Glaucoma

Human eye cross-sectional view. Courtesy NIH National Eye Institute

Glaucoma is a group of diseases of the optic nerve involving loss of retinal ganglion cells in a characteristic pattern of optic neuropathy. Although raised intraocular pressure is a significant risk factor for developing glaucoma, there is no set threshold for intraocular pressure that causes glaucoma. One person may develop nerve damage at a relatively low pressure, while another person may have high eye pressure for years and yet never develop damage. Untreated glaucoma leads to permanent damage of the optic nerve and resultant visual field loss, which can progress to blindness.

Glaucoma has been nicknamed the "sneaky thief of sight" because the loss of visual field often occurs gradually over a long time and may only be recognized when it is already quite advanced. Once lost, this damaged visual field can never be recovered. Worldwide, it is the second leading cause of blindness.^[1] Glaucoma affects one in two hundred people aged fifty and younger, and one in ten over the age of eighty.

Pathophysiology

The major risk factor for most glaucomas and focus of modeling and treatment is increased intraocular pressure. Intraocular pressure is a function of production of liquid aqueous humor by the ciliary body of the eye and its drainage through the trabecular meshwork. Aqueous humor flows from the ciliary bodies into the posterior chamber, bounded posteriorly by the lens and the zonule of Zinn and anteriorly by the iris. It then flows through the pupil of the iris into the anterior chamber, bounded posteriorly by the iris and anteriorly by the cornea. From here the trabecular meshwork drains aqueous humor via Schlemm's canal into scleral plexuses and general blood circulation. ^[2] In open angle glaucoma there is reduced flow through the trabecular meshwork^[3]; in angle closure glaucoma, the iris is pushed forward against the trabecular meshwork, blocking fluid from escaping.

The inconsistent relationship of glaucomatous optic neuropathy with ocular hypertension has provoked hypotheses and studies on anatomic structure, eye development, nerve compression trauma, optic nerve blood flow, excitatory neurotransmitter, trophic factor, retinal ganglion cell/axon degeneration, glial support cell, immune, and aging mechanisms of neuron loss.^{[4] [5] [6] [7] [8] [9][10] [11] [12] [13][14]}

The major types of glaucoma are discussed below.

Risk factors

A normal range of vision. Courtesy NIH National Eye Institute

The same view with advanced vision loss from glaucoma.

Ocular hypertension is the largest risk factor in most glaucomas, though, in some populations only 50% of patients with primary open angle glaucoma have elevated ocular pressure. ^[15] Diabetics and those of African descent are three times more likely to develop primary open angle glaucoma. Higher age, thinner corneal thickness, and myopia are also risk factors for primary open angle glaucoma. People with a family history of glaucoma have about a six percent chance of developing glaucoma. Asians are prone to develop, and Inuit have a twenty to forty times higher risk than Caucasians of developing primary angle closure glaucoma. Women are three times more likely than men to develop acute angle-closure glaucoma due to their shallower anterior chambers. Use of steroids can also cause glaucoma.

Primary open angle glaucoma (POAG) has been found to be associated with mutations in genes at several loci ^[16]. Normal tension glaucoma, which comprises one third of POAG, is associated with genetic mutations.^[17]

There is increasing evidence of ocular blood flow to be involved in the pathogenesis of glaucoma. Current data indicate that fluctuations in blood flow are more harmful in glaucomatous optic neuropathy than steady reductions. Unstable blood pressure and dips are linked to optic nerve head damage and correlate with visual field deterioration.

A number of studies also suggest that there is a correlation, not necessarily causal, between glaucoma and systemic hypertension (i.e. high blood pressure). In normal tension glaucoma, nocturnal hypotension may play a significant role. On the other hand there is no clear evidence that vitamin deficiencies cause glaucoma in humans, nor that oral vitamin supplementation is useful in glaucoma treatment ^[18]

Various rare congenital/genetic eye malformations are associated with glaucoma. Occasionally, failure of the normal third trimester gestational atrophy of the hyaloid canal and the tunica vasculosa lentis is associated with other anomalies. Angle closure induced ocular hypertension and glaucomatous optic neuropathy may also occur with these anomalies. ^[19][20][21] and modelled in mice ^[22].

