EPIDEMIC KERATOCONJUNCTIVITIS 1367

14. Guyton, J. S., and McGovem, F. H.: Diathermy coagulation in the treatment of angiomatosis retinae and of juvenile Coats's disease. Am. J. Ophth., 26:675,1943.

15. Moore, R. F.: Presidential address: Tr. Ophth. Soc. United Kingdom, 55:3,1935. 16. Craig, W., Wagener, H. P., and Kernohan, J. W.: Lindau-von Hippel disease: A report of four

cases, Arch. Neurol. & Psych., 45:36,1941. 17. Cordes, F. C, and Hogan, M.: Angiomatosis retinae: Report of a case in which roentgen therapy

was used in an early stage. Arch. Ophth., 23:253,1940. 18. Ballantyne, A. J.: Angiomatosis retinae: Account of a case, including the histological results of

X-ray treatment. Proc. Royal Soc. Med., 35:345,1941. 19. Craig, W., and Horrax, G.: The occurrence of hemangioblastomas in three members of a family.

J. Neurosurg., 6:518, 1949. 20. Hirschfeld, Mervyn, Hemangioblastoma of the medulla—Lindau's disease: Response to radiation

therapy. J. Nerv. & Ment. Dis., 99:6S6,1944.

EPIDEMIC KERATOCONJUNCTIVITIS A STUDY OF A SMALL EPIDEMIC

T . AlDAN COCKBURN,* M . D . , AND H . NlTOWSKY,* M . D . Greeley, Colorado

T. RoBiSON.t M.D. Kansas City, Kansas

AND F. S. CHEEVER,! M.D. Pittsburgh, Pennsylvania

Epidemic keratoconjunctivitis occurred in large scale epidemics before and during the war years,1-3 but since then has been rarely reported. This paper describes a small epi­demic in detail and draws attention to the fact that numerous other small outbreaks have come to our attention. Apparently the dis­ease is still present in many places. Sero-logic studies in a few cases failed to dem­onstrate any connection between the cases and the EK virus of Sanders and St. Louis encephalitis virus.

The causal virus was claimed to have been isolated by Sanders and his associates,4 in 1942, and evidence in support of the identity of this virus was that neutralizing antibodies in high titer persisting for at least two

* Encephalitis Investigations Unit, Communica­ble Disease Center, Department of Health, Educa­tion and Welfare.

t Department of Ophthalmology, Medical School, University of Kansas.

t University of Pittsburgh Graduate School of Public Health.

months could be demonstrated in the con­valescent sera of patients. In some instances, a rising titer with a two-or-three-logarithmic increase was found in paired acute-conva­lescent sera 17 to 34 days apart.

In the later epidemic in New York,3 sera from all convalescent cases six to 10 weeks after the onset of illness and 40 percent of cases tested five months after onset showed definite neutralization against the EK virus.

It is well known that herpes virus pro­duces a clinical picture of the disease undis-tinguishable from the epidemic type, al­though no one has yet shown that the her­pes virus can cause epidemics on the scale of those occurring in the shipyards and else­where.

Sanders and others found that the EK virus was not neutralized by antiherpes se­rum,4 but Maumenee and co-workers differed from this,5 stating that there is marked simi­larity between the herpes virus and the EK virus in both the clinical picture they pro­duce and in their immunologic reactions.

1368 T. COCKBURN, H. NITOWSKY, T. ROBISON, AND F. CHEEVER

Ruchman6 and Cheever7 found a close immunologic relationship between the EK virus and the St. Louis encephalitis virus. These two viruses could not be differenti­ated by the mouse intracerebral neutraliza­tion test, and the only difference was that the EK virus was more pathogenic for rabbits.

There is obviously some confusion as to the nature of the etiologic agent and, to clar­ify this, an attempt was made to obtain fresh isolation of the virus, with the assistance of ophthalmologists in Colorado, Missouri, Kansas, and Iowa. Although six epidemics in the area as well as a number farther afield were reported, these were only recog­nized in retrospect, no acute cases were forthcoming and only serologic studies could be made. The transmission of infection in all six outbreaks in the four-state area was associated with eye clinics, but in only one instance was the recording of the clinical and laboratory data complete and exact enough to allow for a reconstruction of events.

This epidemic had been recognized in June, 1951, and an attempt at this recon­struction was made in this one instance about six months later. The eye clinic concerned was a large one employing nine ophthalmolo­gists and treating all forms of eye disorder.

Study of the records revealed that the cases had not been infected simultaneously in one episode as thought at the time, but that transmission from case to case had taken place over a period of many weeks. The long duration of symptoms had led to an accumu­lation of cases which, when recognized, gave a superficial appearance of an explosive out­break.

