CURRENT CONCEPTS IN DIAGNOSIS AND MANAGEMENT OF GLAUCOMA PROF. M. R.JAIN, M.S., F.I.C.S.(USA), FAMS, FACLP( London) MEDICAL DIRECTOR M.R.J.INSTITUTE & JAIN EYE HOSPITAL JAIPUR E MAIL : drmrjain55@gmail.com There has been a revolutionary change in understanding, diagnosis and management of glaucoma. Earlier the glaucoma was defined as a condition of raised intraocular pressure, not compatible with health and function of eye. Presently, American Academy Of Ophthalmology has defined glaucoma as an optic neuropathy with characteristic structural damage to optic nerve, associated with progressive retinal ganglion cell death, loss of nerve fibers and visual field loss. The importance of intraocular pressure above 21.0 mm of Hg as a singular factor has been significantly minimized since about one-third of patients might show classical glaucomatous damage with normal intraocular pressure (1,2) or in spite of controlled IOP after glaucoma surgery, there may be progressive loss of fields. The definition of glaucoma is based on visually significant end-organ damage (3) . It is conclusively opined that IOP related damage can occur at all levels of IOP, and hence almost 50 percent of glaucoma patients remain undiagnosed (4-6) . However, Baltimore Eye Survey and Aravind Comprehensive Eye Study reveal that the relationship between the intraocular pressure and the prevalence of glaucoma is positive. Generally, 21mm of Hg is considered as a cutoff point. Top MODERN DIAGNOSTIC MODALITIES OPTIC NERVE HEAD IMMAGING In addition to the well established Direct Ophthalmoscopy and Slit Lamp Indirect Ophthalmoscopy using 90 diopters of lens, newer diagnostic tools are available to precisely visualize and document subtle changes in the disc, depending upon the contour, colour, cupping and the health of neuroretinal rim. (7-10) These are as follows: 1. PHOTOGRAPHY TECHNIQUE (a) STEREO PHOTOGRAPHS 2. COMPUTERISED IMAGE ANALYSIS (a) OPTICAL COHERENCE TOMOGRAPHY (OCT) (b) CONFOCAL SCANNING LASER TOMOGRAPHY (CSLT) (c) SCANNING LASER POLARIMETRY (SLP). These modalities are especially useful to quantitatively assess retinal nerve fibre layer (RNFL) thickness in addition to changes in the disc in suspected cases of glaucoma. It is established that retinal nerve fibre layer in glaucoma may show thinning even before the field changes are detected (11-14). Optical Coherence Tomography (OCT) scan of a normal 2 glaucomatous eye, showing nerve fibre thickness. Heidelberg Retinal Tomograph (HRT and HRT II) is a confocal laser scanning system for acquisition and analysis of three-dimensional images of optic nerve head. HRT imaging system has the highest diagnostic precision, 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 that imaging techniques were not better than quantitative assessment of disc photographs. In addition to progressive excavation of the optic disc, the health of neuroretinal rim evidenced by its width and colour is very important (8) . Localized unilateral notch in the inferio-temporal or superio-temporal part of neuroretinal rim is strong indicator of glaucoma. Several other soft signs like asymmetry of cup/disc ratio greater than 0.2, peripapillary halo, disc hemorrhage, Herschler's sign of exposed floor vessels, vertical ovality of optic cup with a ratio of greater than 3 and few others when present, adds to suspicion of glaucoma. In recent years, more importance is given to a disc hemorrhage crossing the rim of the optic nerve and it is considered to be associated with the acquired pit of the optic nerve (APON), which is a very strong association of glaucoma (16,19) . Top ADVANCEMENT IN AUTOMATED FIELD RECORDING Introduction of computerized automated field testing has helped us significantly to diagnose glaucoma at an early stage as well as it provides certain amount of documentation to monitor the control and progression of glaucoma. Last decade has seen immense advances in test strategies, which has made the process quick, precise, reliable and reproducible. (20,21) SITA (Swedish Interactive Threshold Algorithm) and TOP (Tendency Oriented Perimetry) test strategies have reduced the testing time and provided variability of automated perimetric testing. Frequency Doubling Technology (FDT) perimetry is very rapid and effective method to detect glaucomatous field loss. Short Wavelength Automated Perimetry (SWAP) is able to predict the onset and progression of glaucomatous visual field deficits much earlier than the Standard Automated Perimetry (SAP) Multifocal Electroretinogram (mfERG) and Multifocal Visual Evoked Potential (mfVEP) provide an objective measurement of the visual field. Recent studies suggest that mfVEP procedures may be able to detect glaucomatous damage earlier than the conventional automated perimetry. Goldberg and associates (22) noted