Glaucoma: Causes

Pathogenesis (development of disease)

Glaucoma is now defined as progressive (advancing) optic nerve degeneration (optic neuropathy), in the course of which retinal (“belonging to the retina”) ganglion cells die and visual field loss to blindness develops. A large proportion of glaucomas are usually caused by excessive intraocular pressure, which then damages the optic nerve by compression, leading to visual field loss. The cause of increased intraocular pressure is an increase in aqueous humor, for which there are basically two possibilities:

1. Overproduction of aqueous humor
2. Obstruction of aqueous humor closure (causative for glaucoma).

There are also forms of glaucoma without classic intraocular pressure elevation (see below). Possible classifications of glaucoma can be according to the age of the patient at the onset of the disease, in primary (without other eye disease) or secondary (as a result of other eye diseases) form or according to the structure of the chamber angle. However, all forms have optic nerve degeneration as a common feature. Primary congenital and infantile glaucoma.

• Primary congenital glaucoma: Congenital glaucoma results from developmental abnormalities of the ventricular angle (trabecular meshwork dysgenesis, which are visible on gonioscopy (diagnostic procedure in ophthalmology (eye care); used to inspect the so-called ventricular angle)) and usually manifests in the 1st year of life. The children stand out with excessively large cornea as well as photophobia, eyelid spasms and lacrimation.Due to significant aqueous humor outflow disorders, high intraocular pressures and severe progressions can occur.
• Infantile glaucoma and early juvenile glaucoma: these forms of glaucoma occur later to adolescence. A large cornea usually does not develop because the cornea is already stably developed when the pressure increase occurs. The chamber angle appears open and without visible developmental abnormalities.At the beginning, these forms of glaucoma are usually asymptomatic, but can show significant optic nerve damage if detected late.

Secondary infantile glaucoma

• As in adults, there are secondary forms of glaucoma in children and adolescents that occur as a result of acquired ocular diseases (e.g., uveitis/inflammation of the medial membrane of the eye, which consists of the choroid, the corpus ciliare, and the iris) congenital ocular defects (e.g. Aniridia / missing or hypoplasia of the iris of the eye), systemic diseases (eg phakomatoses / group of diseases with malformations in the skin and nervous system / cerebellum) and after eye surgery can arise.All are also common here disorders in the chamber angle area, which lead to an increase in pressure with subsequent optic nerve degeneration.

Primary open angle glaucoma

• Primary open-angle glaucoma (POAG; here: high-pressure glaucoma): slowly progressing eye disease; the risk of disease increases with age, especially after the age of 50. Usually both eyes are affected. The disease is accompanied by a typical visual field loss. Although the chamber angle remains open, deposits of hyaline material (plaque deposits) in the trabecular meshwork cause an increase in the outflow resistance of the aqueous humor, so that the intraocular pressure can or does rise.The “European Glaucoma Society, (EGS)” defines open angle glaucomas as follows: “Open angle glaucomas are chronic, progressive optic neuropathies with morphologic change in the retinal nerve fiber layer of the optic disc (area of the retina where retinal nerve fibers gather to form the optic nerve after leaving the eyeball) without ocular disease. They are associated with retinal ganglion cell death and visual field loss. “The exact etiology (cause) is unknown. Currently, deformities of the lamina cribrosa at the optic disc are thought to result from individual differences in tolerance to intraocular pressure. Possibly other risk factors play a role, so that the eye pressure can no longer be attributed as the sole cause of the disease. In addition, gene mutations are assumed.Conclusion: the correct definition of normal-tension glaucoma via the intraocular pressure (IOP) is no longer possible!
• Primary open-angle glaucoma (POAG; here: Normal-tension glaucoma; obsolete: Low-pressure glaucoma; NDG; engl.NTG = normal tension glaucoma, approx. 17 % of all forms of glaucoma): By definition, typical glaucomatous optic nerve damage occurs at intraocular pressure levels that are not problematic for most of the population. As with high pressure glaucoma, the etiology is unclear. Other factors appear to play a more important role than intraocular pressure in the development of NDG:
  • Impaired autoregulation: the ocular vessels are no longer sufficiently able to adapt to the required perfusion. As a result, an undersupply occurs.
  • Low blood pressure with nocturnal blood pressure drops (caveat: overdosed antihypertensive treatment with “normal” daytime values). The ocular perfusion pressure is here relative to the intraocular pressure is no longer sufficient for adequate optic nerve and retinal perfusion (consequence: oxygen deficiency with death of ganglion cells).
  • Slim stature
  • Psychological factors such as stress (oxidative) and tendency to perfectionism.
  • Diseases: Diabetes mellitus, myopia (nearsightedness), migraine, Raynaud’s disease (circulatory disorders in the hands or feet caused by vasospasm (vascular spasm)), sleep apnea, tinnitus (ringing in the ears) and vascular dysregulation: the vessels react more strongly to external stimuli (cold e.g. cold sauna infusion, stress or increased perception sensitive stimulus).
  • Cold hands / feet

