There are 20 million blind from cataracts in developing countries, and this number doubles every 20 years. There are insufficient ophthalmic surgeons and funds to solve this problem with the standard techniques of intracapsular or extracapsular cataract extraction.

In 1992, one of us (LJG) suggested that the problem could be solved by the use of zonulolytic enzymes such as alphachymotrypsin (ACT) to produce displacement (not extraction) of the cataractous lens and the use of inexpensive, mass-produced spectacles (see Ocular Surgery News, February 1, 1993).

He proved his idea was possible by injecting 20 consecutive eye-bank eyes with ACT 1:5000. Displacement of the lens took place in all 20 eyes within 1.5 hours. He then performed injection of ACT (1:5000) intracamerally into the blind, glaucomatous eye of a volunteer patient, and displacement took approximately 1.5 hours. There was a temporary elevation of intraocular pressure (IOP) in the eye, which was controlled with medication. The patient has been followed for 7 years without any complications observed.

Research studies

Injection of alphachymotrypsin 1:5000 into the retrolental space via the pars plana.	Beginning of displacement of cataract after injection of alphachymotrypsin 1:5000.
Displacement of cataract below the visual axis into the canal of Petit anterior to the anterior vitreous hyaloid.	Fundus photograph taken immediately after lens displacement showing unsuspected advanced glaucomatous optic nerve cupping and pallor.

Research studies were begun at Baylor College of Medicine in Houston and the University of Texas Medical Branch at Galveston to determine the best zonulolytic agent; the best dosage; the best site of injection, either in the anterior chamber or through the pars plana into the retrolental space; whether the agent could be made to pass through the cornea and produce zonulolysis; and methods for prevention of any complications.

The results of these studies can be summarized as follows: ACT, collagenase, brinolase, papain, ficin, bromelain and dithiothretiol have been investigated, and all of these will produce zonulolysis and displacement of the lens in eye-bank eyes. However, some of these agents produce toxic effects in animal eyes.

Additionally, cathepsin G, collagenase and L-homocysteine have been tested and did not produce zonulolysis in eye-bank eyes. Efforts to make ACT and other zonulolytic proteases penetrate through the cornea have thus far been unsuccessful because of the size of the molecule (25 to 28 kDa).

Enzymatic displacement of the lens is possible in primates if the ACT is given in sufficient concentration. However, treatment to prevent a temporary or a prolonged rise in IOP is necessary, as previously demonstrated by others. Research is ongoing.

This report describes the preliminary results of a small human pilot study using ACT that was conducted in one developing country.

Materials and methods

The location of the canal of Petit.

Twenty-seven patients, aged 65 to 80 years, who were bilaterally blind from mature cataracts, were selected for the study from a group of approximately 255 patients examined for serious ocular conditions. Vision ranged from finger counting at 1 foot to light perception and light projection. External examination was performed with loupe and flashlight. Patients with corneal pathology and those whose pupils did not react to light were eliminated. Tensions were estimated by manual palpation.

Patients signed an informed consent agreement for the procedure. They were dilated preoperatively in one eye with tropicamide 1% and phenylephrine hydrochloride 2.5% and received an intramuscular injection of ketorolac tromethamine. In the operating room, patients were skin-prepped with povidone iodide 10% and 5% instilled into the conjunctival sac. Anesthesia consisted of one drop of tetracaine.

Under aseptic conditions and using a Welsh portable operating microscope, 0.25 mL of aqueous was aspirated and 0.25 mL of ACT in two different concentrations (1:5000 or 1:2500) was injected, either into the anterior chamber or into the retrolental space via the pars plana. Tobramycin drops were instilled and given to the patient to use postoperatively four times a day.

Patients were observed the same day as well as the following 2 days, examined with loupe, flashlight, direct and indirect ophthalmoscope. Pressures were taken by portable applanation tonometry. Eyes were photographed with a portable fundus camera. Patients whose lens displaced were given cataract spectacles (+10 D or +12 D spherical equivalents) donated by the Lions Club of Houston. Vision was estimated with the illiterate E test. There were no facilities for refracting the patients. Vision was considered good if it was 20/200 or better and poor if it was less than 20/200.