that 60 percent of fellow eyes of glaucoma patients that had normal Humphrey visual field were identified as abnormal by the mfVEP. Top INTRAOCULAR PRESSURE Last decade has not seen any significant advancement in the methodology of recording IOP. In spite of several types of tonometers including Applanation Pneumatonograph, Mackay Marg Electronic Tonometer, (23-27) , Tonopen XL (blood flow tonometer) (28) and even Non Contact Tonometer, Goldman Tonometer remains the most reliable clinical Tonometer, wherever it is possible to employ this technique. Non Contact Tonometer is convenient to the patient and to the doctor but the readings quite often does not compare well with the Goldman Tonometer. The machine needs repeated standardization and has several limitations. Apart from scleral rigidity, abnormal central thickness of the cornea can affect the intraocular pressure reading (29, 30) . What has changed in the last decade is the understanding of ideal IOP. Such an IOP has been labelled as TARGET IOP. Target IOP is defined as that IOP which is safe for that particular person. It may be anywhere between low-teens to 21 mmHg. Target IOP is set on following principles : a. Mild Field Loss: Reduce IOP 20% less of initial IOP b. Moderate Damage: 30% reduction or more. c. Severe Damage: 40% reduction or more. There is no IOP at which an individual is completely safe from glaucoma damage and hence target IOP has to be individualized depending upon repeated examination of disc and the fields. Risk factors such as aging, myopia, heredity, diabetes etc (31) too have to be kept in mind. The outcome of the Advanced Glaucoma Intervention Study (AGIS) data suggest that lower the IOP the better, regardless of other risk factors that are accounted for clinically. In younger patients, the IOP should be maintained relatively low (32) . Most therapeutic decisions in glaucoma are based on the steady state pressure. Ophthalmologists rarely document transient or episodic spikes in pressure or consider the damage that such spikes can cause. But such episodic spikes are significantly damaging to the RGS (33) . Postural change in IOP where the IOP is reported to increase in supine posture as compared to sitting posture, which is usually employed in Goldmann or Non- Contact Tonometry, may miss some of the glaucoma cases (23-27). Top PERFUSION PRESSURE Glaucomatous field damage is associated with decrease in perfusion pressure of lamina cribrosa and neuroretinal rim. It is opined that vascular deregulation interferes with the auto regulation of ocular perfusion and renders the eye more sensitive to IOP increase or blood pressure decrease. This partly explains the theory of field loss at low intraocular pressure and highlights the significance of using only those anti-glaucoma drugs, which do not compromise the perfusion pressure of the optic disc (34,35). Perfusion pressure of the disc can be measured precisely by following techniques: Heidelberg Retinal Flometer OBF Tonograph Scanning Laser Doppler Flometry Colour Doppler Measurements Some workers have stated that lack of proper perfusion of optic disc is the main cause of field loss. Such a decrease in perfusion pressure may be due to raised IOP or may be pressure independent, which explains the occurrence of Low Tension Glaucoma (36-40) . Some patients with normal tension glaucoma are particularly at risk if they have history of vasospasm and migraine headache 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 disc can recover with the lowering of IOP, especially after a successful trabeculectomy (41). Top APOPTOSIS (PROGRAMMED CELL DEATH) A normal person loses almost 10,000 ganglion cells per year, and by the time they are 80 years of age, they will have lost 30 percent of their ganglion cells. In the case of open angle glaucoma, by the time vision loss becomes 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, intracellular fragmentation, and internucleosomal DNA fragmentation. (42-44) Retinal ganglion cell death is initiated when some pathological event, such as ischemia, axonal injury, or changes in the lamina cribrosa leads to activation of apoptosis (programmed cell death). Apoptosis may occur due to primary or secondary mechanisms. Primary Mechanisms are: Mechanical Stress : Raised IOP can interfere with retrograde axoplasmic flow of essential growth factors produced by the lateral geniculate nucleus. Vascular Compromise : Elevated IOP, vascular disease or drugs can reduce perfusion of optic nerve, causing ischemic conditions. Genetic Determinants : Genetic determinants may also contribute to the ganglion cells susceptibility to damage (45) Diseases like diabetes may also make neurons more vulnerable to damage. Secondary Mechanisms: In this the neuronal damage is believed to be driven by toxic