapro phytes found in the disease were not concerned etiologically; (4) that mul tiplication of the elementary bodies oc curred when the disease was trans ferred to a new host; (5) that bacteriafree filtrates containing elementary bodies were capable of producing the disease; and (6) that nitrates not con taining elementary bodies were not in fective. It was concluded, therefore, that the elementary body was the virus and that the inclusion bodies were cytoplasmic colonies of the virus. 3. Nature of the elementary body of trachoma. The studies on the elemen tary bodies of inclusion conjunctivitis supported the view that the morpho logically identical trachoma elementary body was of virus nature. Its similarity to psittacosis virus 37 in morphology and staining reactions was also highly sug gestive. 4. Probable identity of the trachoma elementary body with trachoma virus. Evidence supporting the theory of identity of elementary body and virus: (1) presence of elementary bodies in an infective filtrate 3 (elementary bodies found in material used for filtration, in filtrate, and in experimental disease) ; (2) presence of elementary bodies in four cases followed from onset; (3) 1 2 8 4 5 8
presence in trachoma in numbers cor responding to clinical severity of dis ease ; for example, in seven cases of tra choma with acute or subacute symp toms but without secondary bacterial infection there were large numbers of elementary bodies, whereas, in chronic cases they were relatively few; (4) ele mentary bodies have been present in a larger percentage of cases than would be expected of a secondary invader: Tunisian series 44 percent, unselected American series 40 percent, selected (for transmission experiments, on the basis of activity) American series 92 percent. Evidence opposing the theory of identity of elementary body and virus: (1) the elementary body has not been found in 100 percent of cases of trachoma; (2) it has not been found in experimental trachoma of the M.rhesus. Thygeson 23 considers the failure to find elementary bodies in all cases of trachoma not incompatible with etiologic significance in view of (1) diffi culty of morphological demonstration due to minuteness of bodies; (2) ab sence of a cultural means of demon stration ; and (3) chronicity of disease. He interprets the failure to demon strate the bodies in the experimental infection of the M. rhesus as being due probably to the mild character of the induced disease, since in two transmis sion experiments to human eyes the bodies were demonstrated without diffi culty. Summary Recent studies support the conclu sion that trachoma is a virus disease. Evidence has been advanced which identifies the elementary body of Halberstaedter and Prowazek with tra choma virus, but no general agreement among investigators on this point has as yet been reached.
References
Michail, D., and Vancea, P. Rev. Internat. Trachome, 1932, 9, p. 33. Thygeson, P. Amer. Jour. Ophth., 1933, v. 16, p. 409. , Proctor, F. I., and Richards, P. Amer. Jour. Ophth., 1935, v. 18, p. 811. Julianelle, L. A., and Harrison, R. W. Amer. Jour. Ophth., 1933, v. 16, p. 857; Ibid., 1934, v. 17, p. 1035. Stewart, F. H. Giza Mem. Ophth. Lab., Cairo, 8th Annual Report, 1934, p. 142. Thygeson, P. Amer. Jour. Ophth., 1932, v. 15, p. 293. ' . Amer. Jour. Ophth. 1934, v. 17, p. 1019. 8 Hetler, R. A., and James, W. M. Amer. Jour. Ophth., 1934, v. 17, p. 1048. 9 Rice, C. E., Sory, R., Smith, J . E., Faed, P. E., and Drake, A. A. Amer. Jour. Ophth., 1934, v. 17, p. 735.