Operated eyes had aspiration of 0.25 mL of aqueous and received 0.25 mL of ACT as follows: group 1 received ACT 1:5000 via the pars plana; group 2 received ACT 1:2500 via the pars plana; group 3 received 1 plus 2 on successive days; group 4 received intracameral ACT 1:2500 plus indomethacin 7.5% and hydrocortisone sodium succinate 8 minim in l5 mL of balanced salt solution.

Results

The patients were examined each of the 3 days following injection(s) and subsequently every 6 to 8 weeks during the next 2 years. The results were as follows:

Group 1 — Pars plana injection of ACT 1:5000 resulted in displacement of the cataractous lens in two of 15 eyes, partial displacement in two of 15 and no displacement in 11 of 15. Good vision was found in the two eyes that displaced. Elevated IOP was found in the injected eye in 10 of 15, which was transient in two and prolonged in eight eyes. On further testing four of the eight patients were found to have glaucoma in both eyes. Glaucoma was diagnosed by examining the optic nerve after cataract displacement and by tonometry. There were no other complications.

Group 2 — Pars plana ACT 1:2500 resulted in displacement of the cataract in four of eight eyes, partial displacement in one of eight eyes and no displacement in three of eight eyes. Vision was good in the four eyes that displaced. Elevated IOP was found in five of eight eyes, transient in two and prolonged in three eyes. All of the latter were found to be in patients with glaucoma in both eyes. There were no other complications.

Group 3 — Pars plana ACT 1:5000 followed by pars plana ACT 1:2500 in those eyes that did not displace with the first injection resulted in displacement of the cataract in seven of 13 eyes and no displacement in six of 13. Vision was good in three of the seven eyes that displaced. Four eyes had poor vision, one from age-related macular degeneration (AMD) and three from glaucoma. Transient elevation in IOP was found in one eye and was prolonged in four eyes, two of which were found to have glaucoma in both eyes. There was one complication; a lens that had displaced 9 months previously entered the anterior chamber causing acute glaucoma and was removed intracapsularly.

Group 4 — Anterior chamber injection of ACT 1:2500 with indomethacin 7.5% and hydrocortisone sodium succinate 8 minim in 15 mL of saline was performed in one eye of four patients. Cataract displacement resulted in three of four eyes, partial displacement in one of four. Vision was good in the three eyes with the cataract displacement. Elevated IOP was prolonged in one of four eyes. In these eyes there was no pre-existing glaucoma.

Group 5 — Intracameral ACT 1:2500 was repeated in 10 eyes that had failed to displace with pars plana ACT 1:5000 and pars plana ACT 1:2500. The cataractous lenses displaced in six of 10 eyes; vision was good in four of six eyes that displaced. There was transient elevation of IOP in three of 10 eyes that were injected, three of 10 had prolonged IOP elevation, and of these, two of 10 were found to have glaucoma in both eyes. Three eyes showed a moderate anterior uveitis that responded to local steroid treatment.

Summary of results

In all eyes injected, 22 of 27 (82%) showed cataract displacement with from one to three injections of ACT 1:5000 or l:2500. Vision in the eyes with displaced cataracts was good in 16 of 22 eyes (73%) and was poor in six of 22 (27%). Reasons for poor vision were: advanced unsuspected glaucoma in four eyes, AMD in one eye and dislocation of a lens into the anterior chamber from rupture of the anterior vitreous hyaloid in one eye.

Of the 27 patients treated, l6 (59%) developed a transient (4) or prolonged (12) elevation in IOP requiring treatment, and 11 patients (41%) showed no glaucoma or postop rise in IOP. On subsequent examination of the 12 eyes showing a prolonged rise, seven (58%) were found to have glaucoma in both eyes. In all, seven of 27 (26%) of the patients had glaucoma in both eyes.

