Glaucoma (the secret thief)

Claucoma is a series of eye diseases ending up in permanent loss of nerve fibers of the optic neerve that translates into loss of optic field and finally in blindness. In ancient egyptian papyrous there are refered treatments with kanabis for eye diseases, that according to modern analysts probably refer to glaucoma or inflammations. The team is being reported first time by Aristotles and derives from the ancient greek word 'glaukos' which means light cyan. Aristotles, Hippokrates, Kelsus and other ancient writers use the word generally for diseases that cause fading of the iris towards the light cyan colour. In advanced disease stages the throating of the termination of the optic nerve in the eye (optic disc) increases and eventually whitening and atrophy of the disc occurs. The consequence of these changes is the formation of scotomas (failures in the optic field) and in exceptional cases the blindness. Characteristic cause of the optic fibers loss is the increase Intraocular Pressure (IOP). Ophthalmic hypertension consists one of the greates risk factors. However, a big percentage of the patients having glaucoma has normal or low IOP. In these patients, high sensitivity of the nerve in arterial pressure (or blood pressure) fluctuations have been observed, a fact that sets necessary the good cooperation between the physician and the ophthalmologist. [1] From the anatomical point of view, glaucomas are roughly separated in open- and closed-angle glaucomas. The angle is the one formed between the cornea and the iris and is the point od exit (drainage) of the aqueous fluid. The aqueous fluid has a composition similar to that of water, is being produced and targets, between others, to maintain the spherical shape of the eye (like a ball). In the case where IOP is too low (eye injury, after a big glaucoma operation etc) the eye (the ball) behaves as if it is 'deflated'. In the opposite case where IOP is too high (e.g. in glaucoma crisis) the eye apart from being painful is also too hard (has the feeling of the ball going to blow out). The very common open-angle glaucoma, also known as 'the secret thief', doesn't have other obvious reasons than the optic field loss, which again due to the interraction of the two eyes is 'covered'. This complicates the detection of patients with glaucoma since almost all of them state that they don't have problems in their vision until it's too late. On the other hand the less common close angle glaucoma makes its presence clear in most of the cases with pain in the eye or headache accompanied by nautia and vomits. Parallely, irritation of the eye, vision blurring as well as appearance of dark circles around light sources (Halo) may exist. This very sharp IOP increase can lead to blindness in some hours if it's not treated. Glaucoma consists worldwidely one of the most common causes of blindness. In Greece and Cyprus it consists the second most common cause of blindness. It is estimated that more than 5% of elderly people over 80 years old suffer from glaucoma in Greece and only half of them know it. 10% of them is threatened by blindness. An IOP value between 10 and 21 mmHg is normal for people not suffering from glaucoma. Fluctuations of the class of 5 mmHg are normal during the day. These values are valid for the majority of the healthy people population and differ between populations and skin colour. The mechanism of glaucoma development is the disproportion between IOP and blood supply of the optic nerve. Better blood supply of the optic nerve increases the resilience of the disc (optic nerve) in higher IOP. In a poor blood supply of the nerve a possibly normal or low IOP is not tolerated well by the nerve (disc). The nerve is significantly susceptible to poor blood supply and high IOP. In alla of these the rate of the flunctuation of these values as well as their duration play a role. The aqueous fluid (humor aquosus) is a clear fluid that is produced in the ciliary projections in the posterior chumber (between the iris and the lens) and flows through the pupil to the anterior chamber (space between the iris and the cornea). There in the angle it is channeled through a network (Trabeculum) int he Schlemm channel (in a way similar to the water distribution system of a settlement). IOP is directly related to the production and channel rate of this fluid. If, for example, the dillution channel blocks somewhere with impurities or is thickened then, as in a settlement, the water would flood, likewise the IOP increases. The optic nerve (disc) blood supply is related mainly to low arterial pressure (hypotension) as well as to factors that cause "bad quality vessels" such as high arterial pressure (hypertension), smoking, diabetes, etc. Glaucoma often consists the combination of the two mechanisms above. In the ophthalmological examination it is recognized during fundoscopy with the disc's characteristic throating. Initially, the optic fibers of the middle periphery (and in extension the optic field) are affected and it is directed to the center. If 70% of these fibers is affected the so known toxoid scotoma (Bjerrum scotoma) is formed, that is often not perceived by the patients. This is where its name as "secret thief" comes from, since it steals the vision (the light) without being perceived. For this reason, ophthalmologists worldwide have suggested the screening of patients for glaucoma with various examinations (such as tonometry, cornea pachymetry, optic fields cupture, OCT, HRT, etc.). 

