AMERICAN JOURNAL OF OPHTHALMOLOGY

VOLUME 62 OCTOBER, 1966 NUMBER 4

ANTICHOLINESTERASE DRUGS AND CATARACTS

ROBERT N. SHAFFER, M.D., AND JOHN HETHERINGTON, JR., M.D. San Francisco, California

It has long been suspected that there is an increased incidence of cataracts in the glau­coma population. Although generally thought to be a part of the glaucoma syndrome, ex­ception can be taken to this point of view. Patients with advanced glaucoma often have no lens changes when their disease is first diagnosed. Patients with advanced glaucoma after prolonged treatment often have lens opacities. Of course, surgical procedures cause cataracts but there is an increasing suspicion that miotic therapy is not harmless.

In 1960, Harrison published the first doc­umented evidence of lens opacities produced by a miotic.1 A 13-year-old girl with esotro-pia had been treated by 0.025% Floropryl for three months when rosettelike anterior subcapsular lens opacities were noted. They did not interfere with vision and slowly dis­appeared after discontinuing the medication.

The current interest stems from a care­fully documented study by Axelsson and Holmberg in the Department of Ophthal­mology, Sabbatsbergs Hospital, Stockholm, Sweden.2 In 1963, they had instituted an in­vestigation on the relative efficacy of Phos­pholine Iodide as compared with pilocarpine in glaucoma therapy. Within a year they had become impressed by the increased inci­dence of cataracts in the Phospholine-treated cases. The direction of the investiga­tion was then changed to compare the fre-

From the Department of Ophthalmology, Uni­versity of California Medical Center. Presented at the 102nd annual meeting of the American Oph-thalmological Society, White Sulphur Springs, West Virginia, May, 1966.

quency of cataract formation in the two groups.

All the patients in the study had newly diagnosed cases of open-angle glaucoma. Since only a few had field defects, it must be assumed that the glaucoma was not ad­vanced. The patients had had no prior anti-glaucoma therapy and were treated with ei­ther pilocarpine, 2% to 4% solutions two to four times a day, or Phospholine Iodide, 0.06% to 0.25% twice a day. The starting point for the evaluation of vision and re­fraction was taken in a careful study several weeks after instituting therapy. Patients with lens changes at the beginning of thera­py were placed in one group with a mean age of 73 years. Those with clear lenses were placed in a second group with a mean age of 63 years. Definite cataract formation was assumed if increasing lens opacities were observed, accompanied by a progres­sive deterioration of vision, especially with a myopic refractive change.

A total of 181 eyes was included. Of 103 eyes treated with pilocarpine for a mean pe­riod of 22 months, 10 eyes, or about 10%, developed or had an increase in lens opaci­ties. Seventy-eight eyes were treated with Phospholine Iodide for a mean period of 12 months. Of these eyes, 39, or 50%, had an increase in lens opacities.

Of the 87 eyes with clear lenses when therapy was instituted, 47 were treated with pilocarpine; three of these eyes were listed as positive. In contrast there were 16 eyes listed as positive among the 40 eyes treated with Phospholine Iodide. Six of these eyes

613

614 AMERICAN JOURNAL OF OPHTHALMOLOGY OCTOBER, 1966

had a visual loss from 20/20 to 20/70 in one year. In the subgroup of 94 older pa­tients who already had lens opacities at the beginning of therapy, there was an even more striking difference. Only seven eyes (12%) of the pilocarpine-treated cases were positive while 16 (60%) of those using Phospholine Iodide were positive.

Included in the study were 12 patients with unilateral glaucoma. Of the six eyes treated with pilocarpine, only one developed a cataract. In contrast, three of the six eyes treated by Phospholine Iodide had lens changes. The untreated eyes were un­changed.

Finally, increasing the duration or the strength of the anticholinesterase therapy significantly added to cataractogenicity. Using Phospholine Iodide, 0.06% twice a day for one year, 10 of 20 eyes (50%) were positive; with 0.25% twice a day for one year, 11 of 13 eyes (84%) became positive. After one year of treatment with Phospho­line Iodide, 19 of 38 eyes (50%) had lens changes; 13 of 18 eyes (72%) developed lens changes in two years.

A letter from Dr. Holmberg3 states that similar lens changes have been seen with other long-acting cholinesterase-inhibiting drugs such as Floropryl and Humorsol. He reported that Tarkanen in Finland has found a similar incidence of lens changes.