Glaucoma was found to be surprisingly common in the population examined and treated. Of 255 patients examined for various complaints, 63% were found to have evidence of glaucoma (elevated pressures and glaucomatous changes in the optic nerve). This is the subject of a separate investigation. Nevertheless, elevated IOP after injection of ACT is a problem.

Three eyes showed moderate uveitis following intracameral ACT l:2500, which responded to local steroid treatment.

Discussion

An estimated 20 million people are blind from cataract in developing countries, and the number doubles every 20 years. Counting caretakers, this accounts for 40 million people taken out of the work force. Using techniques of intra- or extracapsular cataract extraction, it would require 20 million hours of ophthalmic surgeons’ time for a brief examination, operation and one postop examination. There aren’t enough ophthalmic surgical hours available for this enormous number using standard cataract techniques (table).

Couching, or surgical displacement of the lens, was invented by the Babylonians circa 1750 B.C. Later adopted by the Greeks, Egyptians, Romans, Europeans and Africans, this technique continued to be the operation of choice in the world into the 1800s.

Jacque Davielle invented the extracapsular cataract extraction in 1754 but it took almost 100 years before this procedure was accepted. In the original couching operation, the instrument for couching was a “curved barley thorn-tipped needle” — a curved needle the tip of which was made of brass and shaped like a barley thorn tapering to a point.

The needle was either inserted at the limbus into the anterior chamber and the lens pushed back into the vitreous or it was inserted through the pars plana and the lens displaced inferiorly. If the lens was completely displaced without rupturing the lens capsule, the lens would lie in the vitreous in the inferior pole and the patient would be able to see large objects. Later, when spectacles were invented, the patient’s vision could be restored completely.

This operation continues to be used by “village couchers” or traditional practitioners in India, Nepal, Africa and China, who have learned the technique from their ancestors.

Rupture of capsule

Unfortunately, couching by instrumentation often produces rupture of the lens capsule and always the anterior hyaloid of the vitreous. Many patients develop endophthalmitis, uveitis, glaucoma and other complications. Brandt and colleagues examined 100 eyes that had undergone couching by village couchers 1 to 10 years previously. At the time of the examination, 42 eyes were found to be blind from complications of ruptured capsules or endophthalmitis. The amazing finding was that 58% of the eyes had vision preserved for the first year, and subsequent loss of vision was less than 10% per year.

Belyaev and Barachkov reported on 68 eyes they had surgically couched under aseptic conditions and followed for 5.5 years. Vision of 20/20 to 20/40 was obtained in 56 of 68 eyes (82.4%). In 26 eyes without other pathology, vision was 20/20. They had three complications: one ruptured capsule requiring extraction and two vitreous prolapses into the anterior chamber, producing glaucoma that required vitrectomy. These phenomenal results show the potential importance of displacement of the cataractous lens as a large-scale treatment for cataract blindness.

When the entire lens, including the intact capsule, is displaced into the vitreous, it is tolerated well and will not cause inflammation or glaucoma. These complications occur only when the lens capsule is ruptured and the lens contents are liberated into the eye. Chandler collected cases of dislocated lenses that had been observed for as long as 50 years without complications. Many ophthalmologists have observed subluxated (ectopic) lenses tolerated by the eye without inflammation for a lifetime. The senior author has observed traumatically dislocated lenses with intact capsules tolerated without inflammation or glaucoma for 16 years.

Traumatically displaced lenses with intact capsules where the vitreous hyaloid is ruptured and the vitreous is liquefied will float into the visual axis if the patient lies on his or her back looking at the ceiling or puts his or her head forward looking at the floor. The cataractous lenses that have been displaced by enzymatic zonulolysis have sunk into the anterior quadrant of the globe between the intact anterior hyaloid of the vitreous and the pars ciliaris (the canal of Petit) (Figure 6). Zonulolytically displaced lenses have shown no tendency to move about within the globe with change in position. In only one eye, with a ruptured vitreous hyaloid, the lens displaced into the anterior chamber and acute glaucoma developed requiring intracapsular removal.

