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1st World Congress on
Controversies in Ophthalmology (COPHy)
Clarion Congress Hotel, Prague, Czech Republic March 4-7, 2010
 
  Speakers Abstracts Print

TO PEEL OR NOT TO PEEL THE INTERNAL LIMITING MEMBRANE (ILM): YES, ILM PEELING IS SAFE AND IMPROVES SURGICAL RESULTS
J. Nawrocki
Poland

Formation of epiretinal membranes (ERMs) is a problematic after-effect of some vitrectomies. While ERMs can be surgically removed or peeled, it is better to deal with the problem prophylactically rather than subject a patient to more than one surgery. We believe that removing the internal limiting membrane (ILM) can be an effective prophylaxis against the formation of ERMs after performing a vitrectomy.
Unfortunately, very little information is available from published literature regarding the status and histology of the retina in cases of ERM formation. Ducournau and Ducournau suggest that epiretinal membrane formation is caused by ischemia and, using an analogy, they suggest that, in cases of ERM, vascular horizontal gliosis happens in the inner retina. This observation may also suggest that the pathologic process of ERM formation is not only epiretinal but also intraretinal. Our own data collected by Spectral domain OCT show that if ERM is present, retina structure is usually deteriorated
When we remove ILM we preclude cells from forming ERM as they have no base membrane on which to grow. The recurrence of rate of ERM after ERM removal is no greater than 56%. Authors who peeled the ILM in cases of recurrent ERM, found no evidence of ERM after surgery. In addition, visual acuity tended to improve. Kwok et al. stated that in one out of 17 cases of macular hole treated with ILM peeling, an ERM developed at the edge of the ILM peeling site close to the superotemporal arcade 10 months after surgery. We have made similar observations in our group of patients followed up with spectral-domain OCT. We found one recurrence in 33 consecutive cases, and if we look more precisely, we do not see recurrence in the fovea, where the ILM was removed, but it is present on peripheral scans of the macula at a site where the ILM was not removed (unpublished data).
These observations seem to be very important. They show definitively that recurrent epiretinal membrane can only be observed on the ILM and, even if the ERM is already present, it cannot cross the boundary between the area of intact ILM and the area from which ILM was previously removed.
ILM peeling is frequently used to increase macular hole closure rate. Different authors confirmed clinically that there was 0% ERM recurrence after ILM peeling with ICG. A study performed by our group, with the use of spectral-domain OCT, showed no evidence in 68 eyes of ERM after macular hole surgery with ILM peeling and staining with trypan blue.
Various authors have also described vitrectomy for treatment of diabetic maculopathy. Their results show that ERM developed after vitrectomy in 10% of eyes. Gandorfer et al. performed additional ILM peeling and postoperatively, they observed no recurrence of epiretinal membrane. Avci reported that he found no epiretinal membrane formation during the mean follow-up of 12.2 months after pars plana vitrectomy with ILM peeling in 54 cases of both diabetic and non-diabetic chronic macular oedema. In a comparative study of vitrectomy for diabetic macular oedema, Yamamoto et al. found no ERM in ILM-peeled eyes and 13% ERM in the ILM-preserved group.
Inner limiting membrane peeling is rarely described as a method of treatment of vein occlusions. Recently, our group published a report on 35 eyes treated with vitrectomy and ILM peeling for both central retinal vein occlusion and branch retinal vein occlusion. Neither condition showed any ERM formation during 12 months of postoperative follow-up. In addition, Mandelcorn et al. found no ERM after ILM peeling for decompression of macular oedema in retinal vein occlusion in 14 cases.
Formation of an epiretinal membrane in the macula is frequently observed after both primary vitrectomy for retinal detachment and vitrectomy for proliferative vitreoretinopathy. Sakamoto et al. presented three cases where they used ICG staining to obtain better visibility of ERM but they also removed the ILM to achieve complete removal of ERM. They observed no reproliferative tissue on the retina where they had removed ILM.
We observed no recurrence of ERMs in any case in a severe PVR group treated with both retinotomy and retinectomy and with ILM peeling. Furthermore, we confirmed this observation using spectral domain OCT. It seems very probable that ILM removal allows the removal of all ERMs, tractions, scaffolds and proliferation environments in the macula. In addition, Aras et al. confirmed that, in 20 operated cases, ERM did not appear if ILM was removed.
In lamellar macular holes we observe ERM which does not cover the fovea. The issue of why ERM is not present in the centre of the fovea in some eyes, but is there in other eyes, seems important. Analogous to the facts mentioned previously, it may be suggested that the lack of epiretinal membrane in the fovea may be preceded by natural removal of ILM by traction.
This may be an additional explanation of the role of ILM peeling as a prophylaxis of ERM formation.