Most recently, de Roetth has reported 19 cases of anterior subcapsular lens changes in patients treated with Phospholine Iodide.4

These patients had been treated for seven to 17 months. He concluded that there was a strong probability that the drug was re­sponsible for the lens changes.

There is some laboratory evidence which suggests an etiologic relationship. In 1954, Diamont5 produced some anterior subcapsu­lar lens changes in guinea pig eyes with massive intracarotid injections of cholines-terase inhibitors. Muller and associates,6 in 1956, reported a 50% reduction in lens res­piration in vitro when lenses were treated with either pilocarpine or the organophos-

phorous compound, Mintacol. No lens changes were produced by topical adminis­tration. At the present time, Kinoshita and Michon at Howe Laboratories7 are studying the isolated lens. In a personal communica­tion they state, "Most of our results have come from studies on the isolated lens, since direct application of the drug on rabbit eyes has not yet produced any lens changes. Most of the results were obtained with Humorsol, although from preliminary experiments it appears that Phospholine Iodide has a similar action." Their observations are sum­marized as follows:

1. Cholinesterase activity can be demon­strated in the capsule-epithelium preparation of calf and rabbit lenses. The enzyme ap­pears to be the specific or "true" acetyl cho­linesterase.

2. Incubation of the lens at 10-3M of the drug causes opacification.

3. With incubation at a lower concentra­tion (10-4M), slight clouding of the epitheli­um can be observed. Preliminary histologic studies suggest changes in the anterior cor­tex.

4. At concentrations of 10-4M, there are changes in cation distribution with loss of potassium and increase in sodium even when the lens remains clear. There is an in­crease in leak-out of rubidium-36, while the active uptake of rubidium seems unim­paired.

5. Microscopic examination of the affect­ed lenses shows changes compatible with those seen clinically.

CURRENT INVESTIGATION

Obviously it is of great practical impor­tance to determine promptly whether or not the Axelsson and Holmberg findings are ap­plicable in this country. No comparable se­ries can be compiled which has been treated only by pilocarpine or by anticholinesterase agents. A double-blind study with alter­nate patients or alternate eyes treated by parasympathomimetic or anticholinesterase drugs would be ideal but could not yield

VOL. 62, NO. 4 ANTICHOLINESTERASE AND CATARACTS 615

definitive results for one or two years. The only practical method is to evaluate eyes which have been treated by these agents in the past.

The difficulties and pitfalls of a retrospec­tive study were obvious when attempts were made to record reliable data from charts mainly concerned with pressure control rather than cataract production. Numerous charts, particularly in the clinic population, had to be disqualified due to misleading or inadequate data, surgical procedures, inter-current eye diseases, etc. Such a study is subject to the investigator's prejudices and can only provide a clinical impression. In the belief that such an impression is better than none at all, this investigation was ini­tiated.

The patients were drawn from the Glau­coma Clinic of the University of California and from our private practices. A control group of similar age was randomly selected from the private practice to show the num­ber of cataracts which might appear in three years in a refraction population. No consul­tation records were used because of the difficulty of being sure of medications pre-

TABLE 2 FINDINGS IN 305 PRIVATE PATIENTS

Age (yr)

20-50 50-60 60-70 70-80 80-90

TOTAL

TABLE 1 FINDINGS IN 129 CLINIC PATIENTS

Parasympathomi-No. metic

Cases Cataracts

9 7 22 11 50 29 40 31

8 1

129 79

None 1 5 5 1

12 (15%)

Anticholines-terase

Cases

2 11 24

9 4

50

Cataracts

None 6 9 4

None

19 (28%)

Mean age of parasympathomimetic-treated cases —66 years

Mean age of anticholinesterase-treated cases —66 years

CATARACT INCIDENCE BY AGE 79 parasympathomimetic-treated eyes:

Age 20-60 18 eyes 1 cataract (6%) Age 60-90 61 eyes 11 cataracts (18%)

50 Anticholinesterase-treated eyes: Age 20-60 13 eyes 6 cataracts—all age

50-60 (50%) Age 60-90 37 eyes 13 cataracts (35%)

Age (yr)