Those at risk for glaucoma are advised to have a dilated eye examination at least once a year.^[23]

Diagnosis

Screening for glaucoma is usually performed as part of a standard eye examination performed by ophthalmologists and optometrists. Testing for glaucoma should include measurements of the intraocular pressure via tonometry, changes in size or shape of the eye, anterior chamber angle examination or gonioscopy, and examination of the optic nerve to look for any visible damage to it, or change in the cup-to-disc ratio and also rim appearance and vascular change. A formal visual field test should be performed. The retinal nerve fiber layer could be assessed with statistical imaging techniques such as optical coherence tomography (OCT), scanning laser polarimetry (GDx), and/or scanning laser ophthalmoscopy or Heidelberg Retina Tomography (HRT3).^{[24] [25]} Owing to the sensitivity of some methods of tonometry to corneal thickness, methods such as Goldmann tonometry should be augmented with pachymetry to measure the cornea thickness. While a thicker-than-average cornea can cause a false-positive warning for glaucoma risk, a thinner-than-average cornea can produce a false-negative result. A false-positive result is safe, since the actual glaucoma condition will be diagnosed in follow-up tests. A false-negative is not safe, as it may suggest to the practitioner that the risk is low and no follow-up tests will be done. The Frequency Doubling Illusion can also be used to detect glaucoma with the use of a Frequency Doubling Technology (FDT) perimeter.^[26] Examination for glaucoma also could be assessed with more attention given to sex, race, history of drugs use, refraction, inheritance and family history.^[24]

Management

The modern goals of glaucoma management are to avoid glaucomatous damage, preserve visual field and total quality of life for patients with minimal side effects.^{[27] [28]} This requires appropriate diagnostic techniques and follow up examinations and judicious selection of treatments for the individual patient. Although intraocular pressure is only one of the major risk factors for glaucoma, lowering it via various pharmaceuticals and/or surgical techniques is currently the mainstay of glaucoma treatment. Vascular flow and neurodegenerative theories of glaucomatous optic neuropathy have prompted studies on various neuroprotective therapeutic strategies including nutritional compounds some of which may be regarded by clinicians as safe for use now, others are on trial.

Drugs

Intraocular pressure can be lowered with medication, usually eye drops. There are several different classes of medications to treat glaucoma with several different medications in each class.

Each of these medicines may have local and systemic side effects. Adherence to medication protocol can be confusing and expensive; if side effects occur, the patient must be willing either to tolerate these, or to communicate with the treating physician to improve the drug regimen. Initially, glaucoma drops may reasonably be started in either one or in both eyes.^[29]

Poor compliance with medications and follow-up visits is a major reason for vision loss in glaucoma patients. Patient education and communication must be ongoing to sustain successful treatment plans for this lifelong disease with no early symptoms.

The possible neuroprotective effects of various topical and systemic medications are also being investigated.^{[18][30] [31] [32]}

Commonly used medications

• Prostaglandin analogs like latanoprost (Xalatan), bimatoprost (Lumigan) and travoprost (Travatan) increase uveoscleral outflow of aqueous humor. Bimatoprost also increases trabecular outflow
• Topical beta-adrenergic receptor antagonists such as timolol, levobunolol (Betagan), and betaxolol decrease aqueous humor production by the ciliary body.
• Alpha2-adrenergic agonists such as brimonidine (Alphagan) work by a dual mechanism, decreasing aqueous production and increasing uveo-scleral outflow.
• Less-selective sympathomimetics like epinephrine and dipivefrin (Propine) increase outflow of aqueous humor through trabecular meshwork and possibly through uveoscleral outflow pathway, probably by a beta2-agonist action.
• Miotic agents (parasympathomimetics) like pilocarpine work by contraction of the ciliary muscle, tightening the trabecular meshwork and allowing increased outflow of the aqueous humour.
• Carbonic anhydrase inhibitors like dorzolamide (Trusopt), brinzolamide (Azopt), acetazolamide (Diamox) lower secretion of aqueous humor by inhibiting carbonic anhydrase in the ciliary body.
• Physostigmine is also used to treat glaucoma and delayed gastric emptying.

