Glaucoma

Glaucoma is a medical condition of an eye disease as result of the damage of the nerve of eye's optic over time. If left untreated, it can lead to permanently vision impair and blindness.

I. Types of glaucoma(a)
There are several types of glaucoma. The two main types are (Chronically)open-angle and (Acutely)angle-closure both as a result of increase of intraocular pressure (IOP), or pressure inside the eye.
A. Open-Angle Glaucoma affects about three million Americans.
Open-angle glaucoma is the most common form of glaucoma. According to the statistic, it effects over 90% in all glaucoma cases:
1. Open-Angle Glaucoma caused by the slow progesion of clogging of the drainage canals, resulting in increased intraocular pressure (IOP). In the study to investigate risk factors for primary open-angle glaucoma (POAG) and pseudoexfoliative glaucoma (PEXG), showed that intraocular pressure (IOP) was the only factor associated with both POAG and PEXG, whereas moderate-to-high myopia showed borderline significance in both. Vascular systemic diseases and their treatment were associated only with POAG. The implications of these differences for the pathogenesis between the 2 common types of OAG should be explored further(1).

2. Open-Angle Glaucoma as a result of the area  between the iris and cornea (The angle) widen.

3. Open-Angle Glaucoma develops slowly and is a lifelong condition
In the 6-year follow-up study of 118 control patients: 46 with high-tension glaucoma (HTG), 57 with normal-tension glaucoma (NTG), and 15 with pseudoexfoliation glaucoma (PEXG)., the median untreated rate of progression corresponded to advancing from normal visual function to blindness in approximately 70 years, whereas on the basis of the mean rate, visual function would show the same deterioration in approximately 25 years. Large differences existed among patients and different glaucoma types, with PEXG progressing considerably faster than HTG, and NTG progressing at the lowest rate(2).

4.  Symptoms and Damage
The symptoms of gradually progressive visual field loss, and optic nerve changes (increased cup-to-disc ratio on fundoscopic examination) has not been noticed in the early stage of the diseases.
There is a report of 3 cases of ocular injuries were described in young patients, due to accidental fall of durian fruit on the forehead and face, while they were taking rest/sleeping /playing under the durian tree. The ocular injuries observed were lacerating injury of cornea with iris incarceration, hyphema, superficial penetrating injury of sclera and angle recession glaucoma in the right eye of first patient; lacerating injury of cornea with iris prolapse in the left eye of second patient; subconjunctival haemorrhage, traumatic mydriasis and superficial penetrating injury of sclera, commotion retinopathy and macular edema in the left eye of third patient(3).

B. Angle-Closure Glaucoma
Angle-closure glaucoma is a less common form of glaucoma
1. Caused by Sudden rise in intraocular pressure due to blockage of drainage canals and Develops very quickly
Psychotropic agents may frequently be associated with ocular adverse effects, which include angle-closure glaucoma. There is a report of a case of pseudoexfoliation glaucoma in which intraocular pressure (IOP) increased within hours after carbamazepine and gabapentin intake, with no observable evidence of any angle closure(4)

2. Caused by a closed or narrow angle between the iris and cornea
In the study of 5,308 respondents to the Baltimore Eye Survey, a cross-sectional, population-based survey conducted in a multiracial urban community, of that 4,870 subjects whose eyes were dilated on screening examination, none developed acute angle-closure glaucoma. However, 38 patients of the 1,770 who were referred for definitive eye examination were judged to have occludable angles on the basis of gonioscopic methods(5).

3. Symptoms and damage that are usually very noticeable
Paience with Angle-closure glaucoma may be experience the symptoms of sudden ocular pain, seeing halos around lights, red eye, very high intraocular pressure (>30 mmHg), nausea and vomiting, suddenly decreased vision, and a fixed, mid-dilated pupil, etc. as a result of damage due to medication, etc.

II. Causes and Risk Factors
A. Causes
1. Gene
a. MYOC, CYP1B1, and FOXC1 mutations
In primary Glaucoma, Matrix metalloproteinases (MMPs) play an important role in remodeling of the extracellular matrix during development and growth of various tissues including the eye and the defect of MMPs (MMP1 rs1799750 (-1607 1G/2G) and MMP9 rs17576 polymorphisms) might be of value as potential gender-dependent risk factors for developing POAG and PACG, respectively, in the Pakistan's study(6). Other study indicated that LTBP2 gene mutations in north Indian patients with PCG are not involved in the pathogenesis of primary congenital glaucoma in our patients. Thus, it is important to screen other glaucoma-associated loci and genes for involvement in congenital glaucoma in cases that are either negative or heterozygous for MYOC, CYP1B1, and FOXC1 mutations to have better insight into the disease pathogenesis(7).

b. Connective tissue growth factor (CTGF)
The most critical risk factor for optic nerve damage in cases of primary open-angle glaucoma (POAG) is an increased intraocular pressure (IOP) caused by a resistance to aqueous humor outflow in the trabecular meshwork (TM). According to the study by the University of Regensburg, the effects of CTGF on IOP appear to be caused by a modification of the TM actin cytoskeleton. CTGF-overexpressing mice provide a model that mimics the essential functional and structural aspects of POAG and offer a molecular mechanism to explain the increase of its most critical risk factor(8).

c. Alterations of this serine protease
Angle-closure glaucoma (ACG) is a subset of glaucoma affecting 16 million people. According to the study by the The Jackson Laboratory, alterations of this serine protease may contribute to a spectrum of human ocular conditions including reduced ocular size and ACG(9).
 