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T H E SCREEN T E S T 10 Noeuchi, 11
H. Jour. Exper. Med., 1928, v. 48, Supplement No. 2. Robbins, A. R. Ophthalmologic review: Role of Bacterium granulosis in trachoma. Arch, of Ophth., 1935, v. 14, p. 629. 12 Julianelle, L. A., and Harrison, R. W. Personal communication. 18 Bengtson, I. A. U. S. Public Health Reports, 1932, v. 47, p. 1914. » Wilson, R. P. Giza Mem. Ophth. Lab., Cairo, 6th Annual Report, 1932, p. 86. "Thygeson, P. Arch. Inst. Pasteur Tunis, 1933, v. 22, p. 157; Arch, of Ophth., 1933, v. 10, p. 1. " W i l s o n , R. P. Brit. Jour. Ophth., 1931, v. 15, p. 433; Giza Mem. Ophth. Lab., Cairo, 8th Annual Re port, 1934, p. 97. " Proctor, F. I., Richards, P., Greenfield, M., Finnoff, W. C , and Thygeson, P. Amer. Jour. Ophth., 1931, v. 14, p. 318. 18 Proctor, F. I., Finnoff, W. C , and Thygeson, P. Amer. Jour. Ophth., 1932, v. 15, p. 206. "Thygeson, P. Arch, of Ophth., 1933, v. 10, p. 1. 20 Nicolle, C , and Lumbroso, U. Arch. Inst. Pasteur Tunis, 1931, v. 20, p. 239. 21 Julianelle, L. A., and Harrison, R. W. Trans. Amer. Acad. Ophth. and Otolaryng., 1935, p. 221. 22 Thygeson, P., and Proctor, F. I. Arch, of Ophth., 1935, v. 13, p. 1018. 28 Thygeson, P. Unpublished experiments. 24 Nicolle, C , Cuenod, A., and Blaizot, L. Compt. Rend. Acad. d. s c , 1912, v. 155, p. 241. 25 Lumbroso, U., and Thygeson, P. Arch. Inst. Pasteur Tunis, 1933, v. 22, p. 178. 29 Candian, F. L. Latenca Parmense, 1933, v. 5, p. 224. Cited from Julianelle and Harrison. 27 27 Julianelle. L. A., and Harrison, R. W. Amer. Jour. Ophth., 1935, v. 18, p. 133. 28 Elford, W. J. Jour. Path. Bact., 1933, v. 36, p. 49. 29 Ledingham, J. C. G. Bull. Johns Hopkins Hosp., 1935, v. 56. p. 247. 80 Halberstaedter, L., and von Prowazek, S. Deutsche med. Wchnschr., 1907, v. 33, p. 1285. 81 Stewart, F. H. Giza Mem. Ophth. Lab., Cairo, 8th Annual Report, 1935. 82 Bengtson, I. A. Amer. Jour. Ophth., 1929, v. 12, p. 637. 88 Tulianelle, L. A., and Harrison, R.W. Amer. Jour. Ophth., 1934, v. 17, p. 1035. " S t e w a r t , F. H. Brit. Med. Jour., 1935, v. 1, p. 1261. 85 Taborisky, J. Arch. f. Ophth., 1929, v. 123, p. 140. 86 Thygeson, P . Arch, of Ophth., 1934, v. 12, p. 307. 87 Bedson, S. P., and Bland, J. O. W. Brit. Jour. Exper. Path., 1932, v. 13, p. 461.
T H E SCREEN TEST A N D ITS APPLICATIONS JAMES WATSON W H I T E , N E W YORK
M.D.
Any test used for the diagnosis of muscle imbalances must be accurate, precise, and quickly applicable in a large percentage of cases. It should make possible the measure ment of phorias as well as trophias and should not be dependent on binocular vision. It should be applicable to very young children. The more objective the test can be made the better. The screen test with its modifications, screen-Maddox rod, and screen-comitance, are described in detail after the physiology and mechanics of the ocular movements have been briefly discussed, and cases are cited to emphasize the benefits of these tests. Cases of combined vertical and lateral deviations are described and the importance of measuring the combined deviations stressed. The tendency in some cases of lateral strabismus to a change from convergent to divergent squint, or vice versa when a vertical deviation is present, is discussed. Cases are cited in which this developed following operation for the lateral deviation, the vertical deviation having remained uncorrected. The same change in deviation has been observed when operation has not been resorted to. The screen test is the only test in the writer's experience that is applicable in all cases in which vision is sufficient for central fixation. Read before the Washington, D.C., Ophthalmological Society, January 6, 1936. A n y t e s t used for t h e d e t e r m i n a t i o n of i m b a l a n c e of the ocular m u s c l e s m u s t b e : (a) a c c u r a t e , (b) precise, (c) quick ly applicable in a l a r g e p e r c e n t a g e of cases. I t s h o u l d m a k e possible ( d ) t h e m e a s u r e m e n t of t r o p i a s as well a s of p h o r i a s ; (e) t h e m e a s u r e m e n t of t h e a m o u n t of deviation w h e n s u p p r e s s i o n is p r e s e n t a n d b i n o c u l a r vision is im possible. (f) I t s h o u l d b e a c c u r a t e in children too y o u n g to a p p r e c i a t e d o u b l e i m a g e s as required b y m a n y of t h e t e s t s . ( g ) T h e m o r e objective a n d t h e less subjective t h e t e s t t h e b e t t e r . M a n y of t h e t e s t s in v o g u e a r e p u r e l y subjective a n d m e a s u r e o n l y t h e p h o r i a s