ILM PEELING CAUSES RETINAL DAMAGE AND REDUCES VISUAL OUTCOMES
W. Mieler

Chicago, Illinois, USA

Vitrectomy for macular hole (MH) was popularized by Wendel (1991), when he reported the surgical results of a pilot study involving 52 patients. He had a surgical success rate of MH closure in 58% of cases. Over the past almost two decades, there has been considerable refinement in surgical treatment and technique, with anatomically successful closure of the MHs often exceeding 90%.
Two main areas of controversy remain at the present time, and they include 1) the type of intraocular tamponade employed along with the duration of postoperative positioning, and 2) management of the internal limiting membrane (ILM), along with possible use of intraoperative dyes and stains. This presentation will deal with issues pertaining to the ILM.
Regarding management of the ILM, the first main issue is deciding whether or not the ILM needs to be surgically removed. Does removal of the ILM lead to a better anatomic rate of MH closure? Additionally, and of great significance, does removal of the ILM impact the potential for visual recovery? Co-incident with removal of the ILM, is the issue of use of intraoperative stains and dyes (ICG, trypan blue), and/or the use of intraoperative corticosteroids, which are utilized to better visualize the ILM. Does this impact the rate of surgical success? And is ICG potentially toxic to the retinal pigment epithelium (RPE)?
Numerous studies have documented similar MH closure rates with or without peeling and/or staining of the ILM. ILM removal may improve the rate of MH closure, though ILM removal along with usage of ICG, may slow the rate of visual recovery and/or lead to alterations in the RPE. A meta-analysis of published reports (Rodrigues 2008) representing 837 surgeries, comparing ILM peeling with and without ICG application demonstrated a worsened functional outcome with the use of ICG, and a higher number of RPE alterations were observed. ICG has also been shown to persist in the eye for six to twelve weeks following usage, potentially setting the stage for prolonged phototoxicity. Additionally, histopathologic studies suggest alteration in the surgical cleavage plane when ICG is employed.
To summarize, there have been numerous reports of comparable anatomic and visual outcomes whether the ILM is removed or not. Of concern is the fact that in most cases, when the ILM is removed, staining with ICG is employed. There have been a significant number of reports describing potential damage to the RPE, delayed or worsened visual recovery, retention of the ICG dye in the eye for up to 12 weeks, and possible alternation of the surgical cleavage plane when the ILM is being removed.
In the majority of cases, it is probably not absolutely essential to remove the ILM. If one decides to do so however, and if the retinal surface can be clearly visualized, removal of the ILM can be accomplished without the use of an intraoperative stain or dye. If it is decided to employ ICG, a very low concentration of the dye should be utilized, and the time of contact with the retina surface should be kept to a minimum.


SURGICAL MANAGEMENT OF CNV SECONDARY TO NEOVASCULAR AMD; MERITAGE: INTERIM RESULTS
P. Dugel, T. Jackson

Retinal Consultants of Arizona, Phoenix, Arizona, USA & Kings College Hospital, London, UK

Purpose: To determine if 24 Gy beta radiations delivered via an epimacular surgical approach can reduce the treatment burden while maintaining vision in patients that require frequent, chronic anti-VEGF intravitreal injections for neovascular age-related macular degeneration (AMD).
Methods: Ongoing study (N=16) who underwent epimacular brachytherapy after vitrectomy. Main outcome: number of re-treatment injections of anti-VEGF therapy deemed necessary, and percentage of subjects losing less than 15 ETDRS letters. ETDRS best-corrected visual acuity (BCVA), full biomicroscopic examination, fluorescein angiography, and optical coherence tomography were carried out at baseline and monthly thereafter. Safety outcomes include incidence of cataract changes and radiation retinopathy. Anti-VEGF re-treatment with Lucentis® was allowed if subjects lost more than 5 letters from baseline, had new/increased subretinal fluid, new neovascularization, and/or new/increased subretinal, intraretinal, or subretinal pigment epithelium fluid.
Results: Baseline BCVA was 20/100 (51 ETDRS letters). Mean number of anti-VEGF injections was 12. At 6 months, there was an average of 2 re-treatment injections as compared to a 12 injections average in the year preceding enrollment. A 50% decrease in the average number of injections was noted at 6 months post epimacular brachytherapy compared to the 6 months preceding epimacular brachytherapy. Three subjects accounted for 37% of all post - surgery injections. Overall, 88% (14 subjects) maintained VA and 63% gained VA (50% gained at least 5 letters). The mean ETDRS letter gain at 6 months was 1.2 letters. In the pseudophakic group (n=12), subjects began showing an increase in VA at month 2, and by month 6 had increased ETDRS letter gain to a mean of 3 letters. In those with no more than 12 anti-VEGF injections pre-surgery (n=11), mean VA improved by a mean of 3.6 letters at month 6. There were no reports of radiation retinopathy and the majority of adverse events were typically associated with routine pars plana vitrectomy.
Conclusion: Epimacular brachytherapy may significantly reduce the number of anti-VEGF injections in patients that require frequent chronic treatment with anti-VEGF agents. The anti-inflammatory, anti-fibrotic and anti-angiogenic properties of beta radiation may also help to further improve visual acuity in this patient population. Further follow up and larger studies are warranted.