2. Iactive congenital syphilitic interstitial keratitis
Iterstitial keratitis(IK) is defined as a condition of corneal scarring as a result of chronic inflammation of corneal stroma. According to the study, there is a report of 35 cases of secondary glaucoma due to congenital syphilitic interstitial keratitis. In four cases which had no opacities in the cornea, but with positive serologic reaction for syphilis, the characteristic goniscopical features such as peripheral anterior synechia, pigment deposits in the trabeculum, and irregularity of iris configuration as observed commonly in cases with inactive congenital interstitial syphilitic keratitis(10).

3. Anatomical disorder 
Chronic angle-closure glaucoma is the commonest form of glaucoma in Sino Mongaloid populations. It is an anatomical disorder of the anterior segment of the eye characterised by permanent closure of part of the filtration angle as a result of iris apposition to the trabecular meshwork. According to the study by Radcliffe Infirmary NHS Trust, two pathways lead to this condition: recurrent pupillary block and "creeping" angle closure(11).

4. Atypical ocular ischaemia
Causes of low intraocular pressure in untreated glaucoma can be due to ciliary shut down, retinal detachment, post filtering surgery and ocular ischaemia. There is a report of  a case of bilateral primary angle-closure glaucoma with atypical features of ocular ischaemia(12).


4. Other causes
In the study to evaluate the incidence of glaucoma in the first 275 consecutive eyes that underwent DMEK for Fuchs endothelial dystrophy (260 eyes) or bullous keratopathy (15 eyes), showed that overall, 18 eyes (6.5%) showed postoperative glaucoma after DMEK. Seven eyes (2.5%) had an exacerbation of a pre-existing glaucoma. Eleven eyes (4%) presented with a de novo IOP elevation, associated with air bubble-induced mechanical angle closure (2%), steroid response (0.7%), or peripheral anterior synechiae (0.4%), or without detectable cause (0.7%). Two eyes (0.7%) required glaucoma surgery after DMEK. At 6 months, all eyes had a BCVA of ≥20/40 (≥0.5), and 81% reached ≥20/25 (≥0.8) (n = 16); mean ECD was 1660 (± 554) cells/mm(2) (n = 15) (P > .1)(13).
  
B. Risk Factors
1. In a Randomly selected subjects 60 years of age and older (n=2554) participated in the Thessaloniki Eye Study by the Aristotle University of Thessaloniki, indicated that(15)
In the study to assess the prevalence of primary angle-closure glaucoma (PACG)n in Northern Italy, showed that In multivariate analysis restricted to persons who participated in clinic visits and who had at least 1 phakic eye (n=2078)
a. Intraocular pressure (IOP)(odds ratio [OR], 1.21 per 1 mm Hg; P<.001),
b. PEX (OR, 2.81; P<.001),
c. History of coronary artery bypass or vascular surgery (OR, 1.95; P=.017), and
d. Moderate-to-high myopia (≥ -3 diopters; OR, 2.40; P=.009) were associated with higher odds for Open-angle glaucoma (OAG).

2. In analysis including all clinic visits (n=2261), age became significantly associated (OR, 1.05; P=.004). In multivariate analysis for primary open-angle glaucoma (POAG) (n=1840), associations were found for
a. Age (OR, 1.04 per year; P=.048), IOP (OR, 1.19 per 1 mm Hg; P<.001),
In recent decades the problem of low vision and blindness in elderly people became major and socially significant issue. The number of patients having age-related macular degeneration (AMD) in association with glaucoma grows all over the world that attaches medical and social value to this problem, according to study
b. History of coronary artery bypass or vascular surgery (OR, 2.09; P=.01), and
c. History of diabetes treated with insulin (OR, 3.05; P=.045).
In multivariate analysis for PEXG (n=238), the latter was associated with increased IOP (OR, 1.25 per 1 mm Hg; P<.001)(14).

3. Medical conditions and medication use
Certain medical conditions, such as diabetes, heart diseases, high blood pressure and hypothyroidism and medication used such as corticosteroid for a prolonged period of time are associated with increased risk of Glaucoma. In a case-crossover study design to investigate the association between recent exposure to antidepressant drugs and AACG, showed that recent exposure to antidepressant drugs is associated with an increased risk of AACG. Clinicians should remain vigilant for the development of this uncommon but potentially serious adverse event after initiating antidepressant therapy(14a).
 
4. Other risk factor
Other study indicated there are growing evidences suggested that other risk factors like age, gender, race, refractive error, heredity and systemic factors may play a role in glaucoma pathogenesis. Many studies found that high myopia has been associated with POAG, however, direct and convincing evidences are still lacking(16). 