CLINICAL DESCRIPTION OF CASES

All nine patients who developed epidemic keratoconjunctivitis were attending the clinic for treatment and observation of glaucoma. In seven of the cases, the onset of conjunc­tivitis was sudden, but in two instances the infections were mild in nature for the first two days before the commencement of the severe inflammations.

TABLE 1 DATA ON CASES OF EPIDEMIC

KERATOCONJUNCTIVITIS

Patient Appearance of

Opacities after Onset

(in days)

Duration of Symptoms (in days)

E.G. L.J. C.J. D. H. B. M. F. B. J.w. C. H. A. W.

N o opacities 7 7 2 14 14 35 14 11

17 11 11 12 SO IS 29 22 26

Averages 13.0 21.4

Symptoms varied from marked discom­fort to severe pain. Inflammation was lim­ited to one eye with intense infection of the conjunctiva and some chemosis. There was little or no purulent discharge, although most of the patients stated that their eyes watered a little. The corresponding pre-auricular glands were enlarged, though pa­tients did not appear to have had much dis­comfort from this. Membrane formation de­veloped in some cases on the conjunctiva.

Cultures and smears showed no abnormal micro-organisms. When smears were made the predominant cells were monocytes; a scraping from one patient (C. H.) showed numerous eosinophils. No inclusion bodies were seen in scrapings. The average dura­tion of the acute symptoms was about three weeks (table 1).

Subepithelial opacities typical of those described in other epidemics of epidemic keratoconjunctivitis were found in eight of the nine cases, the only one not developing them being the first case (E. G.). The time of appearance of these is given in Table 1.

EPIDEMIOLOGY

On investigation it was found that the patients who had developed epidemic kerato­conjunctivitis were limited to those attend­ing the clinic for glaucoma and that patients with other ailments were not affected. In 1951 there were 5,176 patients treated for all

EPIDEMIC KERATOCONJUNCTIVITIS 1369

PATIENT

E.G.

L.J.

C.J.

J.W.

C.H.

B.M.

F.B.

D.H.

A.W.

0 T.F

O T.D

o

27 APR.

T.E T 8

O T.D

O T.A

O

© T.A

4

?

0 T.A

® T.A

II

T.B

• D

• T.A

© T.A

18 MAY

O T.C

i. D T.C

1. T.D 8

• T.8

+

0 © T.B TA

O O T . I T.B

25

O T.B

O to

O te

• T.A

• A

OO T.I A

O

o T.B

1

• T.A

i A

A A A A

© T.A

© T.A

© T.A

8 J

T#A

• T.B

• A

• T.A

0 T.A

O TE

i T.A

O T.C

i H

• A

+ * • • 8

15 UNE

• T.I

• I

22

A,B

O T.A

i A

• B

i T.I

LEGEND O Attendance at clinic

0 Presumed date of Infection

+ Date of onset of symptoms - * Attendance at clinic with v symptoms of Infection T Teneion checked

C t e ta Physician who checked patient

▼ Opacltiee present

• • O T.I

29 6 13 20 27 JULY

Chart 1 (Cockburn, Nitowsky, Robison, and Cheever). Infectious keratoconjunctivitis in patients attending a glaucoma clinic.

types of eye conditions, the attendances in May, June, and July being 467, 504, and 473, respectively. In these months the average number of tension checks for glau-comatous patients was about 175 per month. In the two-month period under study when patients were being infected, approximately 40 patients with glaucoma were attending, and nine of these became ill, an attack rate of 23.5 percent.

The nine patients with the infection had been attending the clinic for some time, for years in some instances, before the appear­ance of the disease. Since no cases appeared among the numerous patients examined for other diseases, it was likely that infection had taken place during the examination for glaucoma.

Examination of the procedures used re­vealed a number of possible mechanisms of infection, such as the fingers of the physi­cians, the eye dropper, various instruments, towels, and the tonometer used for measur­

ing the intraocular pressure. Only this tonometer was considered as

being the likely vehicle of transmission, for the remainder were used in common for all patients with or without glaucoma, and the latter did not become infected. This tonome­ter was used for all patients with glaucoma and was sterilized after use by swabbing with alcohol.

The dates of attendance together with in­formation on the physicians making the ex­amination, the use of the tonometer, appear­ance of symptoms, and the calculated time of infection are shown in Chart 1. The day when each patient was presumed to be in­fected was calculated by allowing for an in­cubation period of about five to 10 days and seeing how the days of attendance at the clinic fitted with this.

Scrutiny of Chart 1 will show that on each day that a patient was presumed to have been infected, another patient with symp­toms of keratoconjunctivitis had attended;

1370 T. COCKBURN, H. NITOWSKY, T. ROBISON, AND F. CHEEVER

and that not only had both the infective and presumably infected patients been tested with the tonomoter, but had also been examined by only one of the physicians (Physician A on the chart). No other physician of the nine in the clinic was recorded as having examined a patient on the presumed date of infection. Unfortunately, it is not known in what order the patients were examined on each day.