20-50 50-60 60-70 70-80 80-90

TOTAL

No. Eyes

42 59

117 73 14

305

Parasympatho-mimetic

Cases Cataracts

39 50 87 58 11

245

1 2 4 5 4

16 (6%)

Anticholin-es terase

Cases

3 9

30 15 3

*60

Cataracts

None 1

12 9 1

23 (38%)

* 13 Floropryl-treated cases—30% cataracts 13 Humorsol-treated cases—40% cataracts 34 Phospholine-treated cases—-35% cataracts

Mean age parasympathomimetic-treated cases —61 years

Mean age anticholinesterase-treated cases —63 years

CATARACT INCIDENCE BY AGE 245 parasympathomimetic-treated eyes:

Age 20-60 89 eyes 3 cataracts (3%) Age 60-90 156 eyes 13 cataracts (8%)

60 anticholinesterase-treated eyes: Age 20-60 12 eyes 0 cataracts (0%) Age 60-90 48 eyes 22 cataracts (46%)

viously used by the referring doctors. It should be emphasized that none of our pa­tients had been treated by the anticholines-terase agents without previous pilocarpine therapy. Despite the many disadvantages of a retrospective study, evidence has been ac­cumulated which gives some support to the Axelsson and Holmberg report.

The glaucoma patients were divided into two groups, those using the parasympatho-mimetic drugs pilocarpine or Carcholin, and those using the anticholinesterase agents, Floropryl, Humorsol or Phospholine Iodide. The former patients used the drug for three years, the anticholinesterase group used the drug for six months to three years. With the exception of two eyes, cataracts were noted in the latter group within two years. To be classified as a cataract, a concomitant reduction in visual acuity of at least two lines on the Snellen chart was required (ta­bles 1, 2 and 3) .

The group of 305 normal eyes of similar age distribution from our private practices was examined three years after routine eye

616 AMERICAN JOURNAL OF OPHTHALMOLOGY OCTOBER, 1966

which compares closely with the 6% inci­dence in the pilocarpine-treated glaucoma cases. The 3 8 % incidence in the anticholin-esterase-treated patients is in striking con­trast. It should also be noted that there is approximately the same percentage of lens opacities with any of the anticholinesterase d rugs : Floropryl, Humorsol, or Phospho-line Iodide.

The cataracts in the anticholinesterase group frequently had the characteristic mossy appearance described by the Swedish authors. They start as tiny vacuoles in and just below the anterior lens epithelium and capsule. Until well advanced they can be seen easily only by retroillumination and cannot be pictured by a Donaldson stereo-camera. Iridescent sparkling opacities are occasionally seen. Later there are posterior subcapsular and nuclear alterations accom-

Fig. 1 (Shaffer and Hetherington). Drawing of kns of a patient uvriving l'liospholinc Iodide. The slitlamp beam shows the patchy superficial opacification. By retroillumination the vacuoles and irregular streaks are better visualized.

TABLE 3 FINDINGS IN 305 NORMAL REFRACTION PATIENTS

Age (yr)

20-30 40-50 50-60 60-70 70-80 80-90

TOTAL

No. Eyes

8 35 59

116 73 14

305

No No

in

Therapy Cataract 3 years

8 35 57

108 61 11

280

No Therapy Cataract in 3 years

2 8

12 3

25 (8%)

CATARACT INCIDENCE BY AGE Age 20-60 100 eyes 2 cataracts (2%) Age 60-90 180 eyes 23 cataracts (13%)

examination and refraction (table 3 ) . Twenty-five of these eyes had developed a cataract, with reduction of visual acuity of at least two lines on the Snellen Chart. This represents an 8% incidence of cataracts

VOL. 62, NO. 4 ANTICHOLINESTERASE AND CATARACTS

Fig. 2 (Shaffer and Hetherington). Low-power and high-power photomicrograph of cataractous lens from a glaucoma patient who had been treated by Phospholine Iodide. The nuclear sclerosis and lamellar separation of the cortex are obvious. In the high-power view the vacuolation of the lens epithelium can be seen. None of these changes can be said to be specific, as similar changes are present in cataracts from nonglaucomatous patients. (Courtesy of Kenneth Grow, M.D.)

panied by myopic refractive changes. Similar lens changes are occasionally seen in eyes which never had antiglaucoma therapy (figs. land 2) .