III. Misdiagnosis and diagnosis
A. Misdiagnosis
1. Scleral buckling dislocation
There is a report of a 71-year-old man with severe permanent optic nerve damage due to previous misdiagnosis of a rare complication of scleral buckling surgery but as misdiagnosed as glaucoma progression(17).

2. Optic neuropathy secondary to compression of the anterior visual pathway
There is a report of a series of six patients who had been receiving treatment for normal tension glaucoma (NTG; five patients) or primary open angle glaucoma (one patient). All of them were found to have optic neuropathy secondary to compression of the anterior visual pathway(18).

3. Chiasmal compression 
Routine neuroimaging for patients with presumed normal-tension glaucoma (NTG) is a contentious issue and it has been suggested that it may be unnecessary due to the low yield for detecting intracranial pathology.  There is a report of 8% of patients diagnosed with NTG have associated compressive lesions of the anterior visual pathways(19).

4. Other cases of misdiagnosis
a. Spinal stenosis 
There is a report of a case of a 66 year old woman was admitted to the orthopaedic ward for elective spinal canal decompression for spinal stenosis, but the diagnosis of bilateral angle closure glaucoma was evebtually made, due to symptoms of visual loss, a red eye, both eyes were red with cloudy corneas; shallow anterior chambers; fixed, mid-dilated pupils; and high intraocular pressures of 45 mm Hg in the right eye and 33 mm Hg in the left eye (normal <21 mm Hg), etc.(20).

b. Left conjunctivitis
There is a report of a case of a 80 year old woman was admitted to the medical ward with sudden onset of severe left periorbital pain, frontal headache, and blurred vision in the left eye. She was diagnosed as having left conjunctivitis, treated with chloramphenicol eye drops, and discharged. 4 months later, she was readmitted after a fall and treated on the medical ward for a urinary tract infection. During admission, she complained of left eye pain and headache of four months' duration. The left eye was red, and the left pupil was dilated and slowly reactive. An ophthalmic examination revealed Snellen visual acuity of no perception of light in the left eye and 6/9 in the right eye, left corneal oedema, shallow anterior chambers, and intraocular pressures of 48 mm Hg in the left eye and 12 mm Hg in the right eye. A diagnosis of left angle closure glaucoma was made, and the standard medical regimen was started(20).

c. Hyperglycaemia and sepsis
There is a report of  a 77 year old woman with angle closure glaucoma, but was misdiagnosed as hyperglycaemia and sepsis, treated with benzylpenicillin and ciprofloxacin, and given a diet to control her diabetes.Then misdiagnosed again as conjunctivitis and  and was treated with chloramphenicol eye ointment by the ward physicians and referred as a non-urgent case to ophthalmology(20).

B. Diagnosis
If you are experience some of the above symptoms, after recording your family history and complete physical exam, including a comprehensive eye examination, the tests which you doctor orders may include
1. Test for intraocular pressure
The aim of the totometry is to measure the internal eye pressure, after numbing your eyes with drops. Unfortunately, in the study  to compare intraocular pressure (IOP) measurements by Perkins tonometer and Tono-Pen in young children with primary congenital glaucoma (PCG), found that Tono-Pen readings disagree with Perkins tonometer measurements for measuring IOP in children with PCG who present with IOP greater than 16 mm Hg and tends to overestimate IOP(21).

 2. Optic nerve damage testA medical instruments used by your doctor to look directly through the pupilinto the back of your eye. Any damage to the optic nerve may be an indication of early case of glaucoma. 

3. Visual field test
The aim of the eye examination that can detect dysfunction in central and peripheral vision.

4. Visual acuity
the aim of the examination is to test how far distance that you eye can see.

5. Test for cornea thickness (pachymetry).
The aim of the test is to determine the thickness of each cornea,  According to the study by the Sungkyunkwan University School of Medicine, in comparison of the potential differences in the phenotypes between Western normal-tension glaucoma (NTG) and Korean NTG. Korean NTG patients showed steeper cup shapes, thicker RNFL thickness, and thinner central corneal thickness compared with Western NTG patients with similar amounts of visual field loss. This result may help clinicians understand the clinical characteristics of NTG patients and points to the heterogeneous character of the glaucomas(22).

6. Gonioscopy
Gonioscopy is the test with the use of a gonioscope in conjunction with a operating microscope
to examine the the drainage angle to distinguish glaucoma, such as open-angle glaucoma and angle-closure. According to the stduy by the The University of Michigan, the examination of Gonioscopy include beginning the examination with the inferior anglewith the inferior angle, methods to help in looking over the iris, cycloplegia, locating the corneal wedge, indentation, van Herick estimation, examining the other eye, and topical glycerin(23).
 
IV. Complications and diseases associated to Glaucoma
A. Complications
1. Psychosomatic symptoms
Studies on open-angle glaucoma have shown that many patients suffering from this disease are anxious, hypochondric, perfectionist and emotional instable, according to the Praxis an der Lichtwiese(24).