Ozurdex in retinal disease
A. Loewenstein

Department of Ophthalmology, Tel Aviv Medical Center, Sackler Faculty of medicine, Tel Aviv, Israel

Background: To evaluate the effect of OZURDEX™ (dexamethasone intravitreal implant) in the treatment of retinal disease.
Methods: The use of ozurdex in retinal vein occlusion, as shown in the GENEVA trial will be reviewed. In addition, the design and preliminary data regarding ozurdex in other retinal disease (uveitis, AMD) will be presented.
Results: In the Geneva trial, at baseline, 136 patients received DEX Implant 700µg and 147 received sham; At least 15 letters of BCVA was gained in 31% of patients 60 days after the first DEX Implant 700µg (peak effect) and 27% gained ?15 letters 60 Days after the second implant (Day 240); 21% of patients from the sham group who received their first DEX Implant 700µg at day 180 gained ?15-letters by Day 240. Increases in IOP were generally transient and similar following each DEX treatment.
Conclusions: Ozurdex has been proven beneficial in a variety of retinal disease including vein occlusion, uveitis and AMD.


THE COURSE OF DIABETIC RETINOPATHY AFTER CATARCT SURGERY
A. Pollack

Kaplan Medical Center, Hadassah Medical School, Hebrew University, Jerusalem, Israel

Purpose: course of maculopathy after cataract surgery in eyes with diabetic retinopathy (DR) is a controversial topic.
A series of studies aimed to evaluate the relationship between cataract surgery and the postoperative course of maculopathy. Study One evaluated the course of DR following extracapsular cataract surgery (ECCE) in non-lasered eyes compared with the course of retinopathy in the fellow non-operated eye. Study Two investigated the course of retinopathy in previously lasered eyes which underwent cataract surgery. Study Three evaluated the incidence of cystoid macular edema (CME) following ECCE. Study Four looked at the course of retinopathy after phacoemulsification and intraocular lens (IOL) implantation. Study Five focused on changes in angiographic scoring of DR following phacoemulsification and the effect of the anti-inflammatory drug Diclofenac on CME prevention and treatment. Study Six evaluated the effect of glycemic control as expressed by HbA1C levels and the anti-inflammatory drug diclofenac on the course of DR and CME after phacoemulsification.
Methods: Type 2 diabetic patients with DR status ranging from no to moderate NPDR, undergoing phacoemulsification with IOL implantation were enrolled and followed up for at least one year. Fluorescein angiography (FA) was performed between: months 0-3 (F1), months 4-6 (F2) and months 7-12 (F3). In studies 5 and 6 either the non-steroidal anti-inflammatory drug Diclofenac (Voltaren Ophtha, Novartis) or placebo drops were given in a randomized, masked fashion, between the third day preoperatively and 3 months postoperatively. The non-operated fellow eyes served as a control.
The eyes were divided into 2 groups. Group A where retinal status remained unchanged was defined as “No Change” group. Group B was the “Progression” group where retinal status progressed from noDR to non-proliferative DR (NPDR) or from NPDR to more severe NPDR or Proliferative DR (PDR).
Results: The results presented herby focus on the course of retinopathy following phacoemulsification –Study Four. Out of 56 eyes, in Study One "no-change" in retinopathy was observed in 37 eyes (66%) and progression in19 eyes (34%). In the "no-change" group 26 eyes (70.3%) had no-DR preoperatively and 11 (29.7%) had preoperative DR. In the "progression" group 8 eyes (42.1%) had pre-existing no-DR and 11 eyes 57.9% had pre-existing DR. Study Five which focused on angiographic scoring, CME development and the response of CME to diclofenac drops. Progression of retinopathy by color photography and an increase in DR scoring was observed in 10/35 studied eyes (28.5 %) post-operatively as compared to one control eye (2.9%) p=0.0035 between F1 and F2. FA analysis revealed progression of retinopathy in 11/35 operated eyes (31.4%) as compared to 2/35 fellow eyes (5.7%) p=0.0139. CME developed in 12/35 (39.4%) studied eyes and one fellow eye (2.9%), p=0.0089. During F3, CME improved in 17.7%, remained stable in 79.4% and developed in one eye (2.9%). Data regarding treatment were available in 29 eyes. In eyes receiving Voltaren drops 13/15 (86.7%) did not develop CME and 2 (13.3%) did. In eyes receiving placebo 4/14 (28.6%) did not develop CME and 10/14 (71.4%) did develop CME p=0.078.
In Study Six the relationship between blood sugar control and the course of retinopathy was investigated. HbA1C <7.5mg% was observed in 24/52 eyes (46.2%) and HbA1C >7.5mg% was observed in 28/52 (53.2%) eyes. In the group with HbA1C <7.5mg% no-change retinopathy was observed in 19 eyes (79.2%) and progression in 5 eyes (20.8%). In the group with HbA1C >7.5mg%, no-change was observed in 17 eyes (60.7%) and progression in 11 eyes (39.3%).
Regarding to visual acuity, in Study Five visual acuity of 20/40 or better was achieved in 68% of eyes with no-change retinopathy but in only 47% of eyes with progressing retinopathy. In eyes with no-DR preoperatively, good visual acuity of 20/40 or better was achieved in 87% of eyes with no-change retinopathy and 67% with progressing retinopathy
CONCLUSIONS: Visual prognosis in diabetics after phacoemulsification with IOL is good; however DR progressed more often in operated eyes than in fellow non-operated eyes. Pre-operated DR is a risk factor for progression. Topical anti-inflammatory drugs significantly reduced the occurrence of CME.
Preoperative DR and HbA1C>7.5mg% are risk factors for progression of diabetic retinopathy post-operatively.


