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CONCEPT existing in the diagnosis and management of glaucoma

(Published by Cipla India which will be distributed to Indian Ophthalmologists)

Dr. M. Jain, a leading glaucoma specialist, is currently Medical Director and Chief Ophthalmologist MR J and Jain Eye Institute Hospital Jaipur, India. He has published textbook on glaucoma and a book on EYE INFLAMMATION and published 130 scientific papers in India and abroad. In the year 2007, he published a book of public education in Hindi on "THE EYES: SAFETY and Treatment"

He received Life Time Achievement Award Rajasthan Ophthalmological Society in 2002 and LIFE TIME Achievement Award by the All India Ophthalmological Society, 2006

Mr. Jain is awarded the gold medal by the National Academy of Medical Sciences' research and clinical work in the field of "glaucoma and distribution of drugs to the eye."

Currently, Dr. Jain is the Chairman, Dr MR J Charitable Trust Chairman, Lucky seventh, Medicos SMS and coordinator of State for the National Academy of Medical Sciences.

Current concepts in diagnosis and

Management of glaucoma

PROF. MRJAIN, MS, FICS (USA), FAMS, FACLP (London) MRJINSTITUTE Medical Director

And an eye hospital JAIN JAIPUR

E MAIL: drmrjain55@gmail.com

There has been a revolutionary change in the understanding, diagnosis and management of glaucoma. Earlier, glaucoma was defined as a condition of intraocular pressure, not compatible with the health and function of the eye. Currently, the American Academy of Ophthalmology has defined glaucoma as an optic neuropathy with structural damage to the nerve optical characteristic associated with progressive retinal ganglion cell death, loss of nerve fibers and loss of visual field. The importance intraocular pressure above 21.0 mm Hg as a singular factor has been greatly reduced since about one third of patients could demonstrate classical damage glaucoma in normal intraocular pressure (1,2) or despite controlled IOP after glaucoma surgery, there may be gradual loss of fields.

The definition of glaucoma based on visually important target organ damage (3). It is strictly the opinion that the IOP may damage related occur at all levels of IOP, and thus almost 50 percent of patients with glaucoma remain undiagnosed (4-6). However, Baltimore Eye Survey, and Aravind Eye comprehensive study reveal that the relationship between intraocular pressure and the prevalence of glaucoma is positive. In general, 21mm Hg regarded as a cutoff point.

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TERMS modern diagnostic

Optic nerve head IMMAGING

In addition to direct ophthalmoscopy well established and slit lamp indirect ophthalmoscope using 90 dioptre lens, new diagnostic tools are available to view and accurately document the subtle changes in the disc, on a contour, color, cupping and health of neuroretinal rim. (10/07) These are the following:

1. PHOTOGRAPHY TECHNIQUE

(A) Photographs STEREO

2. Image analysis COMPUTERIZED

(A) Optical coherence tomography (OCT)

(B) Confocal laser scanning TOMOGRAPHY (SCTL)

(C) SCANNING LASER polarimetry (SLP).

These arrangements are particularly useful to quantitatively evaluate retinal nerve fiber layer (RNFL) thickness in addition to changes in the disc is suspected glaucoma. It is established that retinal nerve fiber layer in glaucoma may show thinning even before the changes are detected on the ground (11-14).

Optical coherence tomography (OCT) scan of a normal eye with glaucoma 2 showing the thickness of nerve fibers.

Heidelberg Retinal Tomograph (HRT and HRT II) is a confocal laser scanning system for acquisition and analysis of three-dimensional images of the optic nerve head. HRT imaging system has the highest diagnostic accuracy, accuracy, reproducibility and is able to diagnose glaucoma before confirmed visual field change. (15.16)

Kamal et al (17) and Greaney et al (18) observed imaging techniques that are not better than the quantitative assessment of disc photographs. In addition to the progressive excavation of the optic disc, the Health neuroretinal rim width and reflects the color is very important (8). Localized unilateral notch in the lower part-time or superiority in temporal neuroretinal rim is excellent indicator of glaucoma. Several other minor signs such as asymmetry ratio Cup / disc higher than 0.2, peripapillary halo, disc hemorrhage, signs Herschler vessels exposed floor, ovality vertical optic cup with a ratio higher 3 and a few others when it is present, adds to the suspicion of glaucoma. In recent years, more importance is given to hemorrhage Crossing the rim of the optic nerve and is considered associated with acquired pit of the optic nerve (UPON), which is a very strong association of glaucoma (16,19).

