History of Glaucoma
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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 Arab 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).
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.[1] 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.[1] 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.[2]
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.[3] These conditions are characterized by severe, excruciating pain in the eye, noticeable inflammation, and rapid vision loss within 3-7 days.
Medieval developments
In the 8th century AD, Arab authors began translating the works of Greek physicians like Hippocrates into Arabic.[1] Husain Ibn Ishaq was one such author, compiling translated Greek texts into a work entitled Book of the Ten Treatises of the Eye. In his works and those from other Arab authors, glaukos was translated to the word zarqaa and was used to refer to light-colored irises. This included both pathological eye conditions and normal eyes of a lighter hue. Much like the Greeks, they noted the greenish pupillary hue seen accompanying blindness and made the correlation.
Arab physicians wrote about zarqaa being due to an anterior lens pathology.[4] The hardening of the eye was thought to be due to the intraocular humor thickening or coagulation, leading to the lenses being more difficult to displace. Abu Ali al-Husain Ibn Sina, also known as Avicenna, described eyes with Zarqaa and lenses that were immobile due to eye hardening.[4] He and other authors diagnosed eye hardness through palpation, diagnosing pathological issues when the lens could not be moved around in the eye.
Beyond the color of the eye, in the 10th century Arab authors also described the deep eye pain with a pressure-like or burning character. Muhammad ibn Ibrahim Ibn al-Akfani described the condition as sida al-hadaqah, which translates to “headache of the pupil”, was associated with ocular fluid opacification.[4]
European authors translated works discussing zarqaa into Latin. In those texts, they described the green hue of the pupil and associated it with a thickening of the anterior lens of the eye. They used the term “viriditas” to describe the condition and did not have a method of curing it. Medieval European authors, like Avicenna, attributed the condition to a thickening of the lens leading to a hard eye.[4]
In the Renaissance, anatomical dissections led to the creation of more comprehensive diagrams of the eye. This informed treatment and led to the discovery that the whole eye was hard in cases of viriditas rather than just the lens. An English Oculist named Richard Banister was one of the first people to describe hardening of the eye in eyes without the glaukos appearance. He described his findings in a book in 1622. He referred to the condition as gutta serena, aka “black cataract”, noting that the hardened eye had a lens that was not opaque like a normal cataract.[4] He concluded that the accompanying blindness was due to a “stopping of the Nerve Optics” rather than opaqueness of the lens as seen in cataracts. This was one of the first times a physician had connected the increased hardness of eyes seen in glaucoma with optic nerve damage.
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.[5] 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.[5] 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.[5][6] 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.[5][6] 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”.[6]
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.[5]
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. [5][6]
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.[5]
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.[5][6]
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.[5] However, the drugs that are routinely used to control IOP today have mostly been discovered in the last 50 years.[7]
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.[7] 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.[7][8]
Adrenergic agonists, the second class of IOP-lowering drugs, would be first introduced in 1901, along with epinephrine.[7] 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).[7] 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.[7] 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.[7]
Carbonic anhydrase inhibitors would appear in the late 1930s and early 1940s.[7] 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.[7] 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.[7] 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.[7]
The first beta blocker to be introduced was propranolol in 1967.[7] 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.[7] Timolol, levobunolol, metipranolol, and carteolol would eventually become the optimal first-line therapy for patients with glaucoma for 20 years.[7] 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. [7]
Prostaglandin analogs are now the main-first line therapy due to how they are safe to use and most effective in treating glaucoma.[7] 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.[7] 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.[7]
Traditional Surgical Approaches
In the early nineteenth century, glaucoma was still being treated through purgatives, blood-letting, leeches, setons, couching, and paracentesis.[5] However, in 1856, German ophthalmologist Albrecht von Graefe discovered that iridectomies could treat glaucoma.[5][6]. 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[9]. 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.[9]
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.[9] 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.[9]
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.[9] The use of antifibrotics in modern day trabeculectomies have helped modulate the wound-healing process and present scarring of the outflow pathways.[9]
After trabeculectomies, attempts were made to create drainage fistulas through the use of implanted materials. On May 5, 1876, Louis de Wecker, a French ophthalmologist, performed an iridectomy in one eye, and placed a gold wire implant in the other eye, of a 45-year-old woman with bilateral "absolute glaucoma" (probably untreated angle-closure glaucoma).[9][10] In 1925, Jon Stefansson (d. 1936) of Winnipeg reported his coiled gold wire implants in 32 eyes of 25 patients with glaucoma, conducted between 1916 and 1920.[11] However, the modern tube shunt was introduced by Anthony Molteno in 1969.[9] 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.[9] In 1993, Mateen Ahmed designed another pressure-sensitive device. These valves had more predictable and controlled outflow after surgery.[9] In the following years, more modifications would be made for better pressure control.[9]
Minimally Invasive Glaucoma Surgery (MIGS)
As compared to traditional surgical approaches that consisted of creating new pathways, micro-invasive glaucoma surgery, commonly known as MIGS, focused on improving or modifying existing, natural outflow pathways through the use of micro-incisions and implants.[9]
One of these implants was known as the iStent, an FDA-approved trabecular bypass invented in 2012 that could treat mild-to-moderate open-angle glaucoma.[9] The device was deployed into the Schlemm’s canal to create an artificial fistula between the anterior chamber and Schlemm’s canal. The CyPass Micro-Stent, approved in 2016, provided supraciliary outflow access but was withdrawn in 2018 due to concerns about endothelial cell loss.[12] The Hydrus Microstent, approved by the FDA in 2018, offered a longer stent designed to scaffold Schlemm’s canal and enhance outflow.[12] The XEN Gel Stent, approved in 2016, created an ab interno path to the subconjunctival space, blending MIGS techniques with the bleb-based approach of traditional filtering surgeries. Each of these devices represented a step toward more targeted, less invasive glaucoma management strategies, expanding treatment options across the disease spectrum.[12] Dr. Ike Ahmed played a pivotal role in refining MIGS techniques and coining the MIGS term, emphasizing the importance of targeted stent placement and the potential benefits of implanting multiple devices to enhance efficacy.