Risk Factors

• High IO
  
• Non-regulated arterial pressure
  
• Diabetes
  
• Smoking
  
• Dark skin colour
  
• High myopia (open angle)
  
• High hyperopia (closed angle and glaucoma crisis)
  
• High age
  

The most common glaucoma types
Ophthalmic Hypertension
Even if ophthalmic hypertension is not glaucoma, however it is classified in this category due to its singularity. In ophthalmic hypertension IOP is high but the disc (optic nerve) hasn't undergone alterations. Often, from this disease the eye is led to glaucoma. The highest the IOP is, the most possible it is for the ophthalmic hypertension to develop into glaucoma. It is considered by some as as a harbinger of glaucoma or very early stage of glaucoma and is often (not always) treated with anti-glaucoma treatment. The results of 'Ocular Hypertension Treatment Study [3]' research have shown that the preventive reduction of IOP reduces the possibility of causing glaucoma alterations [4].

Primary chronic open angle glaucoma
Glaucoma chronicum simplex 
It's the open angle glaucoma that doesn't have any other cause in the background. It is the most common glaucoma type. It usually starts in middle age even though it is observed also in younger patients. Genetic predisposition has been proved. The cause of this glaucoma is the obstruction of aqueous fluid drainage due to degenerative alterations, same as in the sewer system of a settlement. The result is the gradual increase of the pressure down the line, without obvious symptoms by the patient. A lot of writers classify here the normal or low IOP glaucoma. In that, a glaucomatic alteration of the optic nerve is observed while the IOP is in normal levels. The thickness of the cornea plays a great role here where in the case of a thin cornea a lower IOP may be falsely measured, up to 6mmHg. However, an important role in normal IOP glaucoma plays the blood supply of the disc. It is considered by many a kind of vascular neuropathy [1]. Rough estimations indicate that 40% of glaucoma patients have normal IOP, a fact that sets necessary the good cooperation of the physician and the ophthalmologist. 
Juvenile or congenital glaucomaDuring embryonic period a disorder in the development of the eye and the formation of a drainage system (angle system/ trabeculum) in the "angle" (angle between the iris and the cornea), causes disorders in the drainage of the aqueous fluid resulting in the increase of IOP already from a juvenile age. This can be combined with other congenital declaratory disorders. A common cause is the infection of the pregnant woman by the rubella virus during the first months of pregnancy [5]. High IOP of the embryo/newborn/infant causes in turn increase of the size of the eye and the cornea (like an overblown sphere) and this appearance of the eye is called "hydrophthalmus" or "bouphthalmus". In an increased cornea diameter, cornea blurring and photophobia in this age should always create the suspicion for congenital glaucoma. In that case, ophthalmological examination and IOP measurement are necessary and according to these a surgical operation under general anaesthesia in order to avoid permanent eye injuries. 

Pseudoexfoliation syndrome and pseudoexfoliation glaucoma 
A special and not so rare glaucoma type is the pseudoexfoliation glaucoma[6]. In pseudoexfoliation syndrome, a white-gray microscopic granular protein fiber deposits in the lens, the iris, zinia zone, cilliary body and the trabeculum (drainage point). Almost 40% of patients with that syndrome will develop glaucoma. IOP increases due to the accumulation of this material at the trabeculum. The origin of this material is not verified yet and it has been found even in other tissues and organs, such as the heart, the lungs, the liver, the kidneys and the gall bladder [7]. It is found to middle age people and the syndrome's frequency is almost 25%.

Pigmentary glaucoma and pigmentary dispersion syndrome

The pigmentary dispersion syndrome consists the dispersion of pigment due to the fraction between the iris and the lens. In theory, iris is slightly bended backwards and as a result, its posterior surface comes in contact with the lens and due to this traction, granules of pigment are attracted by the iris. This pigment accumulates on the cornea (Knukenberg's splindestone) and the trabeculum and as the years pass it can lead to pigmentary glaucoma (less than half that have the syndrome will develop glaucoma). Usually these patients have light myopia and are from 30 to 45 years old.

