By Pamela Sample 

Epidemiology, Early Diagnosis, and Progression of Glaucoma

I was fortunate to moderate with Jost Jonas this exciting session of the Glaucoma In the 21st Century meeting, which included experts from all over the world to address this worldwide problem. Appropriately, the session opened with a talk by Dr. Ivan Goldberg of the Sydney Eye Hospital in Australia. Dr. Goldberg highlighted the importance of early detection and effective treatment of glaucoma by presenting the prevalence figures for the disease worldwide, about 65 million individuals, with nearly 7 million of these currently expected to go blind.

Following were several excellent talks on assessment of the glaucomatous optic disc and nerve fiber layer. Dr. Jost Jonas from the Friedrich-Alexand-University of Erlangen-Nürnberg, Germany provided an explanation of classification of glaucomatous optic neuropathy using morphological changes in the intrapapillary and parapapillary region of the optic nerve head and nerve fiber layer. The techniques he outlined can be used clinically for early detection of damage and to follow progressive changes.

Several new techniques for imaging the optic nerve and nerve fiber layer and providing quantitative data have recently been developed. Dr. Reinhard Burk, University of Heidelberg, Germany, provided an introduction to these techniques and illustrated how information from these devices can be used to follow change in a given patient prior to evidence of glaucomatous visual field defects. The techniques covered were scanning laser tomography, scanning laser polarimetry, and optical coherence tomography.

Dr. Goji Tomita, University of Tokyo, Japan followed with a report on a new analysis strategy for comparing location of defect using confocal scanning laser ophthalmoscopy with location of parafoveal defects in the visual field. The topographic parameter is designated as an angle of "q" degrees based on the intersect of the line from the optic disc center to the foveal pit and a second line from the disc center to the nearest point showing NFL defects. A highly significant correlation was found between this angle and the location of the visual field defect nearest the fovea.

Several talks dealt with the most difficult aspect of glaucoma management, the early and accurate identification of glaucomatous progression. Dr. Linda Zangwill, University of California, San Diego, USA, provided an excellent overview of the different clinical, photographic, and imaging methods for detecting optic disc progression, giving the advantages and disadvantages of each. Currently, new analysis techniques using these devices are under study to determine whether these instruments can assist in the clinical assessment of glaucomatous progression.

The latter half of the session moved from assessment of the optic disc and nerve fiber layer to the use of visual fields to assess glaucoma. Dr. Anders Heijl, Malmö University Hospital, Sweden began with an overview of recommended analysis strategies for automated perimetry. These included the use of probability maps for confirming diagnosis and the use of several serial fields for assessment of progression using change probability maps. Dr. Heijl also discussed newer methods for perimetry including shorter testing algorithms and visual function specific tests, such as short-wavelength automated perimetry.

What is visual field progression? Dr. Chris Johnson of the Devers Eye Institute, Portland USA, tackled this most difficult topic. He described the differing methods currently in use in several large multi-center studies. He then broke these down into four main categories of clinical judgement, classification systems, linear regression, and event analysis and described the advantages and disadvantages of each. The key to improved identification of progression, he concluded, lies in the development of: 1) new non-traditional analysis methods, 2) test procedures with lower variability, and 3) test procedures which show larger changes in visual function with increasing pathological change.

I followed Dr. Johnson with a description of some candidates for procedures that may show these larger changes in visual function. These included short-wavelength automated perimetry, frequency-doubling technology perimetry, motion automated perimetry, and high-pass resolution perimetry. Each of these is designed to test a specific visual function and to indirectly assess the type of retinal ganglion cell responsible for that visual function. Results comparing several eyes on these tests showed they are superior to standard fields in detection of vision loss and, that in a given eye, damage is present on all tests at a similar retinal location. This indicates that glaucoma first affects an area of the retina regardless of the type of visual function under test.

Putting all this together into a picture of glaucoma's effects on optic nerve structure and visual function was Dr. Alfonso Antón-López, Hospital General de Segovia, Spain. A review of several studies and reports from clinical experience showed that the relationship between structural and functional damage in glaucoma is complex and influenced by a variety of factors. These included the degree of glaucomatous damage, the type of damage, the methods used for assessment, the specific parameters taken from each method, and whether the analysis includes a few or many variables. In general, there is strong evidence that a quantitative and topographical relationship exists between the location of structural damage to the optic nerve head and functional damage assessed with visual fields.