2. Scotomas
In the study to characterize the progression pattern of initial parafoveal scotomas (IPFSs)  in Glaucoma using cross-sectional and longitudinal 10-2 visual field (VF) data, showed that superior and inferior IPFS have a similar characteristic pattern of progression, although the latter tend to be farther from fixation. Understanding these patterns should help in the management of such patients and in improving VF testing algorithms(25).

 3. Abnormal central visual function
Glaucoma has traditionally been thought to affect peripheral visual function in its early stages and to spare central visual function until late in the disease process. According to the study by Dr. Stamper RL., histologic studies of the nerve fiber layer in eyes with glaucoma suggest that the number of ganglion cells subserving macular function is decreased even in early stages of the disease. In addition, afferent pupillary defects (a gross measurement of macular nerve fiber function) may also be present in eyes with early glaucoma. Several studies have demonstrated that color perception (largely mediated by the fovea) is defective in glaucoma. Furthermore, defects in color perception may even precede the development of visual field abnormalities. Seventy-eight percent of patients with early glaucomatous visual field defects were found to have a defect in color perception when tested with a desaturated D-15 color panel that tests only the central 1.5 degrees. In addition, both chromatic and achromatic foveal perception channels are defective in eyes with glaucoma and even in some eyes of those with suspected glaucoma. Contrast sensitivity has become recognized as an important component of visual function(26).

3. Retinal ganglion cell loss (RGC)
Late stage of Glaucoma  may result in progressive death of the retinal ganglion cells (RGCs) of that can leads to optic nerve degeneration and vision loss. According to the study by the University Eye Diseases Clinic, bearing in mind the fact that the exact pathogenic mechanism is still not completely established, glaucoma treatment strategies so far are based upon the identification of glaucoma risk factors. Among them, only elevated intraocular pressure (IOP) could undergo therapeutic treatment. However, in spite of the adequate therapy and IOP lowering, very often the disease is still progressing, leading to definite visual loss and permanent blindness. This especially refers to "normal tension glaucoma". Over the last decade, there has been significant scientific research on new strategies for the delay or prevention of retinal ganglion cell loss (RGC), which is the basic pathophysiological event that initiates the cascade of processes leading to optic atrophy(27).

B. Diseases associated to Glaucoma
1. Familial exudative vitreoretinopathy 
There are cases of angle-closure glaucoma in patients with familial exudative vitreoretinopathy have been reported secondary to neovascularization of the anterior segment. According to the Thomas Jefferson University, there may be an association between familial exudative vitreoretinopathy and angle-closure glaucoma as a direct result of a retrolental process or more likely a relative lens-iris pupillary block with a large lens(28).

2. Diabetes
Diabetes mellitus contributes to an earlier and a quicker development of opacities of the lens and worsening of the vision in affected people. According to the study by Z Kliniki Okulistyki Uniwersytetu Medycznego w Białymstoku, the main source of energy in the human lens is glucose, which is metabolised through the glycolytic process. When the level of glucose increases in blood, its content also increases in aqueous humour and in the lens. It causes a saturation of the glycolytic process and the activation of the sorbitol pathway with participation of aldose reductase. The accumulation of sorbits responsible for the growth of osmotic pressure inside the lens, inflow of water and gradual swelling of its fibres. In extreme cases a swelling of the lens can even lead to occurrence of cataracta intumescens and secondary glaucoma(29).

3. Headache
Acute headache is a common presenting symptom in the acute medical unit. There is a case of Acute Angle Closure Glaucoma (AACG) presenting with acute severe headache(30).

4. Retinal Detachment
In the study of a 63-year-old Caucasian man with a 55-year history of long-standing retinal detachment after trauma presented to our facility with pain and redness, a total hyphema, no light perception vision and an intraocular pressure of 60 mmHg (right eye and had a history of diabetes mellitus and coronary artery disease, found that  following anterior chamber washout, he was found to have neovascular glaucoma, for which intravitreal bevacizumab was administered(31).

5. Marfan Syndrome
There is a report of a case of a 41-year-old woman with bilateral lens subluxation and medically uncontrolled glaucoma in whom Marfan syndrome (MFS) was diagnosed(32).

6. Uveitis
There is a reprot of a 43-year-old Cuban pseudophakic male was seen multiple times over a 3-year period complaining of floaters and blurry vision in his left eye. He was noted to have an inferotemporally displaced posterior chamber intraocular lens and recurrent microhyphemas with elevated intraocular pressure (IOP) readings between 29 and 46 mm Hg with each episode. He was diagnosed with UGH syndrome(33).

7. Cataract
There is a report of a case of lens particle glaucoma in a child with an untreated unilateral congenital cataract and persistent fetal vasculature (PFV) and to discuss the implications for the management of unilateral congenital cataract.
Methods(34).

8. Scleritis
There is a report of a 14-year-old boy with unilateral acute angle-closure glaucoma secondary to posterior scleritis associated with Sturge-Weber syndrome, according to the Hirosaki University School of Medicine(35).