Other secondary open-angle glaucoma
Open angle glaucomas with other etiology (of eye or systemic nature) are also classified. These include glaucoma after eye injury, after uveitis (eye's urea inflammation), intravitreal tumours, neoangiosis in the angle e.g. due to diabetes and/or due to pharmaceutical etiology such as the chronic use od corticosteroids (locally or systemically). 

Primary closed-angle glaucoma
Closed-angle glaucoma consists of aqueous fluid drainage disorders due to the narrowing of the drainage spot in the angle (trabeculum). This narrowing changes according to the size of the pupil (this means that the thickness of the iris changes also), a fact that is affected by various anti-cholinergic medicine such as some anti-depressants or anti-vomits. Furthermore, patents with high hyperopia due to small eye construction and spot of drainage construction but also patients with progressed cataract (due to increase of the lens thickness) tend to develop this type of glaucoma. All the factors mentioned above can lead to acute closed-angle glaucoma that consists an urgent case at any point. 

Acute closed-angle glaucoma 
Glaucoma acutum 
Acute closed-angle glaucoma is an urgent case that has to be treated in some hours. In this glaucoma, also known as glaucoma crisis, the angle closes suddenly and due to that the aqueous fluid cannot be drained. This leads to rapid and intense increase of IOP and "the eye is as hard as a stone" when you touch it. The spots and symptoms vary from red eye, nautius or vomiting, visual acuity loss, intense headaches, hard rate disorders, appearance of black circles near luminous sources (halos) to absence of reaction of the pupil to the light. This crisis may reside and reappear after a while or remain and lead to blindness without treatment. In any glaucoma crisis the other eye must be also examined and if it's needed to be operated preventionally. We must say here that one type of glaucoma does not exlude the existence of another. Whereas, the existence of chronic closed-angle glaucoma leads to the development of chronic open-angle glaucoma. 

Treatment
In this point, it must be noted that the different types of glaucoma (with one exception) don't completely cure and neither can the destroyed fibers be restored. As soon as the diagnosis is made by the doctor, the treatment with IOP decrease to the desired levels for the patient (IOP-target = personalized highest IOP so that to decrease or stop the rate of nerve fibers loss). This IOP-target is unique for each patient and for the stage of glaucoma they are. IOP-target is being defined after multiple IOP measurements during the day (also known as 24H IOP profile). The european glaucoma company has already set the direction lines for treatment as follows [9]:First step is the single therapy with local anti-glaucoma drops. If the IOP-target isn't accomplished then drops of different classes are combined. If the IOP-target still isn't accomplished then the patient is led to operation. A Gold standard in glaucoma surgery is the Trabeculectomy (for goniotrepaniosis based on Fronimopoulos-Valser). 

Pharmaceutical treatment
For the pharmaceutical treatment of glaucoma there are 5 different classes of medicine in the market, mainly in the form of eye drops:

- B-Receptors antagonists
- Cholinergics: mainly for closed-angle glaucoma- Alfa-2-Receptors agonists
- Carbodehydrase inhibitors: locally as drops and systemically as pills or for intravenous use. 
- Prostaglandin analogues
- Rho-kinase inhibitors (in USA since April 2018) 
- Hyperosmotic factors

Action mechanism: 
- Reduction of aqueous fluid production: B-receptors antagonists, Alfa-2-Receptors agonists, Carbodehydrase inhibitors.- Increase in aqueous fluid drainage: Alfra-2-receptors agonists, Rho-kinase inhibitors, hyperosmotic factors.
- Prostaglandin analogues increase aqueous fluid's permeability at the cilliary body as well as the so known "non-conventional drainage" through the ureoscleral ouflow.
- Cholinergics cause contractions to the cilliary body and in that way the angular web widens more. Miosis of the pupil and widening of the angle also are used mainly in closed-angle glaucoma. 
- Moreover, Alfa-2-receptors agonists provide neuroprotective action to the optic nerve and carbodehydrase inhibitors promote the blood supply of the optic nerve. 