The session ended with a discussion of two of the newest techniques being evaluated for diagnosis of glaucoma. The first technique, measurement of ocular blood flow, was presented by Dr. Makoto Araie, University of Tokyo, Japan. Dr. Araie compared two noninvasive methods, scanning laser Doppler flowmetry (SLDF) and colour Doppler imaging with an established invasive method in rabbit eyes. He found the SLDF blood flow correlated well with the microsphere-determined retinal blood flow, but not with the microshpere-determined choroidal blood flow. In addition, he presented a new technique to obtain colour Doppler imaging in a sitting position.

Dr. George Cioffi, Devers Eye Institute, Portland, USA, presented the second new technique in the final talk of the session. He described the multi-focal electroretinogram (MERG), which allows assessment of multiple retinal areas within the same test. Like traditional ERGs and PERGs, this technique is objective in that it

requires no response from the patient. This technique has demonstrated value for identifying early change in retinal function due to diabetes. It has recently been evaluated in glaucoma. Dr. Cioffi and his colleagues studied patients with clear asymmetrical glaucomatous visual field defects. Their findings are somewhat surprising. The MERG provided important information about abnormal macular function in these patients, but did not show responses that corresponded topographically with even advanced hemispheric visual field defects.

Following the session there was a lively discussion among the speakers and the audience. The several new techniques presented have provided new avenues for exploring and understanding the pathophysiology of glaucoma and its clinical affects. However, it was also clear that much more is needed before we can significantly reduce the number of eyes affected and those going blind worldwide.

Pamela Sample

Congenital, Pigmentary, Pseudoexfoliation, Normal Pressure, and Angle Closure Glaucoma

Hong from Korea reported on congenital glaucoma: the incidence varies between 1:10 000 and 2.85: 100 000 newborns. He found 10 mmHg to be the normal infant IOP. His experience with trabeculectomy is more favorable than with goniotomy or trabeculotomy, although the overall success rate was 78.2% only. Thirty one percent of the first operations succeed. Genetic prevention may be an option.

Liebmann of New York, USA discussed the pigment dispersion syndrome (PDS). The pigment granules cause blockage of the trabecular meshwork. Less than half develop ocular hypertension or glaucoma. PDS is a caucasian disease. Ninety percent of patients are myopes. After description of the clinical findings Liebmann pointed out the relation between PDS and iris concavity. This in turn relates to the therapeutic use of pilocarpine which stretches the iris and induces relative pupillary block. Peripheral iridectomy may be helpful. Its long term effect on IOP and progression is unknown.

Geijssen, The Netherlands discussed whether the differentiation between NPG and POAG should be based on the IOP level or on other factors. Pressure is an arbitrary measure and misleading. High pressure glaucoma is characterized by a concentrically enlarged disc. Within the NPG group a substantial percentage also has this type of disc. These could very well be the "pressure" glaucomas within the NPG-group. Other subtypes (Myopic NPG, Focal Ischemic NPG and Senile Sclerotic NPG) exist which have other signs like disc hemorrhages, peripapillary atrophy, vasospasm, nocturnal hypotension and/or myopia which could indicate that they are PRESSURE UNRELATED glaucomas. She proposes that differentiating between PUG (Pressure Unrelated Glaucoma) and PRG (Pressure Related Glaucoma) might be more worthwhile in the approach of treatment and also for future research (see also full paper in this issue of IGR on page 22).

Ritch, New York, USA described exfoliation syndrome (XFS), a progressive accumulation of extra-cellular material (ECM) in many ocular tissues. In addition there is pigment liberation from the iris. The composition of the material is unknown, however XFS is a disorder of ECM. XFS is associated with cataract. Cataract surgery may be complicated and so may be the post-operative period. Ocular and perhaps systemic ischaemia has been found. XFS is a risk factor for disc hemorrhages. Glaucoma in XFS may have a worse prognosis than POAG. Angle closure is common in XFS. Treatment is similar to POAG. Argon laser trabeculoplasty is effective, though some 20% of patients develop sudden late rises of IOP in the first two years post-operative.