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PROMOTION IN AUTOMATIC field recording

Introduction of field testing automated computer helped us significantly to diagnose at an early stage glaucoma stage as it provides some amount of documentation to monitor and control the progression of glaucoma.

decade has seen tremendous progress in testing strategies, which made the process fast, accurate, reliable and reproducible. (20.21)

SITA (Swedish Interactive Threshold Algorithm) and TOP (Tendency Oriented Perimetry) test strategies have reduced the test time and provided variability automated perimetric tests.

Frequency doubling technology (FDT) perimetry is very fast and efficient method to detect glaucomatous field loss.

Short wavelength automated perimetry (SWAP) is able to predict the onset and progression of glaucomatous visual field defects much earlier than standard automated perimetry (SAP)

Multifocal electroretinogram (MfERG) and multifocal visual evoked potential (mfVEP) provides an objective measure of visual field.

Recent studies suggest procedures that mfVEP may be able to detect glaucomatous damage earlier than conventional automated perimetry. Goldberg and Associates (22) noted that 60 percent of eyes of patients with glaucoma had normal colleagues Humphrey visual field were identified as abnormal by the mfVEP.

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Intraocular pressure

last decade has not experienced significant progress in the methodology of recording the IOP. Despite several types of applanation tonometers including Pneumatonograph Mackay Marg electronic tonometer, (23-27), XL Tonopen (tonometer blood flow) (28) and even non-contact tonometer, Goldman tonometer is the most reliable tonometer clinics, to the extent it is possible to employ this technique. Non Contact Tonometer is convenient for the patient and the physician, but the readings very often do compare well with the Goldman tonometer. The machine needs standardization and repeated several limitations. Outside the scleral rigidity, abnormal thickness central cornea can affect the reading of intraocular pressure (29, 30).

What has changed in the last decade is the understanding of the ideal of the IOP. This IOP was labeled target IOP.

Target IOP is defined as IOP that is safe for that individual. It can be anywhere between the bottom of adolescence to 21 mmHg.

Target IOP is fixed on the following principles:

a. Slight loss of land: reduce IOP by 20% lower IOP

b. Damage moderate: 30% discount or more.

C. Severe damage: reduction of 40% or more.

There is no IOP during which an individual is completely safe against damage of glaucoma and thus target IOP should be individualized based on repeated examinations of records and fields. Risk factors such as aging, myopia, diabetes, heredity etc., (31) also have to keep in mind.

The result of the Advanced Glaucoma Intervention Study (AGIS) data suggest that the decrease in IOP is better, regardless of other factors risk are recognized clinically. In younger patients, the IOP should be kept relatively low (32).

Most therapeutic decisions in glaucoma are based on the steady state pressure. Ophthalmologists rarely document transient spikes or episodic pressure or consider the damage that can cause these spikes. But these episodes are clearly detrimental spikes at the Royal Geographical Society (33). change of posture in IOP when the IOP is reported to increase in lying posture from a sitting position, which is generally used in non-contact Goldmann tonometry, may miss some cases of glaucoma (23-27).

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PERFUSION PRESSURE

Glaucomatous damage on the ground is associated with a decrease in perfusion pressure of neuroretinal rim and lamina cribrosa. He believes that deregulation vascular interferes with the automatic regulation of ocular perfusion and makes the eye more sensitive to increase or decrease the IOP blood pressure. This explains part of the theory of field loss in low intraocular pressure and stresses the importance of using only the anti-glaucoma, which do not perfusion pressure of the optic disc (34,35).

perfusion pressure of the disk can be accurately measured by following techniques:

Heidelberg retinal Flometer

OBF Tonography

Scanning Laser Doppler Flometry

Color Doppler measurements

Some workers reported that the lack of proper perfusion of the optic disc is the main cause of loss field. Such a reduction in perfusion pressure may be due to elevated IOP, or pressure may be independent, which explains the appearance of low tension glaucoma (36-40). Some patients with normal-tension glaucoma are particularly at risk if they have a history of vasospasm and migraine and that accounts for the use of calcium channel blockers to prevent glaucomatous damage. It is note worthy that the perfusion pressure of the optic nerve can recover with the lowering of IOP, especially after trabeculectomy with success (41).

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Apoptosis (programmed cell death)

A normal person loses about 10,000 ganglion cells per year, and when they are 80 years they have lost 30 per cent of ganglion cells. In the case of open angle glaucoma, by the time vision loss is apparent, more than 50 percent of ganglion cells are destroyed.