Compounds in research

Natural compounds

Natural compounds of research interest in glaucoma prevention or treatment include: fish oil and omega 3 fatty acids, bilberries, vitamin E, cannabinoids, carnitine, coenzyme Q10, curcurmin, Salvia miltiorrhiza, dark chocolate, erythropoietin, folic acid, Ginkgo biloba, Ginseng, L-glutathione, grape seed extract, green tea, magnesium, melatonin, methylcobalamin, N-acetyl-L cysteine, pycnogenols, resveratrol, quercetin and salt. ^{[30] [31] [32]} Magnesium, ginkgo, salt and fludrocortisone, are already used by some physicians.

Cannabis

Studies in the 1970s showed that marijuana, when smoked, lowers intraocular pressure.^[33] In an effort to determine whether marijuana, or drugs derived from marijuana, might be effective as a glaucoma treatment, the US National Eye Institute supported research studies from 1978 to 1984. These studies demonstrated that some derivatives of marijuana lowered intraocular pressure when administered orally, intravenously, or by smoking, but not when topically applied to the eye. Many of these studies demonstrated that marijuana — or any of its components — could safely and effectively lower intraocular pressure more than a variety of drugs then on the market. In 2003, the American Academy of Ophthalmology released a position statement asserting that "no scientific evidence has been found that demonstrates increased benefits and/or diminished risks of marijuana use to treat glaucoma compared with the wide variety of pharmaceutical agents now available." The study goes on to say, "studies demonstrated that some derivatives of marijuana did result in lowering of IOP when administered orally, intravenously, or by smoking, but not when topically applied to the eye. The duration of the pressure-lowering effect is reported to be in the range of 3 to 4 hours".^[34][33]

The first patient in the United States federal government's Compassionate Investigational New Drug program, Robert Randall, was afflicted with glaucoma and had successfully fought charges of marijuana cultivation because it was deemed a medical necessity (U.S. v. Randall) in 1976.^[35]

5-HT_2A agonists

Peripherally selective 5-HT_2A agonists such as the indazole derivative AL-34662 are currently under development and show significant promise in the treatment of glaucoma.^[36][37]

Surgery

Conventional surgery to treat glaucoma makes a new opening in the meshwork. This new opening helps fluid to leave the eye and lowers intraocular pressure.

Main article: Glaucoma surgery

Both laser and conventional surgeries are performed to treat glaucoma.

Surgery is the primary therapy for those with congenital glaucoma.^[38]

Generally, these operations are a temporary solution, as there is not yet a cure for glaucoma.

Canaloplasty

Canaloplasty is a nonpenetrating procedure utilizing microcatheter technology. To perform a canaloplasty, an incision in made into the eye to gain access to Schlemm's canal in a similar fashion to a viscocanalostomy. A microcatheter will circumnavigate the canal around the iris, enlarging the main drainage channel and its smaller collector channels through the injection of a sterile, gel-like material called viscoelastic. The catheter is then removed and a suture is placed within the canal and tightened. By opening the canal, the pressure inside the eye may be relieved, although the reason is unclear since the canal (of Schlemm) does not have any significant fluid resistance in glaucoma or healthy eyes. Long-term results are not available.[2][3]

Laser surgery

Laser trabeculoplasty may be used to treat open angle glaucoma. It is a temporary solution, not a cure. A 50 μm argon laser spot is aimed at the trabecular meshwork to stimulate opening of the mesh to allow more outflow of aqueous fluid. Usually, half of the angle is treated at a time. Traditional laser trabeculoplasty utilizes a thermal argon laser. The procedure is called Argon Laser Trabeculoplasty or ALT. A newer type of laser trabeculoplasty exists that uses a "cold" (non-thermal) laser to stimulate drainage in the trabecular meshwork. This newer procedure which uses a 532nm frequency-doubled, Q-switched Nd:YAG laser which selectively targets melanin pigment in the trabecular meshwork cells, called Selective Laser Trabeculoplasty or SLT. Studies show that SLT is as effective as ALT at lowering eye pressure. In addition, SLT may be repeated three to four times, whereas ALT can usually be repeated only once.