Note: There are benign (benign) elevations of intraocular pressure, which do not cause damage to the optic nerve (ocular hypertension, OHT), at least for some time. Secondary glaucoma

• Neovascularization glaucoma: Diabetes mellitus or central retinal vein occlusion can lead to retinal ischemia (decreased blood flow to the retina). In response, the retina produces vascular endothelial growth factors (VEGF), which enter the anterior chamber via the aqueous humor. Here, these factors lead to neovascularization (formation of additional, pathological blood vessels in the eye) on the iris (iris) or in the chamber angle, so that it is narrowed and displaced. Consequently, the aqueous humor can no longer drain and the intraocular pressure increases.
• Pigment dispersion glaucoma: When the iris slackens, it rubs with its back against the zonular fibers, whereby pigment granules are exfoliated. These are transported with the aqueous humor into the anterior chamber and displace the chamber angle.
• Pseudoexfoliative glaucoma (synonym: PEX glaucoma): fine fibrillar material (also known as pseudoexfoliative material), formed predominantly by the ciliary epithelium, is deposited in the chamber angle. In this form of glaucoma, intraocular pressure values are often subject to high fluctuations. A measurement of the daily pressure curve can be helpful.
• Cortisone glaucoma: administration of ointments or eye drops with corticosteroids can block the trabecular meshwork by accumulation of mucopolysaccharides. The chamber angle remains open. Note: The prescription of ointments or eye drops containing corticosteroids always requires regular ophthalmologic control. This also applies to systemic medication.
• Phacolytic glaucoma: proteins of the crystalline lens can penetrate through the lens capsule and block the trabecular meshwork in hypermature (“overripe”) cataract (cataract).
• Inflammatory glaucoma: inflammation may cause edema of the trabecular cells, or inflammatory proteins may be produced, which in turn obstruct the trabecular meshwork.
• Traumatic glaucoma: In case of injury, blood may obstruct the angle of the ventricle, also the vitreous may press on the angle from the inside. Tears of the trabecular meshwork may cause compressive scarring. Burns can lead to Schlemm’s canal obliteration.
• Glaucoma in developmental disorders and malformations: Most often it is an increase in volume of the choroid or sclera (eg, hemangioma/blood sponge), so that ipsilateral (“on the same side of the body”) glaucoma develops in childhood.

Primary angle-closure glaucoma

• Primary angle-closure glaucoma (PWG): Caused by chamber angle closure through the base of the iris, especially when the chamber angle is congenitally narrow or the crystalline lens is enlarged (age lens).
  • Acute occlusion with extremely high intraocular pressures represents an emergency situation (glaucoma acutum/acute glaucoma attack) and must be treated immediately with medication and by peripheral iridectomy.
  • Chronic angle-closure glaucoma results from goniosynechiae, which are usually the consequence of acute glaucoma cases that have not been treated in time.