Apoptosis is a genetically programmed process in which cells commit suicide, characterized by chromatic condensation, fragmentation, intracellular and internucleosomal DNA fragmentation. (42-44)

Retinal ganglion cell death is initiated when an event pathology, such as ischemia, axonal injury, or changes in the cribriform leads to activation of apoptosis (programmed death cell).

Apoptosis can occur because of primary or secondary mechanisms.

Main mechanisms are:

The mechanical stress: elevated IOP may interfere with retrograde axoplasmic flow of essential factors growth produced by the lateral geniculate nucleus.

Vascular compromise: high IOP, vascular disease or drugs can reduce perfusion of the optic nerve, causing ischemic diseases.

Genetic factors: the genetic determinants may also contribute to the susceptibility of ganglion cells damage (45)

Diseases like diabetes can also make neurons more vulnerable to damage.

Secondary mechanisms:

In that damage neurons appears to be motivated by toxic factors such as high levels of glutamate (in normal level, it is a neurotransmitter), free radicals of oxygen, nitrogen or oxide, which can be released by a primary insult, leading to further damage, even after the primary insult has been controlled or dissipated.

Glutamate, an amino acid when in excess is toxic to neuronal cells, thus initiating the process apoptosis. The dead cells are thought to release glutamate and other amino acids, which maintain the vicious circle of "programmed death ganglion cells. We now know that glutamate is a neurotransmitter in the normal retina, if accumulated beyond probably result dead or dying cells, causing further damage to living cells.

Oxygen Free Radicals (OFR) are molecules containing oxygen that carries one or more unpaired electrons. These molecules react with lipids, nucleic acids and proteins and cause cell death. Ischemia which may be independent of pressure, is supposed to help in the process of releasing the OFR.

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Neuroprotection (Enhanced cell survival)

The term "neuroprotection" to refers to the protection of healthy but vulnerable neurons in the vicinity of the dead and dead cells, which are at risk of injury, even after the removal the primary insult. In glaucoma, the goal of neuroprotection is to limit or delay the damage pressure-dependent or independent of the pressure retinal ganglion cells (RGC) by interfering with the processes and substances that cause neuronal cell death either by improving routes signaling increased neuronal survival under stressful conditions. (42,43, 45-47)

Researchers are trying to find the intrinsic processes or natural ways to interrupt the process of apoptosis and promote survival of ganglion cell death by inhibiting signals released in the presence of ischemia, caused by deprivation of growth factors or caused by the accumulation over the excitatory amino acids such as glutamate (48).

Glutamate quantity is shown to increase at double the vitreous in glaucoma.

Neuroprotection is based on the principle of

Reducing risk factors: Lowering IOP reduces ischemia.

Promote neuronal survival

And / or inhibit cell death

excess glutamate can be toxic to normal RGSS by stimulation of more than N-methyl-D-aspartate (NMDA). The NMDA receptor is a major type of glutamate receptor that can kill most active when the ganglion cells the retina. Memantine, amantidine from shows promise for neuroprotective efficacy in glaucoma. interaction with non-compete memantine NMDA receptors results in blockade of the toxic effects of glutamate, without significant effect on normal cell function. Over the NMDA receptor activation by glutamate, more effectively blocks the action of memantine glutamate, thus preventing the death of ganglion cells. (49)

The Bcl-2 family protein gene plays a central role in regulating apoptosis. The family members Bcl-2 genes that promote cell death Bad and Bax are scheduled, however, the expression of bcl-2 and bcl-xl apoptic removes the program. To date, A-2 pathways have been identified that increase the expression of bFGF, induce bcl-2 and bcl-xl genes, and improve the availability of important neurotrophic factors. By activating receptors alpha-2 in the retina, Brimonidine (Brimodin) is shown to increase the expression of genes anti-apoptic thus preventing retinal ganglion cell death and promote axonal growth (50). Brimonidine also neutralizes kainic acid, which is toxic to neuronal cells.

The antioxidants, superoxide dismutase free radical scavenger, catalase and vitamin E are also found potential neuroprotective utility.

calcium channel blockers (diltiazem, nicardipine, nilvadipine, nifedipine, etc.), semax (neuropeptide Russia), citicoline, eliprodil, etc. riluzole and L-deprenal are the study as neuroprotective agents.

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MEDICAL THERAPY

With many existing drugs and new classes of drugs now available to lower IOP, practitioners are faced with complex decisions on treatment strategies for patients with glaucoma. Traditionally, beta-blockers have been considered the standard treatment for glaucoma, but other agents, such as A-2 agonists, carbonic anhydrase inhibitors and prostaglandins have offered other options for the clinician. More recently, a new group, namely, prostamides group came on the scene claims of safety, effectiveness and determination of compliance treatment by the patient, compared to previously available agents.