Chew of Singapore described the huge problem of angle closure glaucoma in Asia. Half of glaucoma cases will be based on angle closure. Late recognition remains a concern. Peripheral iridectomy is usually insufficient, sixty percent progress with peripheral iridotomy. Trabeculectomy may be associated with more complications than in open angle glaucoma; failurerate 55%. Cataract extraction should be considered.

Erik Greve

Basic Sciences

Albert Alm reviewed the anatomic, physiologic and biochemical basis for aqueous humor production, the methods for measuring the rate of aqueous production in human subjects, and pharmcologic approaches for manipulating those mechanisms to therapeutic advantages in glaucoma. There was discussion as to whether polypharmacy suppression of aqueous flow, or re-routing flow away from the trabecular mesh-work to the uveoscleral pathway, might adversely affect the cornea, lens,or trabecular meshwork, but no definitive conclusion at this point was reached. Elke Lütjen-Drecoll was unable to attend because of illness, so Paul Kaufman incorporated some of her material on conventional and unconventional outflow into his own presentation in a subsequent session. The important role of the ciliary muscle in regulating both conventional and unconventional outflow was stressed. Recent findings about the rich peptidergic innervation of the trabecular meshwork, the complex cytoskeletal, cell junctional and extracellular matrix interactions in the trabecular meshwork and their role in conventional outflow regulation and as potential therapeutic targets, were presented. The physiology and regulation of uveoscleral outflow, and especially the prostaglandin-matrix metalloproteinase-collagen modulatory pathway was stressed. Jon Polansky discussed the TIGR saga, reviewing the nature of the protein, its genetic and pathophysiologic association with JOAG, POAG and other glaucomas, and its future diagnostic and therapeutic implications and applications for glaucoma. Finally, Robert Weinreb reviewed the molecular pathophysiology of glaucomatous optic neuropathy, and the numerous diagnostic and therapeutic possibilities associated with this complex sequence of events All the speakers emphasized how the explosion of basic biological knowledge has began to impact our understanding of glaucoma pathophysiology and therapy, and opened heretofore unimaginable possibilities for the future.