a n d t h e lesser a m o u n t s of t r o p i a s w h e n s u p p r e s s i o n is n o t p r e s e n t . M o s t t e s t s m e a s u r e t h e deviation for distance only, while some m e a s u r e it for b o t h distance a n d near, b u t only in the p r i m a r y position. If a m e a s u r e m e n t is desired in t h e six cardinal fields, an e n t i r e l y different t e s t is n e c e s s a r y , w h i c h m a y a l t e r t h e fusion t e n d e n c y entirely. D u a n e in a n article on t h e p a r a l l a x test, w r i t t e n in 1895, s t a t e d , " A s far as m y experience goes, t h e impulse t o w a r d s b r i n g i n g t w o dissimilar i m a g e s i n t o line is a l m o s t as s t r o n g as w h e n t h e i m a g e s are a l i k e . " T h i s h a s been
Pertinent trachoma studies of the past few years have been analyzed and the following conclusions as to etiology have been drawn: (1) Trachoma is a specific communicable disease. (2) It is not caused by a specific bacterium nor by repeated infection with or dinary conjunctival bacteria. (3) The etiologic agent belongs to the group of filtrable viruses. (4) The particle size of the virus is probably relatively large. (5) The virus may be identical with the elementary body of Prowazek and Halberstaedter. From the De partment of Ophthalmology, College of Medicine, University of Iowa. Read before the Chicago Ophthalmological Society, December 16, 1935.
Trachoma has been studied exten sively during the past five years, and in this country systematic programs for determining the etiology of the disease have been undertaken by the University of Iowa and by Washington University. Definite progress has been made and it now seems worth while to analyze available reports and to draw such con clusions as the evidence warrants. In this survey no attempt is made to re view the entire literature, only pertinent reports of recent date being cited.
contributing factor seems to have been definitely ruled out by the studies of Hetler and James 8 who found that mon keys (M. rhesus) on deficient diets were not more susceptible to trachoma than monkeys on adequate diets. Rice and co-workers, 9 at the United States tra choma hospital at Rolla, Missouri, failed to find clinical improvement in patients fed on adequate diets reinforced with vitamin A. Abundant clinical records are available to show that trachoma oc curs in individuals on adequate diets; for example, trachoma in wrestlers.
Trachoma is a specific communicable disease Trachoma is not a specific bacterial disease The communicability of trachoma has been confirmed by the inoculation ex No specific bacterium has been dem periments of Michail and Vancea, 1 and onstrated as the cause of trachoma. 2 of Thygeson, in which trachomatous While Bacterium granulosis (Nogumaterials were transferred directly to chi 10 ) has been shown 11 to produce in normal human conjunctivae, and by the monkeys a follicular disease resembling experiment of Thygeson, Proctor, and trachomatous infection, it has been Richards 3 in which filtered material pro eliminated as a causal factor for the fol duced trachoma in a human volunteer. lowing reasons: (1) it has not been The susceptibility of the monkey con found with sufficient constancy in the junctiva to trachoma has been demon lesions of the disease, by either bacstrated by Julianelle and Harrison 4 and terioscopic or cultural methods, to in by Stewart. 5 dicate etiologic significance (Julianelle 12 Bengtson, 13 Wilson, 1 * The specificity of the disease is in and Harrison, 15 dicated by the fact that the human in Thygeson, and others) ; (2) it has not oculations have resulted in typical clin produced trachoma when inoculated in 16 ical trachoma. No conclusions as to the human conjunctiva (Wilson, Proc 17 specificity are derivable from monkey tor and co-workers, Proctor, Finnoff, 18 Thygeson, 19 Nicolle inoculations since the induced infection and Thygeson, 20 and many others) ; lacks the diagnostic signs of pannus and and Lumbroso, scarring; experimental trachoma in (3) tissue transfer from Bacterium monkeys is a granular conjunctivitis granulosis conjunctivitis of the M. and cannot be differentiated with cer rhesus to the human conjunctiva did 19 (4) trachoma tainty from Bacterium granulosis con not induce trachoma; 6 7 has been induced with material not con junctivitis, inclusion conjunctivitis, or taining Bacterium granulosis (testicuspontaneous folliculosis. Dietary deficiency as an etiologic or lar passages of Julianelle and Harri649
650
PHILLIPS THYGESON
son, 21 nitration experiments of Thygeson and Proctor, 22 and of Thygeson, Proctor, and Richards 3 ). Other bacteria occurring on the trachomatous conjunctiva have been eliminated as causal agents by inocula tions of pure and pooled cultures on the human conjunctiva (Thygeson 15 ) and on the monkey conjunctiva (Julianelle and Harrison, 21 Stewart 5 ).