In general, anti-glaucoma are selected based following criteria:

Efficiency is the most vital

systemic safety profiles

The convenience of treatment OD preferred treatment

The cost of therapy

Local tolerance

According to the criteria listed above, beta-blockers, especially timolol, which is the most effective agent outside the group, dominated the anti-glaucoma. The drug is considered highly effective in reducing IOP by 15-30 percent, with relatively inexpensive excellent tolerance ocular tissues makes them even strongly recommended primary therapy for glaucoma in the world. (What's mandate is systemic adverse effects on respiratory and cardiovascular systems, and issues such as depression, powerlessness, lack of libido, diabetes and hypo tension night (51,52)). The lack of vigilance on the part of doctors may cause patient death due to status asthmaticus or cardiovascular complications. Since the introduction of the drug in 1978, 40 deaths due to drug have been reported. Systemic toxicity can be greatly minimized if the clinician is prudent to advise the use of this medication and take measures to prevent systemic absorption through distributors Specifically, the pressure on the lower puncta or using once a day to form a gel (Timolet GFS) application. Selective beta-blockers such as betaxolol, is relatively safe in patients suffering from respiratory problems, but is less effective than timolol.

Pilocarpine continues to occupy its importance in primary angle glaucoma closed. The drug has a synergistic effect with beta-blockers, brimonidine and topical and systemic acetazolamide group of drugs.

Adrenergic agents (agonists) as dipivefrine, clonidine and apraclonidine have limited specific indications, because they are often associated with conjunctival allergy and other side effects, including reduction of perfusion pressure of the disc.

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New Drugs

Brimonidine tartrate 0.2%

Latanoprost 0.005%

Bimatoprost 0.03%

Travoprost 0.004%

Isopropyl Unoprostone 0.12%

Dorzolamide 2%

Brinzolamide 1% (Azopt)

Brimonidine tartrate:

Brimonidine is a selective 2-agonist. It is an analogue of clonidine. It is about 30 times more selective -2 and has a very low affinity for a -1. Due to this reason, mydriasis and lid lag found with nonselective agonists such as clonidine are eliminated.

Its main mechanism of action is the suppression of aqueous formation, but it is also requested to increase to some extent the flow of uvéoscléral -.

(The largest value of brimodine (Brimodin) is its safety profile and its function on systemic postulated neuroprotection by upregulation of cell survival factors and nervous, as bFGF1 in response to activation of receptors at -2 adrenergic, and increased ocular blood flow. (53-55)) The drug should be instilled twice a day and its IOP lowering effect may be compared with timolol. The demerit is higher IOP trough. The limiting factor is its brimonidine allergic reactions in the form of contact and dermatoconjunctivis follicular conjunctivitis (about 30 percent eyes), which may justify stopping the drug. In recent years, few reports have shown occurrence of uveitis after prolonged use of brimonidine tartrate. Other occasional side effects reported were fatigue, drowsiness and dry mouth. Most recent introduction of brimonidine unpreserved would be far fewer allergies (50%) from the place of benzalkonium chloride, sodium chloride used as a preservative. Therapy, it is equally effective as briomonidine.

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Prostaglandin analogues and prostamides

Prostaglandins and prostamides are newer group of drugs. In Despite their high cost, they are of greater importance because of their greater efficacy in reducing IOP, requiring instillation within 24 hours and have a relatively safe profile, systemic (56-62)

Prostaglandin prostamides and have a common origin in the cell membranes, but are derived from different membrane lipids are mobilized and undergo their biosynthetic pathways of compounds. Prostaglandin analogues F2 alpha are derived from arachidonic acid, an intermediate in their metabolism and training, but prostamides are from a path anandamide where different enzymes are involved. Although prostamides are structurally similar in some respects, prostaglandins, functionally prostamides differ.

Latanoprost, bimatoprost and travoprost are reported to reduce IOP by 30-40 percent and, therefore, they may be the drug of choice as monotherapy in eyes requiring IOP less than target. Superior control day (control 24 hours) with to these drugs, preventing spikes related damage to eyes (56). A comparison of bimatoprost with timolol have shown that many statistically significant of patients using bimatoprost achieved given target IOP at each moment compared to those using timolol. (63) reached target IOP Latamoprost too, but bimatoprost often achieved lower IOP.

analogues of prostaglandin release uvéoscléral without affecting production output or trabecular aqueous humor. The outputs have increased uvéoscléral appears to be mediated by a modification of the extracellular matrix and muscle relaxation ciliary.