Paul Kaufman

By Albert Alm

Xalatan® Update 1   Recent studies have demonstrated that several prostaglandin and prostaglandin analogs, including latanoprost, modify the extracellular matrix of the ciliary muscle. Studies on cell cultures and in vivo studies have demonstrated that prostaglandins induce matrix metalloproteinases resulting in reduced amount of collagens in the extracellular matrix, These changes are likely to explain the mechanism of action of prostaglandins as ocular hypotensive drugs. One might expect that theonset of effect on IOP by this mechanism would be slower than the 6-8 hours shown in clinical studies and other mechanisms are probably also be involved. Latanoprost is now used in a large number of patients world-wide. Apart from side effects reported in the Phase Ill studies about 100 cases each of cystic macular edema, iritis or corneal changes have been       reported. The frequency is too small to prove or disprove a relationship with latanoprost but caution should be used when latanoprost is prescribed to patients with increased risk of developing ' an intraocular inflammatory response. Comparison with other drugs have shown that latanoprost reduces IOP more efficiently than either unoprostone or dorzolamide and that its effect is comparable to that of the combination timolol and dorzolamide (Cosopt). It also has en effect in chronic angle closure glaucoma similar to that of timolol. Clinical studies comparing the effect of adding latanoprost to timolol latanoprost in patients no longer well controlled with timolol alone have shown that switching is an effective alternative in many of  these patients.  Aqueous flow The production of aqueous humor is essential for the eye. It helps to maintain the pressure in the eye necessary for stable optical conditions and to provide the avascular structures with nutrients and to remove waste products. The ciliary processes form the aqueous. They consist of highly permeable capillaries surrounded by connective tissue and covered by a double epithelial layer. The ciliary capillaries are thin walled, fenestrated and highly permeable. The first step in the formation of aqueous is ultrafiltration through the walls of the ciliary epithelium. The  rate of aqueous flow, however, is largely independent on the rate of  blood flow. Only a few percent of the plasma passing through the highly vascularized ciliary processes is utilized for the production of aqueous.Active secretion by the ciliary epithelium is the main mechanism for aqueous humor production. Several enzymes and transport proteins are involved, most importantly Na+ and K+ ATPase, adenylate cyclase and carbonic anhydrase. The final aqueous is similar to but not identical to a plasma dialysate due to differences induced by the secretory processes involved. Active secretion explains the high concentration of ascorbate found in aqueous and tight junctions between the epithelial cells (the blood-aqueous receptor barrier) explains the low concentration of proteins, 0.5% of that of plasma. As aqueous bathes the iris, cornea and lens its composition changes. Nutrients and oxygen enter the aqueous by passive of facilitated and waste products from surrounding tissues are added. The rate of flow can be determined clinically by measuring the clearance of fluorescein from cornea and aqueous.' The rate of aqueous humor formation shows a circadian variation. It is almost 3gm/min during the day, and it is reduced to about half that during the night? The circadian variation of aqueous flow is mediated at least partly by circulating catecholamines. Several drugs can reduce aqueous flow, either by interacting with receptors on the ciliary epithelial cells or by inhibiting the enzymecarbonic anhydrase. Although these drugs are effective suppressors of aqueous flow none of them will reduce flow to the same low level as occurs spontaneously during night. Stimulation of adrenergic alpha 2 receptors as well as inhibition of adrenergic beta 2 -receptors reduces flow through opposite effects on adenylate cyclase. Blocking the beta has little effect at night when the adrenergic tone is low. There are at least seven different carbonic anhydrase isoenzymes and two of them, the cytoplasmic CA II and the membrane bound CA IV seem to be involved in the formation of aqueous humor. An effect on Flow is only seen when the enzyme is almost completely blocked. Acetazolamide is a potent CA inhibitor and reduces aqueous flow with 30% or more. CA inhibitors that reduce aqueous flow when applied topically have recently been introduced. Even though they are potent enzyme inhibitors they have less effect on aqueous flow than acetazolamide, possible explained  by insufficient inhibition of both enzymes. Albert Alm   Xalatan® Update 2 The update on Xalatan (latanoprost) session examined some of the most recent study data and clinical experiences regarding the product's efficacy and safety profile. Preliminary 3-month results of a prospective, randomised study investigating whether dual therapy, of which one is a beta-adrenergic receptor antagonist, can be replaced with latanoprost monotherapy in glaucoma patients showed that 92% of the 225 patients who were switched to latanoprost therapy and who completed the study succeeded in reaching the predefined IOP criteria. A multicentre, 3-month study conducted in United Kingdom & Ireland comparing latanoprost administered once daily with dorzolamide administered three times daily showed that latanoprost was significantly (p<0.001) more effective in reducing mean diurnal IOP. The difference between treatments was 2.9 mmHg in favour of latanoprost. In a safety update Carl Camras discussed that the proven side effects of latanoprost include iris colour change, eyelash changes and mild conjunctival hyperaemia. Rare instances of cystoid macular edema (CME) and iritis occur almost exclusively in eyes with multiple risk factors and are reversible, Carl Camras