indicate that a noncultivable bacterium* or protozoon is concerned in the etiolo gy of the disease. 2. Evidence obtained from filtration experiments. Filtration experiments in trachoma have for the most part been negative. In 1913, however, Nicolle, Cuenod, and Blaizot 24 reported positive results in two experiments with modi fied Berkefeld-V filters. Of particular significance was the fact that, in one experiment, the infection in the chim Trachoma is not due to repeated panzee inoculated with filtrate was infection with nonspecific proved to be trachomatous by transfer bacteria to a blind human eye. In recent years Whereas trachoma has been trans negative filtrations have been reported mitted to monkeys, attempts to trans by Lumbroso and Thygeson, 25 Candimit ordinary bacterial conjunctivitis an,26 and Stewart. 5 Julianelle and Har have failed (Stewart 5 ). Trachoma has rison 27 obtained infection with Berke been seen to start and to progress feld-V filtrates in three of 44 animals, a through its usual course with pannus in result which they considered unimpor the absence of pathogenic bacteria tant in view of the large proportion of (Thygeson, Proctor, and Richards 3 ). negative results. They concluded that Over a three-year period no clinical the agent of trachoma was generally evidence was found to indicate that not filterable. nonspecific chronic conjunctivitis is ca The varied results from filtration ex pable of developing into trachoma. 23 periments led Thygeson, Proctor, and Richards 3 to examine the technique Trachoma is a virus disease used by Nicolle and co-workers in their Evidence obtained from three differ sharply positive filtrations. In order to ent methods of attack on the problem reduce loss of active agent in the filter, now indicates that trachoma belongs to the French workers had employed a disc of Berkefeld-V substance cemented the group of virus diseases. 1. Evidence obtained through a proc into the end of a glass tube. It seemed ess of elimination. Julianelle and Harri reasonable, therefore, that the inactivity son 21 made extensive inoculations in of filtrates might be due primarily to the conjunctiva of the M. rhesus, using adsorption of the agent rather than to pure cultures or cultures of bacteria large particle size. Experiments were pooled in the proportions found on the conducted, therefore, in which a high trachomatous conjunctiva, without re virus content of the suspension was sult. Stewart 5 inoculated 30 baboons insured by the use of pooled epithelial with various conjunctival bacteria in scrapings from selected cases in Indian cluding staphylococci, gonococci, strep children with active disease. Loss in the tococci, Koch-Weeks, and influenza ba filter28 was controlled by the use of Elcilli, with negative results. Thygeson 15 ford gradocol membranes which be inoculated all forms of bacteria isolated come saturated with very little virus. from 63 cases of trachoma into the hu In four experiments on baboons, using man conjunctiva without producing the 0.75-micron membranes (membranes of disease. In view of the consistently largest pore size which will retain con negative results of these experiments junctival bacteria), bacteria-free fil and of the many other inoculation ex trates were found to be active. To periments recorded in the literature of eliminate the possibility that inclusionthe past 50 years the negative role of * Rickettsialike bodies have been de the conjunctival bacteria in trachoma scribed by Busacca and by Cuenod and Nataf should be accepted. in follicular material from trachoma. Their There is no morphologic evidence to significance has not yet been established.