There are two instances where the re­corded notes in the patients' charts are in­complete: On May 11th, when patients L. J. and C. J. were presumably infected, they were examined by Physician A but, al­though infective patient E. G. was present, it is not recorded which physician examined her.

Also, with patient C. H. there is a choice of two possible dates of infection, giving alternative incubation periods of four or 17 days. If the shorter period of time is used, then on the day of attendance no infective patient was present; but if the longer one is accepted, then the patient was examined by Physician A at a time when infective patient E. G. was present. It is not recorded that Physician A examined patient E. G., al­though it is understood that this quite pos­sibly did happen.

The nature of the epidemic and the possi­

bility of the tonometer spreading the infec­tion was recognized late in June when five patients were attending at the same time with the disease. Further infections were pre­vented by the adoption of a more efficient method of sterilizing the tonometer.

SEROLOGY

Sera were obtained from four of the pa­tients in the outbreak (epidemic No. 1) and from five patients in a similar outbreak oc­curring in another eye clinic in November and December, 1951 (epidemic 2) . All pa­tients had the classical combination of signs —conjunctivitis without purulent discharge, enlarged pre-auricular glands, absence of pathogenic bacteria, and subepithelial opaci­ties after the appearance of the acute phase of the illness. The sera were tested for neu­tralizing antibodies against St. Louis en­cephalitis and epidemic keratoconjunctivitis (Sanders strain) viruses.

Neutralization tests against the viruses of St. Louis encephalitis (Webster strain) and of epidemic keratoconjunctivitis (Sanders strain) were carried out using undiluted serum and decimal dilutions of virus accord­ing to the method recommended by the Neu-rotropic Disease Commission as quoted by Paul.8 The convalescent serum specimens which arrived in the laboratory in a liquid

TABLE 2 CONVALESCENT SERA FROM PATIENTS WITH EPIDEMIC KERATOCONJUNCTIVITIS TESTED FOR

NEUTRALIZING ANTIBODIES AGAINST THE S T . LOUIS ENCEPHALITIS AND THE SANDERS EK VIRUSES

Epidemic

I

II

Patient

F . B. D. H. C. H. A. W.

W. E. K. M. R. V. K.

H. E. V. H. E. B.

Corneal Opacities Present

+ + + + + +

Not examined Not examined

+

Collection of Sera after Onset of

Illness (in days)

328 333 344 330

63 105 34

109 93

Virus Tested

St. Louis Encephalitis (Webster)*

<10 <10 <10 < 1 0

<10 125

<10 <10 <10

Sanders EK*

<10 < 1 0 <10 <10

<10 <10 <10 <10

10

* Neutralization index.

EPIDEMIC KERATOCONJUNCTIVITIS 1371

state were frozen promptly and kept at —20°C. until tested. These sera were not inactivated prior to testing. Normal horse serum inactivated at 56° C. for 30 minutes was employed as a control serum.

Tenfold dilutions of a 20-percent infected mouse-brain suspension were made in 0.4-percent bovine albumen broth. Equal amounts (usually 0.2 cc.) of the virus di­lutions and undiluted serum were mixed and incubated in a 37°C. water bath for two hours. Immediately after incubation the se­rum-virus mixtures were placed in an ice water bath and held there until inoculated into mice. Six three- to four-week-old mice were inoculated per dilution, using the standard inoculum of 0.03 ml. Neutralization indices were calculated in the usual manner.

The results of the tests are given in Table 2. It will be seen that all were negative ex­cept for one positive against St. Louis en­cephalitis virus. This one positive is not sig­nificant, for serum surveys in this area show that up to 20 percent of the population may have these antibodies,9 and one positive out of 10 could well happen by chance.

DISCUSSION

It is apparent that epidemic keratocon-junctivitis is still appearing in epidemic fashion, although the epidemics are much smaller than during the war years, and all six notified to us were centered around eye clinics. The outbreak reported in this paper demonstrates a method by which the virus can be maintained permanently and in a form that might well escape notice until events provide for a more widespread infection.

The acute phase of the disease may last for several weeks and the likelihood of infected cases wandering from clinic to clinic during the infective acute stage or incubation period and spreading infection wherever circum­stances are favorable provides a real danger to ophthalmologists and their patients.

A particular hazard arises in the large clinics, to which patients are sent by oph­thalmologists for special consultations, for

should infection be transmitted at such a central point, secondary foci might appear in smaller clinics throughout the country.