Transient IOP rise

A transient rise in IOP after irrigation with ACT during intracapsular extraction has been reported, extensively investigated and reviewed. Sears and Sears postulated that the transient rise in pressure after irrigation of rabbit eyes with ACT was due to blockage of the angle meshwork by zonular filaments. This was confirmed by Chee and Hamasaki in 1971, Worthen in 1972 and Anderson in 1971.

Sears and Sears showed that in rabbits the transient rise lasted for approximately 1 week. However, a prolonged rise lasting 1 year, thought to be due to a disruption of the blood-aqueous barrier, could be prevented by the preoperative administration of indomethacin.

In our study, 16 of 27 eyes (59%) injected with ACT developed a transient or prolonged increase in IOP requiring treatment in spite of pretreatment with intramuscular ketorolac tromethamine and local beta-blockers. ACT may not be the best zonulolytic enzyme. Other zonulolytic agents and drugs to control IOP are being studied.

In this study, 27 eyes of 27 patients were injected into the retrolental space or intracamerally with ACT 1:5000 or 1:2500. Pars plana injection seemed to be the logical site since the flow of aqueous is toward the anterior chamber and would give maximum exposure to the zonules by the enzyme. However, both routes can be effective, and more experience is needed to determine the best site of injection. Interestingly, no retinal or vitreous complications resulted from the retrolental injection of ACT in this series.

The authors have no good explanation for not obtaining displacement of the cataractous lens with every injection. In eye-bank eyes, 20 of 20 eyes (100%) showed displacement of the lens from the intracameral injection of ACT 1:5000 0.25 mL. Of course, in these eyes, there was no aqueous outflow, and the enzyme was given a prolonged opportunity to produce zonulolysis. Perhaps in living eyes, larger amounts of the enzyme would be more effective.

Unfortunately, no good animal model has been found. Dogs, cats and rabbits have lenses that are approximately 50% of the volume of the globe and do not displace readily. Primates, while having lens size and lens:globe ratio approximating that of humans, demonstrate severe reactions (vitritis, glaucoma and uveitis) to ACT in doses sufficient to produce displacement of the lens (Girard LJ, unpublished results).

Long-term complications

What is the long-term probability of complications from a displaced lens? Interestingly, the enzymatic displacement of the lens does not cause rupture of the anterior vitreous hyaloid. In the patients studied, the lens dislocates inferiorly between the anterior hyaloid and the pars ciliaris into an area called the canal of Petit. The dense vitreous base attachments to the pars plana prevent further displacement.

The technique of anterior chamber aspiration and injection could be taught to nonmedical personnel. However, if the enzyme, applied locally, could be made to pass through the cornea in sufficient strength to produce zonulolysis, this would allow health workers to go to the villages, diagnose patients who are blind from cataract using a pencil flashlight (clear cornea, reactive pupil and white cataract), treat them with the zonulolytic agent and give them a pair of mass-produced, inexpensive cataract spectacles. Motivating blind patients to leave their villages to be treated in major centers or in cataract camps has been a serious problem in developing countries.

The implications of this type of treatment are overwhelming: 40 million people (the blind and their caretakers) returned to the economic work force.

The authors hope that other investigators will accept the challenge to prove or disprove this concept.

For Your Information:

Louis J. Girard, MD, FACS, is former professor and chairman of the department of ophthalmology of Baylor College of Medicine. He can be reached at 20126 Indigo Lake Drive, Magnolia, TX 77355; (281) 356-9076; fax: (281) 356-8269; e-mail: Manalay@worldnet.att.net.

Tom Ghuman, MD, focuses on retina/vitreous in his practice in Morgantown, W. Va.

Jeffrey D. Lanier, MD, FACS, is a clinical professor of ophthalmology in the department of ophthalmology of the University of Texas Medical School in Houston.

Neil B. Griffin, MD, practices in Southern Pines, N.C.

Jorge Rodriguez, MD, MPH, is president of Surgical Eye Expeditions International in Santa Barbara, Calif.

Kenley Donaldson, MD, practices in Casa Grande, Ariz.

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