History of Glaucoma

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Sruti Rachapudi MD MBA, Yumin Kim

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The perception of glaucoma has changed significantly from antiquity to modern day, including approaches to management. In ancient Greece, the term "glaukos" described both healthy light-colored irises and diseased, cloudy eyes. During the Hippocratic era, a pathological glaukos pupil referred to a cloudy appearance, likely due to media opacity, which may align with the greenish hue seen in acute angle-closure glaucoma. Galen associated this discoloration with an enlarged, anteriorly displaced, or hardened crystalline lens, often linked to severe eye disease and poor visual outcomes. Medieval Arabic scholars translated "glaukos" to "zarqaa," describing light-colored irises but also associating the hue with advanced eye diseases. Though the full syndrome of acute angle closure was not defined, the glaucous pupil was well-understood to be a poor prognosis of significant vision loss. These ancient insights into eye disease prefigured the later understanding of glaucoma, which has since progressed through centuries of innovation to modern treatments like IOP-lowering drops, tube shunt surgeries, and minimally invasive glaucoma surgeries (MIGS).

Introduction

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Previous Glaucoma Understandings

Ancient Societies

It is important to recognize that the definition of glaucoma has changed over time as medical knowledge of the disease has advanced. In ancient times, the understanding of glaucoma was severely limited by technology and was largely determined by the gross appearance of the eye.

In ancient Greek, glaukos likely referred to the color green, and when applied to the eye referred to the pupillary hue. As early as the Hippocratic era, the color of the eye was observed to hold significance in predicting the prognosis of certain conditions. Hippocrates described glaukosis as a condition primarily affecting the elderly, noting that once the pupils became glaukoumenai (bluish-green, argyreodiees (silvery), or kyaneai (blue), the eye would be rendered ineffective. Glaukosis likely encompassed several different conditions, including cataracts, keratitis, and glaucoma. When ancient descriptions matched what we now recognize as glaucoma, they were most likely referring to acute angle-closure glaucoma, which, given its severe symptoms and rapid, irreversible blindness, would have drawn significant interest from medical writers of the time.

Glaucoma was also mentioned in classical Ayurvedic texts of Ancient India. Renowned Indian surgeon Sushruta (800-700 BC) wrote the Sushruta Samhita, which was one of the earliest comprehensive texts on medicine and surgery. In it, he describes multiple types of Adhimantha, which correspond to what we know today as acute angle-closure glaucoma. These conditions are characterized by severe, excruciating pain in the eye, noticeable inflammation, and rapid vision loss within 3-7 days.

Medieval ages/ Early Modern Era/ Renaissance

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19th Century

In the early eighteenth century, Michel Brisseau would define glaucoma and cataracts as two different diseases by noting that glaucoma happened deeper in the eye. However, until Hermann von Helmholtz discovered the ophthalmoscope in 1851, there would still be many misunderstandings surrounding what glaucoma was. For example, Jules Sichel, a Jewish ophthalmologist who had received their medical degree in France in 1833, insisted that glaucoma was a choroidal disease, ignoring the optic nerve during his studies of glaucoma, and was unable to realize the connection with increased intraocular pressure. Without the ophthalmoscope and slit lamp, the only ways to examine the eyes were with loupes and moderate lighting, setting limitations on what physicians could perceive.

After the introduction of the ophthalmoscope in 1851, a German ophthalmologist named Albrecht von Graefe would begin writing his notes about glaucoma. von Graefe had completed medical school by the age of 19 and had studied under leading ophthalmologists from Prague, Paris, Vienna, London, and Glasgow between 1848 to 1850 and the summer of 1851. In 1854, he founded the second ophthalmology journal “Archiv für Ophthalmologie” (which exists today as Graefe’s Archive for Clinical and Experimental Ophthalmology), and he would eventually be known as the “The father of modern ophthalmology and glaucoma”.

von Graefe’s classification of glaucoma in the first issue of Archiv für Ophthalmologie in 1854 would still be very different from modern classification due to the lack of optical coherence tomography and other imaging techniques. He hypothesized that chronic glaucoma was caused by an increase in IOP while glaucomatous amaurosis, blindness in the eye, was caused by an external pull at the optic trunk.

von Graefe’s main contribution was in 1857, when he showed in the first International Congress of Ophthalmology how iridectomy, the surgical removal of a small piece of the iris, could be used as treatment for glaucoma.