Nd:YAG Laser peripheral iridotomy may be used in patients susceptible to or affected by angle closure glaucoma or pigment dispersion syndrome. During laser iridotomy, laser energy is used to make a small full-thickness opening in the iris. This opening equalizes the pressure between the front and back of the iris correcting any abnormal bulging of the iris. In people with narrow angles, this can uncover the trabecular meshwork. In some cases of intermittent or short-term angle closure this may lower the eye pressure. Laser iridotomy reduces the risk of developing an attack of acute angle closure. In most cases it also reduces the risk of developing chronic angle closure or of adhesions of the iris to the trabecular meshwork.

Diode laser cycloablation could be considered to be performed. It lowers IOP by reducing aqueous secretion by destroying secretory ciliary epithelium.^[24]

Trabeculectomy

The most common conventional surgery performed for glaucoma is the trabeculectomy. Here, a partial thickness flap is made in the scleral wall of the eye, and a window opening made under the flap to remove a portion of the trabecular meshwork. The scleral flap is then sutured loosely back in place. This allows fluid to flow out of the eye through this opening, resulting in lowered intraocular pressure and the formation of a bleb or fluid bubble on the surface of the eye. Scarring can occur around or over the flap opening, causing it to become less effective or lose effectiveness altogether. One person can have multiple surgical procedures of the same or different types.

Glaucoma drainage implants

There are also several different glaucoma drainage implants. These include the original Molteno implant (1966), the Baerveldt tube shunt, or the valved implants, such as the Ahmed glaucoma valve implant or the ExPress Mini Shunt and the later generation pressure ridge Molteno implants. These are indicated for glaucoma patients not responding to maximal medical therapy, with previous failed guarded filtering surgery (trabeculectomy). The flow tube is inserted into the anterior chamber of the eye and the plate is implanted underneath the conjunctiva to allow flow of aqueous fluid out of the eye into a chamber called a bleb.

• The first-generation Molteno and other non-valved implants sometimes require the ligation of the tube until the bleb formed is mildly fibrosed and water-tight^[39]This is done to reduce postoperative hypotony -- sudden drops in postoperative intraocular pressure (IOP).
• Valved implants such as the Ahmed glaucoma valve attempt to control postoperative hypotony by using a mechanical valve.

The ongoing scarring over the conjunctival dissipation segment of the shunt may become too thick for the aqueous humor to filter through. This may require preventive measures using anti-fibrotic medication like 5-fluorouracil (5-FU) or mitomycin-C (during the procedure), or additional surgery. And for Glaucomatous painful Blind Eye and some cases of Glaucoma, Cyclocryotherapy for ciliary body ablation could be considered to be performed. ^[24]

Veterinary Implant

TR BioSurgical has designed an implant specifically for veterinary medicine. The implant consists of a new biomaterial which consists of silicone with a very precise homogenous pore size, which reduces fibrosis and improves tissue integration. The implant contains no valves and is placed completely within the eye without sutures. To date, it has demonstrated long term success in a pilot study in medically refractory dogs with advanced glaucoma ^[40]

Major studies

• Advanced Glaucoma Intervention Study (AGIS) - large American National Eye Institute (NEI) sponsored study designed "to assess the long-range outcomes of sequences of interventions involving trabeculectomy and argon laser trabeculoplasty in eyes that have failed initial medical treatment for glaucoma." It recommends different treatments based on race.
• Early Manifest Glaucoma Trial (EMGT) -Another NEI study found that immediately treating people who have early stage glaucoma can delay progression of the disease.
• Ocular Hypertension Treatment Study (OHTS) -NEI study findings: "...Topical ocular hypotensive medication was effective in delaying or preventing onset of Primary Open Angle Glaucoma (POAG) in individuals with elevated Intraocular Pressure (IOP). Although this does not imply that all patients with borderline or elevated IOP should receive medication, clinicians should consider initiating treatment for individuals with ocular hypertension who are at moderate or high risk for developing POAG."
• Blue Mountains Eye Study "The Blue Mountains Eye Study was the first large population-based assessment of visual impairment and common eye diseases of a representative older Australian community sample." Risk factors for glaucoma and other eye disease were determined.