factors, such as high levels of glutamate (in normal levels it is a neurotransmitter), oxygen free radicals, or nitric oxide, which can be released by a primary insult, leading to continued damage, even after the primary insult has been controlled or dissipated. Glutamate, an amino acid when in excess becomes toxic to the neuronal cells, thereby initiating the process of apoptosis. Dead cells are thought to liberate glutamate and other amino acids, which keep on the vicious circle of “Programmed Death of Ganglion Cells”. It is now known that glutamate is a normal neurotransmitter in the retina which when accumulates in excess probably as a result of dead or dying cells, cause further damage to living cells. Oxygen Free Radicals (OFR) are oxygen-containing molecules that carry one or more unpaired electrons. These molecules react with lipids, nucleic acids, and proteins and cause cell death. Ischemia which may be pressure independent, is supposed to help in the process of liberation of OFR. Top NEUROPROTECTION (ENHANCING CELL SURVIVAL) The term “neuroprotection” refers to the protection of healthy but vulnerable neurons in the vicinity of dead and dying cells, which are at risk of injury even after the removal of the primary insult. In glaucoma, the goal of neuroprotection is to limit or retard pressure-dependent or pressure-independent damage to retinal ganglion cells (RGCs) by interfering with the processes and substances that cause neuronal cell death or by enhancing signaling pathways that increase neuronal survival under stressful conditions. (42,43, 45-47) Researchers are trying to find the intrinsic processes or natural pathways to interrupt the process of apoptosis and promote survival of ganglion cells by inhibiting death signals released in the presence of ischemia, elicited by the deprivation of growth factors, or caused by over accumulation of excitatory amino acids such as glutamate (48) . Glutamate quantity is demonstrated to increase to double in the vitreous in cases of glaucoma. Neuroprotection is based on the principal of Reduce risk factors: Lower the IOP, reduce ischemia. Promote neuronal survival And/or inhibit cell death Excess glutamate can be toxic to normal RGSs through over stimulation of N-Methyl-D-Asparate (NMDA) receptors. The NMDA receptor is a major type of glutamate receptor that when over activated can kill retinal ganglion cells. Memantine, derived from amantidine, shows considerable promise for neuroprotective efficacy in glaucoma. Memantine's non-competitive interaction with the NMDA receptor results in blockade of the toxic effects of glutamate without significant effect on normal cellular function. The greater the NMDA receptor activation by glutamate, the more effectively memantine blocks the action of glutamate, thereby preventing ganglion cell death. (49) The Bcl-2 family of gene proteins performs a central role in regulating apoptosis. Members of Bcl-2 gene family that promote programmed cell death include bad and bax; in contrast, the expression of bcl-2 and bcl-xl suppresses the apoptic programme. To date, a -2 pathways have been identified that increase expression of bFGF, induce bcl-2 and bcl-xl genes, and enhance the availability of important neurotrophic factors. By activating the alpha-2 receptors in the retina, Brimonidine (Brimodin) is demonstrated to increase anti-apoptic gene expression, thereby, preventing retinal ganglion cell death and promoting axonal growth (50) . Brimonidine also neutralizes Kainic acid, which is toxic to neuronal cells. Antioxidants, free radical scavenger superoxide dismutase, catalase and vitamin E are also found to have potential neuroprotective utility. Calcium channel blockers (diltiazem, nicardipin, nilvadipine, nifedipine etc), semax (Russian neuropeptide), citicoline, eliprodil, riluzole and L-deprenal etc are under study as neuroprotective agents. Top MEDICAL THERAPY With numerous existing drugs and new classes of medications now available for lowering IOP, practitioners are facing complex decisions regarding treatment strategies for glaucoma patients. 