CASE REPORTS Representative case histories have been

chosen to show the varied susceptibility of individual patients:

618 AMERICAN JOURNAL OF OPHTHALMOLOGY OCTOBER, 1966

G. S., a 60-year-old white man, had open-angle glaucoma under good control for nine years using Humorsol 0.25% alternating with Phospho-line Iodide 0.25% twice daily. Vision was 20/20 in each eye. Absolutely no sign of cataracts was seen in either eye.

M. W., a 65-year-old white woman, had open-angle glaucoma under good control for two years on Phospholine Iodide 0.125% twice daily and Glaucon once a day. Vision was 20/20 in each eye. Two or three tiny vacuoles were seen in the lens epithelium of each eye.

E. G., a 65-year-old white man, had open-angle glaucoma under good control for one year on 2% pilocarpine three times a day. Vision was 20/20 in each eye. He was changed to Phospho­line Iodide 0.06% once a day. In six months vi­sion was 20/30 in the right eye and 20/60 in the left eye. The lenses had the typical woolly streaks and patches of coalescing vacuoles in the lens epithelium. Eight months after stopping Phos­pholine Iodide the vision had decreased to 20/60 in the right eye and 20/200 in the left, requiring cata­ract extraction.

E. L., a 78-year-old white woman, had a newly diagnosed case of open-angle glaucoma. She had had no therapy. With this investigation in mind, she was placed on Phospholine Iodide 0.06% once a day in her right eye, which was the eye with the lower tension, and on pilocarpine 2% four times a day in the left eye. In three months there were definite epithelial vacuoles and slight diminution of vision in the right eye. The left eye remained unchanged. In six months, the opacities had in­creased and vision was reduced to 20/50.

CONCLUSION

It is our clinical impression that anticho-linesterase agents can initiate cataract for­mation. The cataracts are specific in type and can be seen at first only by retroillumi-nation through a dilated pupil.

The lenses of patients over 60 years of age seem more vulnerable to cataractous changes than those of younger individuals. In all three series, few lens opacities were noted in patients under the age of 60 years. This may explain the absence of reports of lens changes in esotropic children who are being treated by such medications.

The patients in the Swedish series seem to have had more severe visual loss and more definite correlation with the duration and the intensity of medication than those in our series. This may reflect some genetic

or environmental difference in the two pop­ulations. The incidence of pseudocapsular exfoliation is known to be high in the Scan­dinavian countries. Four of our patients treated with anticholinesterase agents had pseudocapsular exfoliation and all four de­veloped cataracts. The variability in suscep­tibility in our patients is shown by the rep­resentative case reports. Some developed vacuoles in only a few months while others used the drug in high concentration for years without any lens changes.

It is our opinion that the anticholines­terase drugs are useful and should continue to be employed when indicated, rather than resorting to surgery which certainly brings the risk of cataract formation. They should not be used if tension can be controlled by the parasympathomimetic agents, combined with epinephrine and perhaps carbonic anhydrase inhibitors. When used, the pa­tient's pupils should be dilated at least every six months and the lenses carefully exam­ined for the characteristic vacuoles.

There seems to be no doubt that there is a tendency for the cataracts to progress even though the drug is discontinued. It is not yet known whether this will be true of cases with minimal epithelial damage.

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REFERENCES

1. Harrison, R.: Bilateral lens opacities associ­ated with the use of di-isopropyl fluorophosphate eyedrops. Am. J. Ophth. 50:153, 1960.

2. Axelsson, U., and Holmberg, A.: The fre­quency of cataract after miotic therapy. To be published in Acta Ophth. in 1966. Permission given by the authors to quote the paper.

3. Personal communication, January, 1966. 4. De Roetth, A., Jr.: Lenticular opacities in

glaucoma patients receiving echothiophate iodide therapy. JAMA, 195:152, 1966.

5. Diamont, H.: Cataract due to cholinesterase inhibitors in the guinea pig. Acta. Ophth. 32:357, 1954.

6. Muller, H. K., Kleifeld, O., Hockwin, O., and Dardenne, U.: Der einfluss von pilocarpin und mintacol auf den stoffwechsel der linse. Ber. Deutsch. Ophth. Gessell. 60:115, 1956.

7. Kinoshita, J. H., and Michon, J.: Personal communication from Howe Laboratory Ophth., Boston, 1966.