Secondary angle-closure glaucoma

• Secondary angle-closure glaucoma: Caused by chamber angle closure due to other eye diseases (eg, inflammation, neovascularization at the base of the iris), surgical complications, lens dislocation (lens is dislocated to the extent that it is displaced into the anterior or posterior chamber of the eye), or even administration of miotics (drugs to constrict the pupil (miosis; pupillary block).

Biographic causes

• Genetic burden – known glaucoma in first-degree relatives (single studies only; risk increase of 2.8-fold).
  • Genetic risk dependent on gene polymorphisms, related to pseudoexfoliation glaucoma (synonym: PEX glaucoma):
    • Genes/SNPs (single nucleotide polymorphism; English : single nucleotide polymorphism):
      • Genes: LOXL1
      • SNP: rs3825942 in the gene LOXL1
        • Allele constellation: CC (10.0-fold, but in 65% of the population).
        • Allele constellation: TT (0.1-fold to 0.03-fold).
        • Allele constellation: CT (slightly lower).
• Anatomical variants – for example, shallow anterior chamber of the eye, narrowing or displacement of the so-called chamber angle; low corneal thickness.
• Ethnic origin – black race (risk increase compared to the white population by four to five times).
• Age – 60 years and older or 40 years and older for African Americans.

Behavioral causes

• Nutrition
  • Micronutrient deficiency (vital substances) – see Prevention with micronutrients.
• Consumption of stimulants
  • Tobacco (smoking) – risk increase of about 88%.
• Psycho-social situation
  • Sleep disturbances: People who slept less than three or more than 10 hours per night were three times more likely to show optic nerve damage from glaucoma than subjects who slept seven hours per night.
• Overweight (BMI ≥ 25; obesity).

Disease-related causes

• Ablatio retinae (retinal detachment).
• Bleeding in the eyeball
• Carotid stenosis (narrowing of the carotid artery)
• Chronic intraocular inflammation – inflammation located in the eye.
• Diabetes mellitus (not an established risk factor for primary open-angle glaucoma; risk factor for secondary glaucoma) Diabetes mellitus, diabetes duration, and fasting glucose levels are associated with significantly increased risk of glaucoma. Diabetes mellitus and fasting glucose levels is associated with slightly increased intraocular pressure
• Hypertension (high blood pressure)
• Insomnia (sleep disorders)?
• Intraocular tumors – tumors located in the eye.
• Myopia (nearsightedness) – risk increase from -5.0 D up to five times.
• Sleep apnea (respiratory failure during sleep).
• Uveitis (inflammation of the middle skin of the eye (uvea), which consists of the choroid (choroid), the ray body (corpus ciliare) and the iris).
• Injuries of the eye
• Central retinal vein occlusion – occlusion of veins supplying the eye.

Laboratory diagnoses – laboratory parameters that are considered independent risk factors.

• Hyperlipidemia (dyslipidemia) – hypercholesterolemia (increased risk of primary chronic open-angle glaucoma (POAG): each 20 mg/dl increase in total cholesterol was associated with a 7% increase in risk of POAG; relative risk of 1.07 was significant with a 95% confidence interval of 1.02 to 1.11; taking statins for at least 5 years reduced risk by 21% (relative risk 0.79; 0.65-0.97))
• Fasting glucose (fasting blood sugar) – diabetes mellitus and fasting glucose levels is associated with mildly elevated intraocular pressure

Medication

• Antidiabetic drugs
  • Biguanides (pressure increase of > 1 mmHg = 14% increased risk of developing glaucoma within five years)
  • Sulfonylureas (pressure increase of > 1 mmHg = 14% increased risk of developing glaucoma within five years).
• Bevacizum – patients with age-related macular degeneration (AMD) who received seven or more intravitreal injections of this drug per year (2.48-fold increased risk)
• Cortisone (ointment or eye drops), long-term treatment.

Environmental pollution – intoxications (poisonings).

• Particulate matter levels – people from neighborhoods in the top quarter of particulate matter levels (PM 2.5) were 6% more likely to suffer from glaucoma than those living in the lowest quarter of particulate matter levels

Other causes

• Increased eye pressure
• Thin cornea (cornea of the eye)