Latanoprost is too essentially a drug improving the output. It is 50% increase in output uvéoscléral (64-68) and 30% increase in trabecular exits through a mechanism that has yet to be explained. It is also somewhat stronger flow. (69) Latanoprost is indicated to increase blood flow to the optic nerve head. (67, 68)

Recent comparative studies Lataoprost show to be more effective than unoprostone and timolol, but less than brimatoprost (56). Bimatoprost lowered IOP by 30% in about 78% of patients, while timolol achieved a reduction of 30% in 61% of patients. (56) In addition, 62% of patients receiving bimatoprost obtained 40% reduction in IOP compared to 35% of patients receiving timolol. The combination of latanoprost with timolol when used once a day to give a better reduction in IOP of latanoprost alone. (69) Few workers (70,71) noted additional decrease in IOP was used during pilocarpine four times daily with a single application latanoprost.

The biggest drawback of prostaglandins and prostamides is significant side effects eye manifests as conjunctival hyperemia (15%), tingling sensations and burning body (30-40%) and foreign (20-22%), lash growth, increased pigmentation of the iris and periorbital tissue, including eyes, cystoid macular edema, herpes simplex keratitis, and uveitis.

These drugs are reported to lose the effectiveness of 10-20% if it is exposed to ultraviolet rays unless stored in opaque bottles or latanoprost brimatoprost refrigerator.

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Carbonic anhydrase inhibitors (CAIS)

Topical CAI have been developed that greatly improved systemic side effect profile compared to their counterparts oral. However, the current CAIS are less effective than oral medications. Dorzolamide and brinzolamide reduce IOP by approximately 15-24% and are not effective in all patients.

significant ocular side effects such as burning, stinging, foreign body sensation, superficial punctate keratitis, etc. are noted. In addition, some cases, sulfonamides, such as systemic effects may be noted. Because of these reasons, these drugs are mostly used as a treatment second or third line.

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OCCASIONAL THERAPY

Brimonidine (Brimodin) is as effective as pilocarpine when used with adjunctive beta-blockers, the reduction in IOP of about 15% more. Dorzolamide added to timolol does not significantly affect IOP. Prostaglandins and prostamides can be used as second line therapy with beta-blockers (69), brimonidine (Brimodin), clonidine and agents CAI. Pilocarpine when used four times a day along with latanoprost, provides further reduction in IOP. (71) pilocarpine causes prostamides relaxation of the ciliary muscle and thus is reported as additive

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ABSTRACT

Much progress has been made in diagnosis and treatment of glaucoma, but number of cases can not be labeled as suspicious and medical management remains a challenge.

cholinergic agents and non-selective antagonists of a-adrenergic receptors have been largely replaced by new agents that are better tolerated and have less effect Secondary ocular and systemic. Although antagonists of beta-adrenergic receptors are very effective in lowering IOP officers who were at standard line of treatment for the past 20 years, but serious cardiopulmonary side effects limit their use. Concept of apoptosis perfusion pressure, of the papilla, neuroprotection, metabolic toxins, autoimmune processes and genetic mutation has added a new dimension to the medical management of glaucoma. brimonidine (Brimodin), an A-2 adrenergic receptor agonist, has good IOP lowering effect and safety profile of systemic and is postulated to have property of neuroprotection, but ocular reactions are always a challenge. Treatment with agents such as CAI dorzolamide and brinzolamide can not be considered as first line therapy and are effective only in some. Systemic and ocular side effects limit their use.

Prostaglandins and prostamides drugs are promising because of their effect increased IOP lowering, once per day and application of high-profile security systemic. However, ocular side effects are a serious concern, especially in the white population.

We always looking for an ideal drug with the safety profile, significant decrease in IOP and demonstrated neuroprotection without compromising the pressure perfusion of the optic disc. Memantine could probably be the drug of tomorrow to be used with other ocular hypotensive as a "cocktail" to achieve the desired results.

A paradigm of new glaucoma management has emerged; for clinical success is more only measured by the level of intraocular pressure control obtained, but also by the quality of patient cost-effectiveness of life, therapy, and long-term preservation of visual function.

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About the Author

Prof Dr M. R. Jain has received LIFE TIME ACHIEVEMENT AWARD fro All India Ophthalmological Society for his contribution in the field of Ophthalmology in India and abroad.He is leading Phaco and Glaucoma surgeon og India. He has been Prof and Head of various nedical colleges in Rajasthan for 17 years.He is presently Medical Director, Dr M. r. J Institute & Jain Eye Clinic & Hospital Jaipur. Link: www. mrj-jaineye.com