9. Etc.

V. Preventions
A. The do and do not's list
1. Eye yearly examination
The exam can detect any eye disease in early stage. It is recommended that people to have regular eye examination every year and comprehensive eye examination every three to five years.

2. Avoid Nutrient deficiency
There is a report of Rats fed a Vit E-deficient diet with surgically induced intraocular pressure (IOP) elevation experience significantly more retinal ganglion cells (RGCs) death than rats fed a normal diet. This phenomenon may be related to the increased level of lipid peroxidation in Vit E-deficient rats(36). Vitamin A, B(9), C, E, and uric acid are well-known antioxidants and may prevent age-related eye disorders, according to the study by, normal-tension glaucoma patients had lower serum levels of vitamin C and increased levels of uric acid. These observations may pave the way for possible alternative treatment for normal-tension glaucoma(37).

3. Avoid vitamin A deficiency
In the study to investigate the prevalence and causes of blindness in sub-Saharan Africa, the existing services and limitations, and the Vision 2020 goals for the future, showed that the bulk of blindness in the region is preventable or curable. Efforts should focus on eye problems which are universally present and for which there are cost effective remedies, such as cataract and refractive problems and on those problems which occur focally and can be prevented by primary healthcare measures, such as trachoma, onchocerciasis, and vitamin A deficiency(38).

4. Glaucoma eyedrops
If you are experience Elevated eye pressurem, some researchers suggested the use of Glaucoma eyedrops as it can significantly reduce the risk that elevated eye pressure of that will progress to glaucoma.

5. Prevention eye damage
There are some reports that serious eye injuries can lead to glaucoma, such as a problem secondary posttraumatic glaucoma caused by perforative eye injuries or contusions of the eyeball(39). or Secondary glaucoma in eye injuries complicated by trauma of the crystalline lens(40).

6. Lower your iblood sugar levels
If you are diabetic, low your sugar levels may reduce the risk of Glaucoma, as diabetes mellitus contributes to an earlier and a quicker development of opacities of the lens and worsening of the vision in affected people(41).

7. Exercise regularly or not
In diabetic rat study, moderate physical exercise has marked anti-inflammatory effects. This may be an efficient strategy to protect diabetics against microorganism infection, insulin resistance and vascular complications(42), but according to the study by the University of Iowa Hospitals and Clinics, although the authors do not believe that all patients with the pigmentary dispersion syndrome or pigmentary glaucoma need to avoid exercise, however, for patients with these disorders who regularly engage in jogging or more strenuous or more jarring types of exercise, they suggest an evaluation before and after the type of exercise in question. If marked exercise-induced pigment dispersion occurs, pilocarpine therapy may be an alternative to avoidance of the exercise(43).

8. Lifestyle 
According to the review by the Massachusetts Eye and Ear Infirmar, various modifiable lifestyle factors, such as exercise, diet, and cigarette smoking, that may influence intraocular pressure and that have been studied in relation to the risk of developing POAG(43a).


B. Diet to prevent Glaucoma 
1. Flaxseed
In the study to determine whether there is an association between dietary omega-3 (omega-3) fatty acid intake, age, and intraocular pressure (IOP) caused by altered aqueous outflow, found that increasing dietary omega-3 reduces IOP with age because of increased outflow facility, likely resulting from an increase in docosanoids. This indicates that dietary manipulation may provide a modifiable factor for IOP regulation. However, further studies are needed to consider whether this can modify the risk for glaucoma and can play a role in treatment of the disease(44).

2. Cod liver oil

According to the study  by the State Key Laboratory of Ophthalmology, Sun Yat-sen University, cod liver oil, as a combination of vitamin A and omega-3 fatty acids, should be beneficial for the treatment of glaucoma. However, further studies are needed to explore the relationship between cod liver oil and glaucoma(45).

3. Green tea
Epigallocatechin-gallate (EGCG) is a powerful antioxidant with suggested neuroprotective action found abundantly inj Green tea. In the study to evaluate the effect of short-term supplementation of EGCG on inner retinal function in ocular hypertension (OHT) and open-angle glaucoma (OAG), showed that although this study cannot provide evidence for long-term benefit of EGCG supplementation in OAG, and the observed effect is small, the results suggest that EGCG might favourably influence inner retinal function in eyes with early to moderately advanced glaucomatous damage(46).

4. Blackcurrant
Cataracts, glaucoma, and age-related macular degeneration (AMD) are common causes of blindness in the elderly population of the United States. According to the study by the Sapporo Medical University School of Medicine, Upon administration of BCACs, the ocular blood flows during the 24-month observational period increased in comparison with placebo-treated patients. However, no significant changes were observed in systemic and ocular conditions including IOP during the 24-month period. Oral administration of BCACs may be a safe and promising supplement for patients with OAG in addition to antiglaucoma medication(47).