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 alternative options to the clinician. More recently, a new group, namely, Prostamide group has come on the scene with claims of improved safety, efficacy and dosing regimen compliance by the patient, compared to previously available agents. In general, anti-glaucoma drugs are chosen based on following criteria : Efficacy is most vital Systemic safety profiles The convenience of treatment- preferred OD therapy The cost of therapy Local tolerances Depending on above referred criteria, beta-blockers, especially the Timolol, which is the most efficacious agent out of the group, has dominated the anti-glaucoma regimen. The drug is considered quite efficacious, reducing IOP by 15 to 30 percent, relatively inexpensive and with excellent toleration by ocular tissue makes them still the highly recommended primary therapy of glaucoma in the world. (What warrant is adverse systemic effects on respiratory and cardiovascular system, and the issues such as depression, impotence, lack of libido, diabetes and nocturnal hypo tension (51,52) ). Lack of vigilance on the part of physician can cause death of the patient due to status asthmaticus or cardiovascular complication. Since the introduction of the drug in 1978, 40 drug-induced deaths have been reported. Systemic toxicity can be significantly minimized if the clinician is cautious in advising the use of this drug and takes measures to prevent systemic absorption by using precise dispensers, pressure on the lower puncta or using once a day gel-forming (Timolet GFS) application. Selective beta-blockers like Betaxolol, is relatively safe in patients with respiratory problems but is less efficacious than timolol. Pilocarpine still continues to occupy its importance in Primary Angle Closure Glaucoma. The drug has synergistic effect with beta-blockers, brimonidine and systemic and topical acetazolamide group of drugs. Adrenergic agents (agonists) like dipivefrin, clonidine and apraclonidine have limited specific indications since quite often they are associated with conjunctival allergy and other side effects including decrease in perfusion pressure of the optic disc. Top NEWER DRUGS Brimonidine tartrate 0.2% Latanoprost 0.005% Bimatoprost 0.03% Travoprost 0.004% Unoprostone Isopropyl 0.12% Dorzolamide 2% Brinzolamide 1% (Azopt) Brimonidine Tartrate: Brimonidine is a-2 selective agonist. It is an analogue of clonidine. It is about 30 fold more a -2 selective and has very low affinity for a -1 receptors. Due to this reason, mydriasis and lid lag as found with non-selective agonists like clonidine are eliminated. Its main mechanism of action is suppression of aqueous formation, but it is also claimed to increase some degree of uveoscleral out - flow. (The most significant merit of brimodine (Brimodin) is its relative systemic safety profile and its postulated function of neuroprotection through upregulation of cellular and neuronal survival factors, such as bFGF1 in response to activation of the a -2 adrenergic receptors, and increase in ocular blood flow. (53-55)) The drug has to be instilled twice a day and its IOP lowering effect can be compared to timolol. The demerit is higher IOP at trough. The limiting factor of brimonidine is its allergic reactions in the form of contact dermatoconjunctivis and follicular conjunctivitis (approximately 30 percent eyes), which may warrant discontinuation of the drug. In recent years, few reports have shown occurrence of uveitis after prolonged use of brimonidine tartrate. Other occasional side effects reported are fatigue, drowsiness and dryness of mouth. The newer introduction of preservative free brimonidine is reported to have much less allergy (50% reduction) since instead of benzalkonium chloride, sodium chloride has been used as a preservative. Therapeutically, it is equally effective as briomonidine. Top Prostaglandin Analogues and Prostamides Prostaglandins and prostamides are newer group of drugs. Inspite of their heavy cost, they are gaining great importance due to their higher efficacy in reduction of IOP, require single instillation in 24 hours, and have relatively safe systemic profile (56-62) Prostaglandin and prostamide have a common origin within cell membranes but they are derived from different membrane-bound lipids that are mobilized and undergo biosynthetic pathways to their final compounds. The prostaglandin F2 alpha analogues are derived from an arachidonic acid intermediary in their metabolism and formation, but the prostamides are derived from an anandamide pathway where different enzymes are involved. Although prostamides are structurally similar in some respects to prostaglandins, functionally prostamides differ. Latanoprost, travoprost & bimatoprost are reported to decrease IOP by 30 to 40 percent and hence they can be the drug of choice as monotherapy in eyes requiring lower target IOP. Superior diurnal control (24-hour control) achieved with these drugs, prevents spikes related damage to the eyes (56) . A comparison of bimatoprost to timolol showed that a statistically significant number of patients using bimatoprost achieved given target IOP at each time point compared to those using timolol. (63) Latamoprost too achieved target IOP but bimatoprost often achieved lower IOP. Prostaglandin analogues increase uveoscleral outflow without affecting trabecular outflow or the production of aqueous humour. The increased uveoscleral outflow appears to be mediated via a modification of the extracellular matrix and a relaxation of ciliary muscle. Latanoprost too is essentially an outflow-enhancing drug. There is 50% increase in uveoscleral outflow (64-68) and 30% increase in trabecular outflow through a mechanism, which is yet to be explained. There is slight enhancement of inflow also. (69) Latanoprost is reported to increase blood flow to optic nerve head. (67, 68) Recent comparative studies show Lataoprost to be more effective than unoprostone and Timolol but less than brimatoprost.