Classification of glaucoma

Glaucoma has been classified into specific types:^[41]

Primary glaucoma and its variants (H40.1-H40.2)

• Primary glaucoma

• Primary open-angle glaucoma, also known as chronic open-angle glaucoma, chronic simple glaucoma, glaucoma simplex
• Low-tension glaucoma
• Primary angle-closure glaucoma, also known as primary closed-angle glaucoma, narrow-angle glaucoma, pupil-block glaucoma, acute congestive glaucoma

• Acute angle-closure glaucoma
• Chronic angle-closure glaucoma
• Intermittent angle-closure glaucoma
• Superimposed on chronic open-angle closure glaucoma ("combined mechanism" - uncommon)

• Variants of primary glaucoma

• Pigmentary glaucoma
• Exfoliation glaucoma, also known as pseudoexfoliative glaucoma or glaucoma capsulare

Primary open-angle glaucoma - This is caused by trabecular blockage which is where the aqueous humor in the eye drains out. Because the microscopic passage ways are blocked, the pressure builds up in the eye and causes imperceptible very gradual vision loss. Peripheral vision is affected first but eventually the entire vision will be lost if not treated. Diagnosis is made by looking for cupping of the optic nerve. The treatment's goal is to release the fluid by opening uveoscleral passageways, which are acted upon by prostoglandin agonists. Beta blockers such as timolol, work by decreasing aqueous formation. Carbonic anhydrase inhibitors decrease bicarbonate formation from ciliary processes in the eye, thus decreasing formation of Aqueous humor. Parasympathetic analogs are drugs that work on the trabecular outflow by opening up the passageway and constricting the pupil. Alpha 2 agonists (brimonidine, apraclonidine) both decrease fluid production (via. inhibition of AC) and increase drainage.

Primary angle-closure glaucoma - This is caused by contact between the iris and trabecular meshwork, which in turn obstructs outflow of the aqueous humor from the eye. This contact between iris and trabecular meshwork (TM) may gradually damage the function of the meshwork until it fails to keep pace with aqueous production, and the pressure rises. In over half of all cases, prolonged contact between iris and TM causes the formation of synechiae (effectively "scars"). These cause permanent obstruction of aqueous outflow. In some cases, pressure may rapidly build up in the eye causing pain and redness (symptomatic, or so called "acute" angle-closure). In this situation the vision may become blurred, and halos may be seen around bright lights. Accompanying symptoms may include headache and vomiting. Diagnosis is made from physical signs and symptoms: pupils mid-dilated and unresponsive to light, cornea edematous (cloudy), reduced vision, redness, pain. However, the majority of cases are asymptomatic. Prior to very severe loss of vision, these cases can only be identified by examination, generally by an eye care professional. Once any symptoms have been controlled, the first line (and often definitive) treatment is laser iridotomy. This may be performed using either Nd:YAG or argon lasers, or in some cases by conventional incisional surgery. The goal of treatment is to reverse, and prevent, contact between iris and trabecular meshwork. In early to moderately advanced cases, iridotomy is successful in opening the angle in around 75% of cases. In the other 25% laser iridoplasty, medication (pilocarpine) or incisional surgery may be required.

Developmental glaucoma (Q15.0)

• Developmental glaucoma

• Primary congenital glaucoma
• Infantile glaucoma
• Glaucoma associated with hereditary of familial diseases

Secondary glaucoma (H40.3-H40.6)

• Secondary glaucoma

• Inflammatory glaucoma

• Uveitis of all types
• Fuchs heterochromic iridocyclitis

• Phacogenic glaucoma

• Angle-closure glaucoma with mature cataract
• Phacoanaphylactic glaucoma secondary to rupture of lens capsule
• Phacolytic glaucoma due to phacotoxic meshwork blockage
• Subluxation of lens

• Glaucoma secondary to intraocular hemorrhage

• Hyphema
• Hemolytic glaucoma, also known as erythroclastic glaucoma

• Traumatic glaucoma

• Angle recession glaucoma: Traumatic recession on anterior chamber angle
• Postsurgical glaucoma

• Aphakic pupillary block
• Ciliary block glaucoma

• Neovascular glaucoma (see below for more details)
• Drug-induced glaucoma

• Corticosteroid induced glaucoma
• Alpha-chymotrypsin glaucoma. Postoperative ocular hypertension from use of alpha chymotrypsin.