ETIOLOGY O F TRACHOMA
conjunctivitis virus was present and had produced the lesions in the mon keys, a single inoculation on a human eye was made with a filtrate which had passed a 0.6-micron membrane. The re sult was positive. 3. Evidence obtained by inoculations with bacteria-free trachomatous mate rial. Julianelle and Harrison, 21 using the method of testicular inoculation which Noguchi developed to rid vaccine virus of contaminating bacteria, were able to obtain active bacteria-free trachomatous material capable of inducing infection in monkeys. Properties of trachoma virus Very little is known concerning the properties of trachoma virus. The ex periments of Stewart 5 indicate that it survives mechanical procedures such as centrifugation and grinding; that it sur vives for at least 24 hours in a mixture of inactivated human serum and Tyrode solution, pH 7.4; but that its activity is quickly destroyed at pH 6.4 either in distilled water or Tyrode solution. Re ports as to the survival of the virus in glycerine are at variance. Nature of trachoma virus Filtration experiments with collodion membranes of graded pore size have shown that viruses vary greatly in par ticle size; some, like foot-and-mouthdisease virus, are very small (8-12[JL[X), and others, like vaccinia virus, are relatively large (125-175^^). In suit ably stained preparations these larger viruses are resolvable under the micro scope as minute coccuslike granules, known as elementary bodies. 29 In the case of vaccinia virus, fowl-pox virus, and certain others, they are about 0.25 microns in diameter when stained. Most of the viruses of large particle size filter with difficulty, whereas small viruses, such as that of foot and mouth disease, readily pass the ordinary bac terial filters. The fact that trachoma virus filters with difficulty suggests that the particle size may be relatively large. Elemen tary bodies, resembling those in other virus diseases, have been known to
651
exist in trachoma since their descrip tion by Halberstaedter and Prowazek 30 in 1907. They were noted both free in the secretion and massed together in the cytoplasm of the conjunctival epithelial cells to form the socalled Halberstaedter-Prowazek inclu sion bodies. The presence of these bodies in tra choma has been reported by investi gators from all parts of the world, but no general agreement as to their nature or as to their etiologic relationship to trachoma has been reached. The inves tigations of Stewart, 31 Bengtson, 32 and Julianelle and Harrison 38 have not sup ported the claims of Halberstaedter and Prowazek. In Egypt, Stewart found the bodies only in trachoma com plicated by secondary bacterial infec tion and concluded that they were the granular products of cellular digestion of phagocyted conjunctival bacteria, particularly the Koch-Weeks bacillus. In a later report 34 he suggested that the elementary bodies were a granular virus which had been introduced into the conjunctival epithelial cells by way of phagocyted bacteria. Bengtson* con sidered the bodies of probable etiologic importance but believed them to be of bacterial origin. Julianelle and Harri son found trachomatous material in which they could not demonstrate the bodies to be infective and also noted the apparent absence of the bodies in experimental trachoma of the Macacus rhesus. The investigations of Taborisky 35 and of Thygeson 36 and of Thygeson, Proctor, and Richards 3 have supported the identification of the elementary body with trachoma virus. The findings of the latter observers may be discussed under the following headings: 1. Relative specificity of the Halber staedter-Prowazek elementary body. The elementary body was not found on the normal conjunctiva. A survey of a thousand cases of conjunctivitis indicated that it was to be found only * In a report appearing while this article was in press, Bengtson (Amer. Jour. Ophth., 1936, v. 19, p. 229) concludes that the inclu sion body is concerned etiologically in tra choma.
652
P H I L L I P S THYGESON
in trachoma and in the nonbacterial conjunctivitis generally known as in clusion conjunctivitis (inclusion blennorrhea, swimming-pool conjunctivi tis). 2. Nature of the elementary bodies of inclusion conjunctivitis. The abun dance of elementary bodies in inclusion blennorrhea and the harmlessness of the disease offered opportunities for study not possible in trachoma. It was shown 7 : (1) that the elementary bodies were constantly associated with the disease; (2) that they were absent in conjunctivitis of known bacterial ori gin; (3) that the occasional sapro phytes found in the disease were not concerned etiologically; (4) that mul tiplication of the elementary bodies oc curred when the disease was trans ferred to a new host; (5) that bacteriafree filtrates containing elementary bodies were capable of producing the disease; and (6) that nitrates not con taining elementary bodies were not in fective. It was concluded, therefore, that the elementary body was the virus and that the inclusion bodies were cytoplasmic colonies of the virus. 3. Nature of the elementary body of trachoma. The studies on the elemen tary bodies of inclusion conjunctivitis supported the view that the morpho logically identical trachoma elementary body was of virus nature. Its similarity to psittacosis virus 37 in morphology and staining reactions was also highly sug gestive. 4. Probable identity of the trachoma elementary body with trachoma virus. Evidence supporting the theory of identity of elementary body and virus: (1) presence of elementary bodies in an infective filtrate 3 (elementary bodies found in material used for filtration, in filtrate, and in experimental disease) ; (2) presence of elementary bodies in four cases followed from onset; (3) 1 2 8 4 5 8
presence in trachoma in numbers cor responding to clinical severity of dis ease ; for example, in seven cases of tra choma with acute or subacute symp toms but without secondary bacterial infection there were large numbers of elementary bodies, whereas, in chronic cases they were relatively few; (4) ele mentary bodies have been present in a larger percentage of cases than would be expected of a secondary invader: Tunisian series 44 percent, unselected American series 40 percent, selected (for transmission experiments, on the basis of activity) American series 92 percent. Evidence opposing the theory of identity of elementary body and virus: (1) the elementary body has not been found in 100 percent of cases of trachoma; (2) it has not been found in experimental trachoma of the M.rhesus. Thygeson 23 considers the failure to find elementary bodies in all cases of trachoma not incompatible with etiologic significance in view of (1) diffi culty of morphological demonstration due to minuteness of bodies; (2) ab sence of a cultural means of demon stration ; and (3) chronicity of disease. He interprets the failure to demon strate the bodies in the experimental infection of the M. rhesus as being due probably to the mild character of the induced disease, since in two transmis sion experiments to human eyes the bodies were demonstrated without diffi culty. Summary Recent studies support the conclu sion that trachoma is a virus disease. Evidence has been advanced which identifies the elementary body of Halberstaedter and Prowazek with tra choma virus, but no general agreement among investigators on this point has as yet been reached.