C. Phytochemicals to prevent Glaucoma
1. Long chain polyunsaturated fatty acids
Recent notions in connection with oxidative stress and the fat balance of long chain polyunsaturated fatty acids (PUFA) families have brought new insight to a probable role of nutritional factors in glaucoma and intraocular hypertony. According to the study by Centre d'Imagerie, Laser, et Réadaptation Basse Vision, a diet with increased omega-3 and decreased omega-6 could thus favor an increase in intraocular pressure reducing synthesis of PG-F2, leading to a decrease in uveoscleral outflow. The true importance of these factors has not yet been solidly determined and studies are in progress to clarify the real implication of these nutritional factors(48).
Other study indicated that since EPA and DHA could modulate impaired systemic microcirculation and ocular blood flow and optic neuropathy, which are the main physiological changes associated with glaucoma(49). 

2. Epigallocatechin gallate (EGCG)
Accoridng to the study by Nuffield Laboratory of Ophthalmology, the study of Orally administered epigallocatechin gallate attenuates retinal neuronal death in vivo and light-induced apoptosis in vitro, support the view for the use of EGCG in the treatment of glaucoma based on the premise that any potential neuroprotective agent must be administered orally, have a safe profile and poses a broad spectrum of properties that allows various risk factors (that include ischemia and light) to be attenuated(50).

3. Anthocyanins
According to the study by the Oklahoma State University, a randomized, placebo-controlled, double-masked 24-month trial (Ophthalmologica 2012;228:26-35), revealed that oral administration of black currant anthocyanins (BCACs) slowed down the visual field deterioration and elevation of ocular blood flow of open-angle glaucoma (OAG)(51).

4. Resveratrol
According to the study by Duke University Medical Center, resveratrol treatment effectively prevented increased production of intracellular reactive oxygen species (iROS) and inflammatory markers (IL1alpha, IL6, IL8, and ELAM-1), and reduced expression of the senescence markers sa-beta-gal, lipofuscin, and accumulation of carbonylated proteins. Furthermore, resveratrol exerted antiapoptotic effects that were not associated with a decrease in cell proliferation. These results suggest that resveratrol could potentially have a role in preventing the TM tissue abnormalities observed in primary open-angle glaucoma (POAG)(52).

D. Antioxidants to prevent Glaucoma
1. Glutathione and vitamin E
There appear to be two different pathways of ECM remodelling and apoptosis induction in POAG. The pathway for collagen remodelling and apoptosis induction seems to be exogenously influenced by water-soluble antioxidants, for example, glutathione. The pathway for elastin remodelling and apoptosis induction seems to be influenced by endogenous lipid-soluble antioxidants, for example, vitamin E. Roles can be defined for antioxidants in the two different pathways of ECM remodelling and apoptosis induction. This suggests that antioxidants are important in maintaining cellular homeostasis relevant to the aetiology of POAG, according to the study by Veach J(53).

2. 3-methyl-1,2-cyclopentanedione (MCP), Red wine-polyphenols, Anthocyanoside, Ubiquinone and Melatonin
Glaucomatous optic neuropathy implies loss of retinal ganglion cells, including their axons, and a major tissue remodeling, especially in the optic nerve head. According to the study by the University Hospital Basel, various natural compounds possess potential antioxidative value. Reduction of oxidative stress at the level of mitochondria can be achieved by gingko biloba. Polyphenolic compounds, such as tea, red wine, dark chocolate, or coffee have antioxidative properties. Coffee contains 3-methyl-1,2-cyclopentanedione (MCP), capable of scavenging peroxynitirite. Red wine-polyphenols (e.g., resveratrol), exert vasoprotective effects by inhibiting the synthesis of endothelin-1. Dark chocolate decreases blood pressure and improves endothelium-dependant vasorelaxation. Anthocyanosides (bilberries) owe their antioxidant effects to their particular chemical structure. Other antioxidants include ubiquinone and melatonin(54).

Unfortunately, in the study to examine the relation between dietary antioxidant intake and primary open-angle glaucoma risk  in participants aged over 40 years in the Nurses' Health Study (n = 76,200) and the Health Professionals Follow-up Study (n = 40,284), indicated that the study did not observe any strong associations between antioxidant consumption and the risk of primary open-angle glaucoma(55). 

VI. Treatments
A. In conventional medicine perspective 
A.1. Eye-drops include
1. Prostaglandins used to treat patients with open-angle glaucoma.
In the study to evaluate the safety and efficacy of tafluprost, a fluoroprostaglandin receptor analog, for reduction of intraocular pressure in open angle glaucoma and ocular hypertension, indicated that Since can not be cure, the aim of the treatment is to lower pressure in your eye (intraocular pressure) or improve drainage of fluid or lower the amount of fluid produced in your eye, depending to the types of the disease. Since its introduction in 2008, initial studies have demonstrated that preserved and preservative-free tafluprost formulations have proven efficacy and safety in the treatment of glaucoma and ocular hypertension. Larger studies with longer follow-up are needed to assess long-term safety, efficacy, and tolerability compared with other prostaglandin analogs used for treating glaucoma(56).