concluded in his safety update presentation. A 3-month randomised study in 246 patients presented by Robert Fechtner, showed an equivalent reduction in mean diurnal IOP with latanoprost administered once daily as compared to fixed combination of dorzolamide and timolol administered twice daily. A pilot study, performed by Paul Chew in Singapore, in primary chronic angle-closure glaucoma patients demonstrated that latanoprost was significantly more effective than timolol in reducing mean IOP in this study series. An 8-week randomised study in Brazil performed by Remo Susanna demonstrated that latanoprost administered once daily was significantly (p<0.001) more effective than unoprostone administered twice daily in lowering mean IOP, while the incidence of adverse events was low and comparable between the two treatment groups. Thom Zimmerman       By Stephen Obstbaum  Surgery   Gunther Krieglstein presented an approach to the management of glaucoma. He stressed the difficulties encountered when one is dealing with a chronic disease as well as the complexities of intervening at various stages of the disease process. Medical treatment with single drugs, multiple drugs and combination drugs each have their place in the management of glaucoma. He stressed the importance of weighing the side-effects of the medications and patient acceptance of the regimen. Surgery for glaucoma is generally used when a greater IOP reduction is required in a patient who has a higher risk profile for glaucoma damage, he explained. Surgery offers the potential for pressure reduction often without the need for medications or with a lessened medication requirement. The surgical management of glaucoma is not without its drawbacks, however, and attention should be paid to managing the complications associated with the intervention. He indicated that the mode of treatment should be tailored to the particular patient. Shlomo Melamed discussed laser angle surgery. He listed the three major approaches as: laser trabeculoplasty, laser trabeculopuncture and laser sclerectomy. With each of these techniques laser energy is applied to the anterior chamber angle with a resultant increase in aqueous outflow and the subsequent reduction in IOP. Laser trabeculoplasty, the most frequently used technique, is believed to alter the mechanical structure of the trabecular meshwork as well as exerting a biological effect. The results of the Glaucoma Laser Trial indicate that eyes with an initial laser trabeculoplasty have better IOP control, less damaged optic nerves and better visual fields than those treated medically, he stated. The major drawback with this procedure is that its effect is not lasting. Laser trabeculopuncture appears to be effective in the management of some juvenile glaucoma patients. Penetration through the trabeculum to Schlemm's canal results in blood reflux through its cut edges. Late scarring, that obliterates the opening, results in the failure of this procedure. Laser sclerectomy by ab externo or ab interno approaches have both been attempted. Although successful sclerectomies have been made, there is a high rate of failure with closure of these openings over time. New techniques combined with the use of anti-metabolites hold the potential for increased success with this approach, he stated. Eve Higgenbotham presented information regarding cyclodestructive surgery. The surgical options include: (1) cyclocryoablation, (2) transscleral Nd:YAG laser cycloablation, (3) argon laser cycloablation and (4) diode laser cycloablation. Cyclocryoablation is efective in IOP reduction but also causes destruction of adjacent tissues, so that it is not suited for eyes that have functional vision. In addition, it is associated with pain, inflammation and at times, phtisis bulbi. Transscleral Nd:YAG laser cycloablation is performed in either a contact or non-contact mode. With regard to tissue destruction, it is more selective than cyclocryotherapy and induces less pain and discomfort. Argon laser cycloablation is delivered directly through the pupil or by a an endolaser system. Diode laser cycloablation is accomplished either by an endoscopic fiberoptic system or delivered transsclerally. She reported on a study usingtransscleral diode laser cycloablation as primary therapy in a patient population in whom medical and conventional surgical interventions were fraught with failure. The results of this small pilot study revealed that at 1 week 8 of 10 patients the procedure was successful in reducing the IOP at least 20% from baseline; at 1 month 7 of 9 patients, at 3 months 6 of 10 patients and at 4 months 3 of 8 patients. In the later time periods the percentage IOP reductions were 23%, 30% and 33% respectively. She believes that more focused tissue destruction with newer techniques lend themselves to expanded applications. Tetsuya Yamamoto dealt with the use of anti-metabolites in filtering surgery. He reported the results of a retrospective review of the records of 522 patients, aged 0.1- 98 years (mean 56 years) with a follow-up of 1.0 -8.3 years (mean 3.8 years), who had trabeculectomy with adjuncive mitomycin C performed between April 1990 to August 1997 at the Gifu University School of Medicine. The complete success rate was 58.5% when an IOP of 15mmHg or less was achieved without any glaucoma medications. Qualified success was 69.4% when 15mmHg was achieved using topical medications, while overall success occurred in 84.4% when the desired IOP level was achieved regardless of the type of glaucoma medications including oral carbonic anhydrase inhibitors. Post-operative complications included: shallow anterior chambers in 128 eyes, choroidal detachment in 95 eyes and bleb leakage in 59 eyes. The clinical factors associated with a poor prognosis were a history of prior intraocular procedures and older age. He concluded that mitomycin C improves the prognosis in cases with uveitic galucoma and in glaucoma in younger