References
Michail, D., and Vancea, P. Rev. Internat. Trachome, 1932, 9, p. 33. Thygeson, P. Amer. Jour. Ophth., 1933, v. 16, p. 409. , Proctor, F. I., and Richards, P. Amer. Jour. Ophth., 1935, v. 18, p. 811. Julianelle, L. A., and Harrison, R. W. Amer. Jour. Ophth., 1933, v. 16, p. 857; Ibid., 1934, v. 17, p. 1035. Stewart, F. H. Giza Mem. Ophth. Lab., Cairo, 8th Annual Report, 1934, p. 142. Thygeson, P. Amer. Jour. Ophth., 1932, v. 15, p. 293. ' . Amer. Jour. Ophth. 1934, v. 17, p. 1019. 8 Hetler, R. A., and James, W. M. Amer. Jour. Ophth., 1934, v. 17, p. 1048. 9 Rice, C. E., Sory, R., Smith, J . E., Faed, P. E., and Drake, A. A. Amer. Jour. Ophth., 1934, v. 17, p. 735.
6S3
T H E SCREEN T E S T 10 Noeuchi, 11
H. Jour. Exper. Med., 1928, v. 48, Supplement No. 2. Robbins, A. R. Ophthalmologic review: Role of Bacterium granulosis in trachoma. Arch, of Ophth., 1935, v. 14, p. 629. 12 Julianelle, L. A., and Harrison, R. W. Personal communication. 18 Bengtson, I. A. U. S. Public Health Reports, 1932, v. 47, p. 1914. » Wilson, R. P. Giza Mem. Ophth. Lab., Cairo, 6th Annual Report, 1932, p. 86. "Thygeson, P. Arch. Inst. Pasteur Tunis, 1933, v. 22, p. 157; Arch, of Ophth., 1933, v. 10, p. 1. " W i l s o n , R. P. Brit. Jour. Ophth., 1931, v. 15, p. 433; Giza Mem. Ophth. Lab., Cairo, 8th Annual Re port, 1934, p. 97. " Proctor, F. I., Richards, P., Greenfield, M., Finnoff, W. C , and Thygeson, P. Amer. Jour. Ophth., 1931, v. 14, p. 318. 18 Proctor, F. I., Finnoff, W. C , and Thygeson, P. Amer. Jour. Ophth., 1932, v. 15, p. 206. "Thygeson, P. Arch, of Ophth., 1933, v. 10, p. 1. 20 Nicolle, C , and Lumbroso, U. Arch. Inst. Pasteur Tunis, 1931, v. 20, p. 239. 21 Julianelle, L. A., and Harrison, R. W. Trans. Amer. Acad. Ophth. and Otolaryng., 1935, p. 221. 22 Thygeson, P., and Proctor, F. I. Arch, of Ophth., 1935, v. 13, p. 1018. 28 Thygeson, P. Unpublished experiments. 24 Nicolle, C , Cuenod, A., and Blaizot, L. Compt. Rend. Acad. d. s c , 1912, v. 155, p. 241. 25 Lumbroso, U., and Thygeson, P. Arch. Inst. Pasteur Tunis, 1933, v. 22, p. 178. 29 Candian, F. L. Latenca Parmense, 1933, v. 5, p. 224. Cited from Julianelle and Harrison. 27 27 Julianelle. L. A., and Harrison, R. W. Amer. Jour. Ophth., 1935, v. 18, p. 133. 28 Elford, W. J. Jour. Path. Bact., 1933, v. 36, p. 49. 29 Ledingham, J. C. G. Bull. Johns Hopkins Hosp., 1935, v. 56. p. 247. 80 Halberstaedter, L., and von Prowazek, S. Deutsche med. Wchnschr., 1907, v. 33, p. 1285. 81 Stewart, F. H. Giza Mem. Ophth. Lab., Cairo, 8th Annual Report, 1935. 82 Bengtson, I. A. Amer. Jour. Ophth., 1929, v. 12, p. 637. 88 Tulianelle, L. A., and Harrison, R.W. Amer. Jour. Ophth., 1934, v. 17, p. 1035. " S t e w a r t , F. H. Brit. Med. Jour., 1935, v. 1, p. 1261. 85 Taborisky, J. Arch. f. Ophth., 1929, v. 123, p. 140. 86 Thygeson, P . Arch, of Ophth., 1934, v. 12, p. 307. 87 Bedson, S. P., and Bland, J. O. W. Brit. Jour. Exper. Path., 1932, v. 13, p. 461.
T H E SCREEN TEST A N D ITS APPLICATIONS JAMES WATSON W H I T E , N E W YORK