2. Beta blockers used to reduce the production of fluid and pressure in your eye.
According to the study by Royal Victorian Eye and Ear Hospital, the most serious side effects of beta-blockers are the exacerbation of chronic obstructive airways disease with nonselective agents and the precipitation of bronchospasm in some patients. Betaxolol seems relatively free of adverse respiratory effects, although this may be dose-related and extreme caution should still be exercised in patients with any history of respiratory illness. Because of the lower risk of precipitating side effects, betaxolol is probably the beta-blocker of first choice for use in glaucoma; timolol or levobunolol are reserved for patients who do not respond satisfactorily to betaxolol and are quite free of respiratory disease(57).

3. Alpha-adrenergic agonists used to reduce the production of aqueous humor and increase outflow of the fluid in your eye.
In the study to compare the alpha2-adrenergic agonist brimonidine tartrate 0.2% to the beta-adrenergic antagonist timolol maleate 0.5% in preserving visual function in low-pressure glaucoma, showed that low-pressure glaucoma patients treated with brimonidine 0.2% who do not develop ocular allergy are less likely to have field progression than patients treated with timolol 0.5%(58).

4. Miotic agents used to  increase the outflow of fluid in your eye.
Pilocarpine, a parasympathomimetic drug used in the treatment of glaucoma, produces a variety of ocular and systemic adverse reactions, such as miosis, accommodative spasm, frontal headaches, twitching lids, conjunctival injection, cataractous changes, allergic reactions, iris cysts, retinal detachment, increased permeability of the blood-aqueous barrier, anterior chamber narrowing, and the potential for inducing an acute angle-closure attack(59).

A.2.  Oral medications if eye-drop fails
Oral medication such as the local carbonic anhydrase inhibitors (CAH) dorzolamide and brinzolamide have become well established in the drug therapy of glaucoma. They lower intraocular pressure (IOP) by blocking specifically carbonic anhydrase in the ciliary epithelium and thereby the secretion of aqueous humor, according to the study by Institut für Anatomie - LS II, Universität Erlangen-Nürnberg(60). With side effects not limit to frequent urination, a tingling sensation in the fingers and toes, depression, stomach upset, etc.

A.3.  Gene therapy

Retinal degenerations encompass a large number of diseases in which the retina and associated retinal pigment epithelial (RPE) cells progressively degenerate leading to severe visual disorders or blindness.
Retinal degenerations can be divided into two groups(environmental and genetic influences, and the second group belong glaucoma, age-related macular degeneration (AMD) and diabetic retinopathy (DR)). According to the study by Universitätsaugenklinik / IZKF Aachen, in the last few years inhibitors of vascularization, especially antibodies against vascular endothelial cell growth factors (VEGF), have been used to prevent the neovascularization that accompanies AMD and DR resulting in the amelioration of vision in a significant number of patients. In animal models it has been shown that transfection (the process of deliberately introducing nucleic acids into cells) of RPE cells with the gene for PEDF and other growth factors can prevent or slow degeneration. A limited number of studies in humans have also shown that transfection of RPE cells in vivo with the gene for PEDF is effective in preventing degeneration and restore vision. Most of these studies have used virally mediated gene delivery with all its accompanying side effects and have not been widely used(61).


A.4. Surgery
Surgery in some cases may be necessary, if patients do not respond to the neither treatments of eye-drops and  oral medication.
1. Laser surgery
The angle closure glaucomas are defined by iridotrabecular contact, trabecular dysfunction, and elevated intraocular pressure (IOP). According to the study by Manhattan Eye, Ear, and Throat Hospital, laser iridotomy successfully eliminates the relative pupillary block component of the angle closure process, regardless of whether the underlying angle closure is related primarily to pupillary block or another mechanism(62).

2. Filtering surgery
The aims of the treatment is to help the eye drain liquid more effectively. According to the study by Capital University of Medical Science and Medical Faculty Mannheim of the Ruprecht-Karls-University Heidelberg, after marked reduction of high IOP, some eyes of young adult patients with glaucoma can show a horizontal shrinkage of the optic nerve head, in addition to a partial restoration of the neuroretinal rim and a flattening of the optic cup. In addition, beta zone of parapapillary atrophy can decrease or increase, complementarily to changes in the horizontal disc diameter(63).


3. Drainage implants
The treatment is often used in patients who are poor candidates for glaucoma filtration surgery. In the study to review  and to critically compare the various glaucoma drainage implants in popular use, showed that there are several glaucoma drainage implants that are currently available, and all have been shown to be safe and effective in reducing intraocular pressure. Greater pressure reduction may be achieved with implants with larger end plates, and valved implants appear to reduce the risk of postoperative hypotony(64).


4. In case of Acute angle-closure glaucoma   
According to the study by Hôpital Saint Joseph, acute angle closure attack is more symptomatic, with a red painful eye and elevated intraocular pressure. In both cases, iridocorneal angle closure is due to an increase in the thickness of the natural lens, which with age has a tendency to close a narrow angle. The rational approach to treating these situations is lens extraction. With today's improved lens extraction techniques, this surgical treatment should be proposed more frequently(65). 