In 1861, Dutch ophthalmologist Frans Donders and his PhD student Jozef Haffmans would conduct studies and eventually introduce the concept of glaucoma simplex, which is known as primary open-angle glaucoma today.

Before the invention of tonometers, measurements of IOP were made with fingers on the upper eyelids. In 1862, von Graefe made one of the first tonometers to measure IOP. Due to the lack of ophthalmic anesthesia, these tonometers were placed on the eyelid rather than the eye. In addition, these designs were deemed unsuitable. Donders would also independently think of designs for a tonometer, but it wasn’t until Hjalmar Schiotz would invent a tonometer in 1905 that it would be used consistently.

Modern Day Glaucoma

Medical Management, Traditional Surgical Approaches, Minimally Invasive Glaucoma Surgery (MIGS)

Medical Management

Glaucoma pharmacology is thought to have begun nearly 150 years ago. In 1830, William Mackenzie suggested the use of daily belladonna drops to treat glaucoma. However, the drugs that are routinely used to control IOP today have mostly been discovered in the last 50 years.

While in 1622, English ophthalmologist Richard Bannister would link glaucoma to IOP, it would take until 1862 for the concept of reducing IOP to take hold, when Sir Thomas Fraser introduced the first IOP-lowering medication, which was the calabar bean. Calabar bean was the original source of physostigmine (eserine), a potent mitotic. Its ability to lower IOP was not fully appreciated until 1876, when it was officially reported. Pilocarpine, the second mitotic, would be introduced soon after by Adolf Weber, a student of Albrecht von Graefe.

Adrenergic agonists, the second class of IOP-lowering drugs, would be first introduced in 1901, along with epinephrine. Their IOP-lowering effect of adrenergic agonists was discovered by Frenchman Jean Darier when he studied the adrenal extracts for other purposes. He described their use as the first adjunctive medication in glaucoma (along with pilocarpine and epinephrine). Epinephrine was not commercially available to treat glaucoma until the 1950s, but its approval was soon followed by clonidine. In 1987, the FDA approved a 1% solution of apraclonidine, an more selective α2-adrenergic agonist that could be used to prevent IOP spikes after anterior segment laser procedures. In 1993, a 0.5% solution was approved for short term management of chronic glaucoma. However, it could not be used for long term due to the gradual loss of efficacy.

Carbonic anhydrase inhibitors would appear in the late 1930s and early 1940s. Acetazolamide first emerged in the early 1950s when Bernard Becker demonstrated its potent IOP-lowering effect in 1954. However, carbonic anhydrase inhibitors were associated with unpleasant and unsafe side effects, and they were also ineffective as topical agents, leading many researchers in the 1970s to believe they could not be developed further and abandoning them. Only Thomas Marin persisted, who synthesized over 1500 molecules in a collaboration between the University of Florida and Merck Research Laboratories. This eventually led to the discovery of MK-507, which would later be known as dorzolamide (Trusopt) and approved by the FDA in 1995. Soon after Trusopt was released, Alcon laboratories developed a second topical carbonic anhydrase known as brinzolamide (Azopt), and both agents are used in glaucoma medications today.