M.D.
Any test used for the diagnosis of muscle imbalances must be accurate, precise, and quickly applicable in a large percentage of cases. It should make possible the measure ment of phorias as well as trophias and should not be dependent on binocular vision. It should be applicable to very young children. The more objective the test can be made the better. The screen test with its modifications, screen-Maddox rod, and screen-comitance, are described in detail after the physiology and mechanics of the ocular movements have been briefly discussed, and cases are cited to emphasize the benefits of these tests. Cases of combined vertical and lateral deviations are described and the importance of measuring the combined deviations stressed. The tendency in some cases of lateral strabismus to a change from convergent to divergent squint, or vice versa when a vertical deviation is present, is discussed. Cases are cited in which this developed following operation for the lateral deviation, the vertical deviation having remained uncorrected. The same change in deviation has been observed when operation has not been resorted to. The screen test is the only test in the writer's experience that is applicable in all cases in which vision is sufficient for central fixation. Read before the Washington, D.C., Ophthalmological Society, January 6, 1936. A n y t e s t used for t h e d e t e r m i n a t i o n of i m b a l a n c e of the ocular m u s c l e s m u s t b e : (a) a c c u r a t e , (b) precise, (c) quick ly applicable in a l a r g e p e r c e n t a g e of cases. I t s h o u l d m a k e possible ( d ) t h e m e a s u r e m e n t of t r o p i a s as well a s of p h o r i a s ; (e) t h e m e a s u r e m e n t of t h e a m o u n t of deviation w h e n s u p p r e s s i o n is p r e s e n t a n d b i n o c u l a r vision is im possible. (f) I t s h o u l d b e a c c u r a t e in children too y o u n g to a p p r e c i a t e d o u b l e i m a g e s as required b y m a n y of t h e t e s t s . ( g ) T h e m o r e objective a n d t h e less subjective t h e t e s t t h e b e t t e r . M a n y of t h e t e s t s in v o g u e a r e p u r e l y subjective a n d m e a s u r e o n l y t h e p h o r i a s
a n d t h e lesser a m o u n t s of t r o p i a s w h e n s u p p r e s s i o n is n o t p r e s e n t . M o s t t e s t s m e a s u r e t h e deviation for distance only, while some m e a s u r e it for b o t h distance a n d near, b u t only in the p r i m a r y position. If a m e a s u r e m e n t is desired in t h e six cardinal fields, an e n t i r e l y different t e s t is n e c e s s a r y , w h i c h m a y a l t e r t h e fusion t e n d e n c y entirely. D u a n e in a n article on t h e p a r a l l a x test, w r i t t e n in 1895, s t a t e d , " A s far as m y experience goes, t h e impulse t o w a r d s b r i n g i n g t w o dissimilar i m a g e s i n t o line is a l m o s t as s t r o n g as w h e n t h e i m a g e s are a l i k e . " T h i s h a s been