patients. Robert Stamper commented on hypotonous maculopathy. He indicated that this entity may result from: filtration surgery, seton implant surgery, cyclodestructive procedures, poor wound apposition during any type of intraocular surgery, cyclodialysis, retinal detachment surgery and chronic inflammation. He stated that younger patients, those who are more myopic and those with coronary artery disease and hypertension are at higher risk for vision loss from hypotony associated with glaucoma surgery. The incidence of hypotony maculopathy has increased with the use of anti-metabolites as adjuncts to filtering surgery. Once the diagnosis is evident treatment is undertaken directed at the apparent cause of the condition. In instances of overfiltration using compression sutures, injecting autologous blood, revising and resuturing the scleral flap and reforming the conjuctival flap are all options that have been applied with varying success. He indicated that treatment is successful in about 80% of cases. Don Minckler presented information on glaucoma tube implants. Approximately 4000-6000 implants are used in the U.S. annually. The implants are composed of various materials. The silicone tube, that enters the anterior chamber, is attached to explants, which are positioned at the equator, and are made of either silicone, polypropylene or methlymethacrylate. A capsule forms around the explant and is the barrier through which aqueous diffuses into the periocular tissues by passive diffusion. The drainage capacity of the device is correlated with the filtering surface area. Tube implants are used in eyes with complicated adult glaucomas, congenital glaucomas and uveitic glaucoma. These devices are also used where primary surgery with or without adjunctive anti-metabolites has failed. There appears to be little benefit of using mitomycin C to improve the results of tube implant surgery. He suggested that tube shunts may have an expanded role in the primary intervention for the combined surgery for glaucoma and cataract. Roberto Carassa discussed the non-penetrating surgical procedures, deep sclerectomy and viscocanalostomy. Each of these procedures attempts to obviate some of the problems related to conventional trabeculectomy with or without the use of anti-metabolites. Deep sclerectomy with a collagen implant is designed to permit aqueous outflow through a trabeculo- descentic membrane into the subconjunctival space. The slow percolation of aqueous humor through this membrane reduces the potential for a flat anterior chamber and development of postoperative hypotony. The published results of several studies showed that an IOP less than 21 mm Hg was achieved in a range of 57- 90% of patients at 12 months, in 69% at 24 months and in 44.6% at 36 months. Nd:YAG laser goniopuncture was required in 40% of eyes to maintain successful IOP levels. In effect, the procedure is thus converted from a non-penetration to a penetrating procedure. In a retrospective study deep sclerectomy wa s compared with trabeculectomy. IOP less than 21 mm Hg was achieved with deep sclerectomy in 69 % of patients compared with 57% of patients with trabeculectomy without anti-metabolites. Viscocanalostomy also creates a Descemet's window to permit aqueous percolation into an intrascleral lake. In addition, Schlemm's canal is unroofed and a high molecular weight viscoelastic material is injected into the exposed ostia of the canal. The dilated proximal portions of the canal encourage aqueous outflow through the conventional outflow channels. The scleral flap is sutured securely and additional high molecular weight viscoelastic material is injected beneath the flap to fill the intrascleral lake. In a randomized prospective study comparing trabeculectomy with viscocanalostomy, Carassa found that an IOP of 21 mmHg was achieved in 76% of eyes with viscocanalostomy and in 94% of the trabeculectomy eyes. In the latter group 9 eyes had 5-FU injections. There were fewer significant complications in the viscocanalostomy group. These are promising techniques that deserve further investigation. Stephen Obstbaum presented an approach to cataract surgery in the patient with glaucoma. The surgical options are: (1) cataract surgery alone for eyes that are medically controlled and have minimal visual field loss and optic nerve damage. With clear corneal phacoemulsification there is an associated reduction in IOP that may favor the use of this approach in a greater number of patients. In addition, with a clear corneal approach the conjunctiva is preserved should filtration surgery be required in the future; (2) glaucoma surgery followed by cataract surgery is generally performed in eyes with more profound glaucomatous damage and whose condition is more difficult to control medically. When sequential surgery is performed, it is advantageous to wait about 6 months before performing cataract surgery to permit the filtering bleb to mature. The concern with this strategy is that bleb function will be diminished; (3) combined surgery for glaucoma and cataract has the benefit of exposing the patient to a single surgical experience. Current techniques of combining small incision cataract surgery and filtration surgery offer the potential for the favorable treatment of each of these conditions. Yet despite the success of these interventions there are significant variations in technique and unresolved issues, especially related to the benefits and risks of the use of adjuncive anti-metabolites, that require additional study. Stephen Obstbaum     Issue 1-3 Table of Contents Editor's Selection Change Issue 24-424-324-1/223-423-323-223-122-422-322-222-121-421-321-221-120-420-320-220-119-419-319-219-118-418-318-218-117-417-317-217-116-416-316-216-115-415-315-215-114-414-314-214-113-413-313-213-112-412-312-212-111-411-311-211-110-410-310-210-19-49-39-29-18-48-38-28-17-37-27-16-36-26-15-35-25-14-34-24-13-33-23-12-32-22-11-31-21-1 advertisement