In addition, several hundreds of cases of acute conjunctivitis were discovered that clin­ically were indistinguishable from epidemic keratoconjunctivitis except that opacities failed to develop in the cornea. The diagnoses of these cases pose a difficult problem for, in past epidemics, many apparently genuine cases failed to produce opacities. It is not known if these are examples of epidemic keratoconjunctivitis without opacities or caused by some as yet unidentified virus. Further viral studies on these cases are urgently required.

The findings of the present study would suggest that St. Louis encephalitis virus was not involved in the cases of epidemic kerato­conjunctivitis found in the study area. Neu­tralizing antibodies against this virus can be readily demonstrated in a case of St. Louis encephalitis by the end of two months, and their absence except in one instance in the present series of cases can be considered significant. The one positive serologic test is of little significance since it is likely to hap­pen by chance in testing any group of 10 sera from persons in the Midwest.

The failure to demonstrate antibodies against the Sanders EK virus is of less sig­nificance, since less is known about how the antibodies against these viruses fluctuate during and after a human infection. How­ever, the studies that have been reported state that high titer antibodies against the EK virus can be found up to 10,000 neutralizing doses two or three months after the onset of the disease1'3'* and, if the present cases had been caused by this virus, antibodies should have been found at least in Epidemic 2. It is possible that there is more than one epidemic keratoconjunctivitis virus and that the cases described in this paper were caused by another such virus not yet isolated.

SUMMARY

1. Epidemic keratoconjunctivitis is still

1372 DANIEL B. KIRBY

occurring, and six small epidemics, all cen­tered around eye clinics, were found.

2. In one epidemic, the infection was maintained in patients with glaucoma for many weeks by transmission from patient to

The multiplicity of procedures and meth­ods for the relief and cure of spastic senile entropion indicates the difficulty of the con­dition. The unsatisfactory results which are obtained when any one method or operation is applied routinely prove that the patient who has spastic senile entropion must be treated as an individual and the appropriate treatment and surgery applied.

It has been my observation that in many of the patients in the senile age group who suffer from spastic entropion, there is pres­ent also a flaccidity and apparent elongation and relaxation of the lower lid which is due undoubtedly to degeneration of the previ­ously dense elastic and fibrous tissue ele-

* Presented at the 88th annual meeting of the American Ophthalmological Society, Hot Springs, Virginia, June, 1952.

patient, probably by a tonometer. 3. Serologic studies showed no relation

between the disease in two epidemics and St. Louis encephalitis and the Sanders EK virus.

ments. It is definitely not the redundancy of skin alone which is at fault. In the presence of irritation or inflammation, entropion may develop through spasm or even through the normal action of the orbicularis muscle.

By removal of the irritation or a cure of the inflammation and by shortening and tens­ing the lower lid, the condition of so-called spastic senile entropion has been overcome and cured in all of the cases in which the procedure to be described has been indicated and applied. It is to be admitted that further degeneration may occur and that, if degener­ation is coupled with irritation or inflamma­tion, the entropion may well recur.

BACKGROUND

It is interesting to describe the develop­ment of the recognition of the principle and

REFERENCES

1. Sanders, M.: Epidemic keratoconjunctivitis (shipyard conjunctivitis). Arch. Ophth., 28:581-586, 1942.

2. Sanders, M., Gulliver, P. D., Forchheimer, C. C, and Alexander, R. C.: Epidemic kerato­conjunctivitis: Clinical and experimental study of an outbreak in New York City. J.A.M.A., 121:250-255, 1943.

3. Korns, R. F., Sanders, M., and Alexander, R. C.: Epidemic keratoconjunctivitis. Am. J. Pub. Health, 34:567-571, 1944.

4. Sanders, M., and Alexander, R. C.: Epidemic keratoconjunctivitis: Isolation and identification of a virus. J. Exper. Med., 77:71-96, 1943.

5. Maumenee, A. E., Hayes, G. S., and Hartman, T. L.: Isolation and identification of the causative agent in epidemic keratoconjunctivitis (superficial punctate keratoconjunctivitis) and herpetic kerato­conjunctivitis. Am. J. Ophth., 28:823-839,1945.

6. Ruchman, I.: Relationship between epidemic keratoconjunctivitis and St. Louis encephalitis. Proc. Soc. Exper. Biol. & Med., 77:120-125, 1951.

7. Cheever, F. S.: A possible relationship between viruses of St. Louis encephalitis and epidemic keratoconjunctivitis. Proc. Soc. Exper. Biol. & Med., 77:125-129, 1951.

8. Paul, J. R.: The Filtrable Viruses in Laboratory Methods of the U. S. Army. Ed. by Simmons, J. S. and Gentzkow, C. J., Philadelphia, Lea and Febiger, 1944, p. 579-600.

9. Cockburn, T.: Unpublished data.

SURGICAL CORRECTION OF SPASTIC SENILE ENTROPION: A NEW METHOD*

DANIEL B. KIRBY, M.D. New York