Future Directions
With the rise of molecular genetics and gene therapy, there are numerous new treatments for glaucoma in development that could change the lives of millions with the disease. One such development is the use of stem cell therapies to repair the optic nerve. In animal models, studies have shown that bone-marrow derived mesenchymal stem cells offer protective effects on retinal ganglion cells and may help with regeneration of the optic nerve in cases of glaucoma.[13] However, these results could not be replicated in human trials, where patients did not have any improvement in vision with the treatment.[14] Future work will need to be done in this area to determine how stem cell technology can be effectively leveraged to improve vision
Another focus of Glaucoma research has been the use of gene therapies to modify expression of genes that play a role in the glaucoma pathogenesis. Studies have utilized genetic technologies like CRISPR-Cas9 to modify gene expression in such a way as to stop glaucoma damage in animal models.[13] However, like stem cell research, further research must be done to fully ascertain the effectiveness of these strategies in humans.
References
- ↑ 1.0 1.1 1.2 Leffler CT, Hadi T, Salman A, Vasuki V, Schwartz S. The early history of glaucoma: the glaucous eye (800 BC to 1050 AD). Clin Ophthalmol. Published online February 2015:207. doi:10.2147/OPTH.S77471
- ↑ Tsatsos M, Broadway D. Controversies in the history of glaucoma: is it all a load of old Greek? Br J Ophthalmol. 2007;91(11):1561-1562. doi:10.1136/bjo.2007.114298
- ↑ Bhishagratna KL, ed. Sushruta Samhita: An English Translation of the Original
- ↑ 4.0 4.1 4.2 4.3 4.4 Leffler CT, Schwartz SG, Giliberti FM, Young MT, Bermudez D. What was Glaucoma Called Before the 20th Century?. Ophthalmol Eye Dis. 2015;7:21-33. Published 2015 Oct 8. doi:10.4137/OED.S32004
- ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 De Jong, Paulus T. V. M. “An Eternal Hunt for Glaucoma.” Graefe’s Archive for Clinical and Experimental Ophthalmology, vol. 262, no. 7, July 2024, pp. 1955–75. DOI.org (Crossref), https://doi.org/10.1007/s00417-024-06441-w.
- ↑ 6.0 6.1 6.2 6.3 6.4 6.5 Ivanišević, Milan, et al. “Albrecht von Graefe (1828–1870) and His Contributions to the Development of Ophthalmology.” International Ophthalmology, vol. 40, no. 4, Apr. 2020, pp. 1029–33. DOI.org (Crossref), https://doi.org/10.1007/s10792-019-01253-y.
- ↑ 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 7.11 7.12 7.13 7.14 7.15 7.16 7.17 Realini, Tony. “A History of Glaucoma Pharmacology.” Optometry and Vision Science, vol. 88, no. 1, Jan. 2011, pp. 36–38. DOI.org (Crossref), https://doi.org/10.1097/OPX.0b013e3182058ead.
- ↑ Packer, Mark, and James D. Brandt. “Ophthalmology’s Botanical Heritage.” Survey of Ophthalmology, vol. 36, no. 5, Mar. 1992, pp. 357–65. DOI.org (Crossref), https://doi.org/10.1016/0039-6257(92)90113-8.
- ↑ 9.00 9.01 9.02 9.03 9.04 9.05 9.06 9.07 9.08 9.09 9.10 9.11 9.12 Kahook, Malik. Migs: Advances in Glaucoma Surgery. 1st ed., CRC Press, 2024. DOI.org (Crossref), https://doi.org/10.1201/9781003525080.
- ↑ Ribard F. Du drainage de l’œil dans différentes affections de l’œil et particulièrement dans le décollement de la rétine. Paris: Parent, 1876. 22-24.
- ↑ Leffler CT, Bansal S. Angle-closure glaucoma since 1871. The History of Glaucoma. Amsterdam: Wayenborgh (an imprint of KKugler). 2020: 309-368.
- ↑ 12.0 12.1 12.2 https://theophthalmologist.com/issues/2017/articles/aug/a-brief-history-of-migs
- ↑ 13.0 13.1 Wang LH, Huang CH, Lin IC. Advances in Neuroprotection in Glaucoma: Pharmacological Strategies and Emerging Technologies. Pharmaceuticals (Basel). 2024;17(10):1261. Published 2024 Sep 25. doi:10.3390/ph17101261
- ↑ Vilela CAP, Messias A, Calado RT, et al. Retinal function after intravitreal injection of autologous bone marrow-derived mesenchymal stromal cells in advanced glaucoma. Doc Ophthalmol. 2021;143(1):33-38. doi:10.1007/s10633-021-09817-z