(56) Bimatoprost lowered IOP by 30% in approximately 78% of patients, while timolol achieved 30% reduction in only 61% of patients. (56) Furthermore, 62% of patients receiving Bimatoprost got 40% reduction in IOP compared to 35% of patients receiving Timolol. The combination of Latanoprost with timolol when used once a day give better IOP lowering than latanoprost alone. (69) Few workers (70,71) noted additional decrease in IOP when pilocarpine was used four times a day along with single application of Latanoprost. The greatest drawback of prostaglandins and prostamides is significant ocular side effects manifested in the form of conjunctival hyperemia (15%), stinging and burning (30-40%) and foreign body sensations (20-22%), growth of eye lashes, increased pigmentation of iris and periorbital tissue including eyelids, cystoid macular edema, herpes simplex keratitis, and uveitis. These drugs are reported to lose efficacy by 10 to 20% if exposed to ultraviolet rays unless kept in opaque bottles brimatoprost or in refrigerator latanoprost. Top CARBONIC ANHYDRASE INHIBITORS (CAIs) Topical CAIs have been developed that have much improved systemic side effect profile when compared with their oral counterparts. However, the topical CAIs are less efficacious than the oral agents. Dorzolamide and brinzolamide reduce IOP by approximately 15 to 24% and are not effective in all patients. Significant ocular side effects like burning, stinging, foreign body sensation, superficial punctuate keratitis etc are noted. In addition, in some cases, sulpha like systemic effects may be noted. Due to these reasons these drugs are mostly employed as second or third-line therapy. Top ADJUNCTIVE THERAPY Brimonidine (Brimodin) is as effective as pilocarpine when used adjunctively with beta-blockers, decreasing the IOP almost 15% more. Dorzolamide when added to timolol does not significantly affect IOP. Prostaglandins and Prostamides can be used as second-line of therapy along with beta blockers, (69) brimonidine (Brimodin), clonidine and CAI agents. Pilocarpine when used four times a day along with latanoprost, gives additional IOP lowering. (71) Prostamides cause relaxation of ciliary muscle and hence pilocarpine is reported to be additive Top SUMMARY Much progress has been made in the diagnosis and management of glaucoma but still certain number of cases can only be labeled as suspicious and the medical management still remains challenging. Cholinergic agents and non-selective a -adrenergic receptor antagonists have been replaced for the most part by newer agents that are better tolerated and have fewer ocular and systemic side effects. Although the beta-adrenergic receptor antagonists are very effective IOP-lowering agents that have been the standard line of treatment for last 20 years but their serious cardio-pulmonary side effects restricts their use. Concept of apoptosis, perfusion pressure of the optic disc, neuroprotection, metabolic toxins, autoimmune process and genetic mutation has added new dimensions to the medical management of glaucoma. brimonidine (Brimodin), an a -2 adrenergic receptor agonist, has good IOP lowering effect and systemic safety profile and is postulated to have the property of neuroprotection but ocular reactions are still a challenge. Treatment with CAI agents like dorzolamide and brinzolamide cannot be considered first line therapy and are effective only in some. Systemic and ocular side effects limit their use. Prostaglandins and prostamides are promising drugs due to their enhanced IOP lowering effect, once a day application and high systemic safety profile. However, their ocular side effects are a serious matter of concern, especially in white population. We are still in search of an ideal drug with safe profile, significant IOP lowering and proved neuroprotection without compromising perfusion pressure of the optic disc. Memantine could probably be the drug of tomorrow to be used with other ocular hypotensive drugs as a 'cocktail' to achieve the desired results. A new glaucoma management paradigm has emerged; whereby clinical success is no longer simply measured by the level of intraocular pressure control achieved but also by patient's quality of life, cost effectiveness of therapy, and the long-term preservation of visual function.