The classes above can be combined (the exceptions are: prostaglandin analogues with cholinergics because the cholinergics reduce the ureascleral drainage). Many of these are already in the market in the form of drops with medicine combination. In the case of secondary glaucomas the cause of glaucoma must be simultaneously treated. 

Laser therapy
- Destruction (heat shock) of cilliary body: with this method the cells that produce the aqueous fluid are destroyed. It is usually the last treatment solution in case that all the other methods fail. 
- Argonlaser-Trabeculoplastic: Increase of the aqueous drainage after opening small channels to the angular web. Due to scar creation it can be done 1 to 2 times. 
- Selective Argonlaser-Trabeculoplastic: Same action mechanism as above but with less tissue injury, so it can be done more times. Its use, before even trying any medication is extensively discusses and opinions diverge. 
- Laser (Nd-YAG)-Iridectomy: Better aqueous drainage from the posterior to the anterior chamber, in small or closed-angle glaucomas making a small opening in iris periphery (same as in surgical iridectomy).
- Trabeculectomy (or goniotrepaniosis according to Fronimopoulos-Valser): With the formation of a fistula in the sclera, the drainage of aqueous fluid from the anterior/posterior chamber towards underneath the conjuctiva is achieved. 
- Cilliary body destruction using cryocoagulation: Same as with laser (view above) also with cooling the cells that produce the aqueous fluid can be destroyed. 
- Trabeculectomy and goniotomy: In dysgenesis (congenital glaucoma) the incompletely angular system opens up so that to achieve a junctions between the anterior chamber and Schlemm's channel.
- Surgical iridectomy: A small hole incision in iris periphery (same as in Laser Nd-YAG-Iridectomy) mainly in closed-angle glaucoma so that to make the pressure in the anterior and posterior chamber equl and the blockage in the angle to be removed. 
- Canaloplastic: It is applied since middle 2000. A ring-shaped implant is placed in Schlemm's channel targetting in permanently remaining open. 
- Drainage tubules (Stents) and Glaucoma microsurgery (Micro Invasive Glaucoma Surgery - MIGS): It has rebuted the glaucoma surgery data worldwide for the last years. The minor invasive operations with the implant tubule placement has not only changed the duration of the surgery but also the majority of big surgeries. The market has 3 tubules of this kind so far. The first iStent that is also the smallest connects the anterior chamber directly to Schlemm's channel. It is used in middle grade glaucomas [10] and its action is described as a combination of 2 anti-glaucomatic medicine taken by the patient [11]. Also, the international market has Cypass-Stent and XEN-Stent. The first connects the anterior chamber with the space between the chorioid and sclera, while the second connects the anterior chamber with the space under the conjuctiva. Both tubules have almost the same effectiveness as trabeculectomy, that has been considered for many years as optional operation, with high surgery duration and high percentage of compilations. Cypass-Stent has been temporarily withdrawn since 28/8/2018 by the market after a study made by COMPASS XT, that showed higher percentage of endothelial cells' loss in patients with Cypass-Stent. 
- Cataract operation also reduces IOP in all patients and also is the election operation at closed-angle glaucoma. 

Prevention
There do not exist preventive examinations for avoiding the disease. The most important with this disease is its early recognition and treatment to avoid optic field decrease and finally blindness. Because the disease's symptoms are being camouflaged by our own brain, early and regular examinations are necessary by an ophthalmologist in order to recognize the disease early. From the financial view, it is intensively discussed whether it is worth it to make pre-glaucomatic examination [12] (with examinations such as IOP measurement, fundoscopy and optic field acquisition) for the whole population, having abroad, on the one hand the medicinal society judges it necessary and on the other hand the insurance funds claim tha this kind of examination should only be done when glaucoma is suspected, like in the case of increased IOP [14]. A study presents Eyemate, a microsensor that's placed in the anterior chamber of the eye, as the equipment to measure 24 hours continuously the IOP. It's in the market since 2017 and has been implanted to a bunch of patients in the university clinic in Aachen. The measurements done by the microchip are recorded on a device that is placed on the patients glasses and the doctor reads them telemetrically. The company promises a better IOP and its deviations recording day and night time.