The first beta blocker to be introduced was propranolol in 1967. While propranolol was found to decrease IOP after IV administration, the drug could not be used as a topical agent due to its corneal anesthetic properties and negative effects on tear production. Other candidate beta blockers faced similar difficulties, with many leading to profound dry eyes syndrome, subconjunctival fibrosis, and tachyphylaxis. In 1976, Merck companies demonstrated that timolol (Timoptic) could lower IOP, and it gained FDA approval 2 years later. Timolol, levobunolol, metipranolol, and carteolol would eventually become the optimal first-line therapy for patients with glaucoma for 20 years. In addition, for patients with pulmonary disease, the cardioselective beta blocker betaxolol was also used, though it was generally thought of as less effective in lowering IOP compared with non-selective beta blockers.

Prostaglandin analogs are now the main-first line therapy due to how they are safe to use and most effective in treating glaucoma. They were first discovered incidentally when Hungarian physiologist Lazlo Bito was researching the mediators of ocular inflammation. In 1982, at Columbia University, he developed the prototype molecule latanoprost, and he and Carl Camras demonstrated that the prostaglandin PGF2ɑ lowered IOP in both healthy and glaucomatous monkeys. In 1996, Columbia and Swedish drug-making company Pharmacia introduced Xalatan, which later was approved by the FDA. Five years after the debut of latanoprost, the FDA approved a pair of prostaglandin analogs known as travoprost (Travatan by Alcon), and bimatoprost (Lumigan by Allergan). Tafluprost (Zioptan by Merck) was also approved soon after.

Traditional Surgical Approaches

In the early nineteenth century, glaucoma was still being treated through purgatives, blood-letting, leeches, setons, couching, and paracentesis. However, in 1856, German ophthalmologist Albrecht von Graefe discovered that iridectomies could treat glaucoma.. In the next few years, this procedure would be modified with the intention of making them safer.

From the early to mid 1900s, glaucoma surgeries evolved to consist of the creation of a full-thickness fistula to increase aqueous outflow. While these procedures temporarily treated the symptoms of glaucoma, they eventually resulted in uncontrolled scarring and even serious vision-threatening complications such as hypotony, flat anterior chamber, cataract formation, and infection. These complications were mainly due to how the aqueous outflow was uncontrolled, and though over time, incision sizes grew smaller, the flow through the fistula would not be limited until the introduction of trabeculectomies.

Trabeculectomies, which consisted of the surgical removal of the trabecular meshwork and adjacent structures to relieve intraocular pressure, was first suggested by H. Saul Sugar in 1961, but the procedure was popularized by John Cairns in 1968. Cairns believed that the site of greatest resistance to outflow was at the trabecular meshwork and the inner wall of Schlemm’s canal and that by removing a piece of trabecular meshwork and Schlemm’s canal, one could create an unobstructed pathway for aqueous fluid to leave from.

While the procedure did lower IOP, the aqueous outflow primarily went around the flap edges rather than through Schlemm’s canal. Modern day trabeculectomies employ similar techniques as Cairn’s operations, but the procedure has been modified so that less trabecular meshwork is removed and so that it focuses more on the creation of a scleral flap that could regulate the flow of aqueous. The use of antifibrotics in modern day trabeculectomies have helped modulate the wound-healing process and present scarring of the outflow pathways.

After trabeculectomies, attempts were made to create drainage fistulas through the use of implanted materials. The earliest report of a tube shunt surgery was in 1876, when Louis de Wecker, a French ophthalmologist, placed a gold wire implant after a failed iridectomy. However, the modern tub shunt was introduced by Anthony Molteno in 1969. The shunt was a long silicone tube with a place of 9 to 10 mm in diameter and was meant to be placed posterior to the limbus and between the rectus muscles of the eye. Molteno’s tube shunt did have unrestricted flow, resulting in hypotony, flat anterior chambers, and choroidal effusions.

Further modifications were made in 1976 after Theodore Krupin and his colleagues introduced the flow restricting valve, which was unidirectional and would only open between an IOP of 9 to 11 mm Hg. In 1993, Mateen Ahmed designed another pressure-sensitive device. These valves had more predictable and controlled outflow after surgery. In the following years, more modifications would be made for better pressure control.

Minimally Invasive Glaucoma Surgery (MIGS)

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Future Direction

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Conclusion

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