 
B. In herbal medicine perspective
1. Ginkgo biloba extract and bilberry
Ginkgo biloba extract (GBE) and anthocyanins are considered beneficial for various vascular diseases. According to the study by the Sungkyunkwan University School of Medicine, indicated that after anthocyanin treatment, the mean BCVA for all eyes improved from 0.16 (±0.34) to 0.11 (±0.18) logMAR units (P=.008), and HVF mean deviation improved from -6.44 (±7.05) to -5.34 (±6.42) (P=.001). After GBE treatment, HVF mean deviation improved from -5.25 (±6.13) to -4.31 (±5.60) (P=.002). A generalized linear model demonstrated that the final best-corrected visual acuity (logMAR BCVA) was not affected by demographic differences among the groups. These results suggest that anthocyanins and GBE may be helpful in improving visual function in some individuals with NTG(66).

2. Physostigma venonosum
Accoring to the study by Phytotherapy Research Laboratory, University of Nigeria, physostigmine (from Physostigma venonosum) used for the treatment of glaucoma to the recently identified antiviral agents from Ancistrocladus abbreviatus(67).

3. Blackberries & Other Berries
Anthocyanins, members of the flavonoid, are water-soluble vacuolar pigments that are responsible for the red, purple, and blue colors of many fruits, such as Blackberries & Other Berries. According to the study by the Oklahoma State University, a randomized, placebo-controlled, double-masked 24-month trial (Ophthalmologica 2012;228:26-35), revealed that oral administration of black currant anthocyanins (BCACs) slowed down the visual field deterioration and elevation of ocular blood flow of open-angle glaucoma (OAG)(68). 

4. Grape seed and skin
Resveratrol is a phytochemical in the class of Stilbenoids, found abundantly in skins and seed of grape wine, nuts, peanuts, etc. According to the study by Duke University Medical Center, resveratrol treatment effectively prevented increased production of intracellular reactive oxygen species (iROS) and inflammatory markers (IL1alpha, IL6, IL8, and ELAM-1), and reduced expression of the senescence markers sa-beta-gal, lipofuscin, and accumulation of carbonylated proteins. Furthermore, resveratrol exerted antiapoptotic effects that were not associated with a decrease in cell proliferation. These results suggest that resveratrol could potentially have a role in preventing the TM tissue abnormalities observed in primary open-angle glaucoma (POAG)(69).

C.  In traditional Chinese medicine perspective 
1. Neiyingxiang (EX-HN 9) 
In the study to observe the effect of pricking blood at Neiyingxiang (EX-HN 9) on the intraocular pressure of patients of primary open angle glaucoma (POAG) in a gtotal of ninty-six cases (166 eyes) were randomly divided into an observation group (44 cases treated with pricking blood at Neiyingxiang (EX-HN 9) and a control group (52 cases treated with 0.5% Timolol Maleate drops in eyes.) found that the intraocular pressure were (29.81 +/- 3.49) mmHg and (23.18 +/- 3.61) mmHg before and after treatment in the observation group, and (29.94 +/- 3.64) mmHg and (23.88 +/- 3.96) mmHg in the control group respectively(70).

2. Acupuncture at bilateral "Qiuhou" (EX-HN 7),"Fengchi" (GB 20) and "Xingjian" (LR 2)
In the study to explore the protection effects of acupuncture on glaucomatous optic nerve damage and its mechanism with the acupuncture group was treated with acupuncture at bilateral "Qiuhou" (EX-HN 7),"Fengchi" (GB 20) and "Xingjian" (LR 2), twice a day. The neurotrophy group was treated with intramuscular injection of Vitamin B1 (100 mg) and Vitamin B12 (500 microg), once a day, and the other groups with no treatment, found that acupuncture can raise the expression of Bcl-xl and BDNF of retina, so as to prevent optic nerve damage caused by intraocular hypertension(71).
Other study to explore the mechanism of acupuncture on the treatment of glaucoma, indicated that after acupuncture, IOP at each time point reduced as compared with that before acupuncture. IOP at 5 a.m., 7 a.m., 10 a.m., 6 p.m. and 10 p.m. after acupuncture was different significantly in statistics as compared with that before acupuncture correspondingly (all P<0.05). After acupuncture, 24 h diurnal IOP variation was (5.31 +/- 2.84) mmHg, which was lower significantly than (7.06 +/- 3.86) mmHg before acupuncture (P<0.05)(72).

3. Treatment on glaucoma with acupuncture of removing the stagnated live qi and activating blood circulation
According to Dr. ZHANG Ren, a chief physician, the treatment is applicable on primary open-angle glaucoma, and especially effective for normal tension glaucoma. His basic point prescription is: Muchuang (GB 16), Taiyang (EX-NH 5), Fengchi (GB 20), Xingjian (LR 2), Xinming1 (Extra), Shangjingming (Extra), Chengqi (ST 1), Shangtianzhu (Extra), etc. Meanwhile, supplementary methods such as acupoint injection, ear therapy and dermal needles are also adopted to improve the eye symptoms and recover the vision in a certain degree(73).

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