• Glaucoma of miscellaneous origin

• Associated with intraocular tumors
• Associated with retinal deatchments
• Secondary to severe chemical burns of the eye
• Associated with essential iris atrophy
• Toxic Glaucoma

Neovascular glaucoma is an uncommon type of glaucoma that is difficult or nearly impossible to treat. This condition is often caused by proliferative diabetic retinopathy (PDR) or central retinal vein occlusion (CRVO). It may also be triggered by other conditions that result in ischemia of the retina or ciliary body. Individuals with poor blood flow to the eye are highly at risk for this condition.

Neovascular glaucoma results when new, abnormal vessels begin developing in the angle of the eye that begin blocking the drainage. Patients with such condition begin to rapidly lose their eyesight. A new treatment for this disease, as first reported by Kahook and colleagues, involves use of a novel group of medications known as Anti-VEGF agents. These injectable medications can lead to a dramatic decrease in new vessel formation and, if injected early enough in the disease process, may lead to normalization of intraocular pressure.

Toxic glaucoma is open angle glaucoma with an unexplained significant rise of intraocular pressure following unknown pathogenesis. Intraocular pressure can sometimes reach 80 mmHg. It characteristically mainfests as ciliary body inflammation and massive trabecular oedema that sometimes extends to Schlemm's Canal. This condition is differentiated from malignant glaucoma by the presence of a deep and clear anterior chamber and a lack of aqueous misdirection. Also, the corneal appearance is not as hazy. A reduction in visual acuity can occur followed neuroretinal breakdown. Associated factors include inflammation, drugs, trauma and intraocular surgery, including cataract surgery and vitrectomy procedures. Gede Pardianto (2005) reports on four patients who had toxic glaucoma. One of them underwent phaecoemulsification with small particle nucleus drops. Some cases can be resolved with some medication, vitrectomy procedures or trabeculectomy. Valving procedures can give some relief but further research is required.^[42]

Absolute glaucoma (H44.5)

• Absolute glaucoma

See also

• List of eye diseases and disorders
• Ocular hypertension
• Glaucoma valves
• Mansour F. Armaly
• Laszlo Z. Bito
• Charles D. Phelps
• American Glaucoma Society

References

External links

• Glaucoma Resource Guide from the National Eye Institute (NEI).
• National Glaucoma Research
• Global Association of International Glaucoma Societies - featuring a hymn about the successful treatment of glaucoma
• EUROPEAN GLAUCOMA SOCIETY
• Glaucoma Research Foundation
• "Glaucoma - What is Glaucoma?". NLM. Retrieved on 2007-04-21. video
• Nonprofit Foundation for Glaucoma
• Asia Ophthalmology Center
• DJO | Digital Journal of Ophthalmology
• Lions Eye Institute, Perth, Australia
• Mar 2008 BBC article on diagnosis advances
• Glaucoma Associates Of New York
• Pediatric Glaucoma and Cataract Family Association
• Morrison JC, Pollack IP (2003) Glaucoma: Science and Practice. Thieme ISBN 0865779155 Google Books
• Kahook M.Y., Schuman J.S., Noecker R.J. Intravitreal bevacizumab in a patient with neovascular glaucoma.Ophthalmic Surg Lasers Imaging. 2006 Mar-Apr;37(2):144-6. [4]

Photographs of glaucomatous eyes:http://webeye.ophth.uiowa.edu/eyeforum/atlassearch1.htm ] This URL will download the search form of the University of Iowa Eye Atlas. Type glaucoma into the Diagnosis space and then click on Run Query to download the annotated photographs.