Cataract surgery has very little effect on diabetic retinopathy
A. Loewenstein

Department of Ophthalmology, Tel Aviv Medical Center, Sackler Faculty of medicine, Tel Aviv, Israel

Background: Cataract is common and age related. Diabetes is common, and incorporates in increased risk for cataract. In addition, retinopathy increases with duration of disease. Therefore, the association between the 2 diseases has been questioned and is still under debate.
Methods: We will review the evidence for progression of diabetic retinal disease with cataract surgery critically, and assess whether cataract surgery exacerbates the development and progression of diabetic retinopathy.
Results: Macular edema after cataract surgery in diabetic patients can be pre existing, be part of post surgical macular edema, or represent worsening of diabetic macular edema as a result of cataract surgery. However, the existing literature, including data from ETDRS does not support a cause and effect relationship between the surgical procedure and the disease.
Conclusion: There is no prospective trial to show this association. Trials which have been performed have not included blind review of photographs following surgery. Diabetic patients with significant cataract should consider cataract surgery.


THE COURSE OF MACULOPATHY AFTER CATARCT SURGERY IN PATIENTS WITH EARLY DRY AMD
A. Pollack

Kaplan Medical Center, Hadassah Medical School, Hebrew University, Jerusalem, Israel

Purpose: The course of maculopathy after cataract surgery in eyes with early dry age-related macular degeneration (AMD) is a controversial topic.
We performed a series of studies evaluating the relationship between cataract surgery and the postoperative course of maculopathy. The first study compared the course of dry AMD in operated and non-operated fellows' eyes. The second study compared the course of maculopathy in operated fellow eyes with dry AMD. The third study investigated whether Yag-capsulotomy is a risk factor for maculopathy progression. The fourth study compared the course of maculopathy following phacoemulsifiacation cataract surgery and extracapsular cataract extraction surgery. The fifth study investigated the relationship between AMD, cataract surgery and photodynamic therapy. The sixth study evaluated the response of phakic and pseudophakic eyes to antiangiogenic intravitreal injections in the treatment of wet AMD
Methods: The first, second third and fourth studies included patients with bilateral. Similar dry AMD consisting of soft and/or hard drusen and pigmentary changes without leakage on fluorescein angiography (FA), undergoing phacoemulsification with IOL implantation; Study Two included patients with bilateral, similar dry AMD, who underwent unilateral cataract surgery with stable maculopathy for at least one year post-operatively, scheduled for surgery in the fellow eye. In studies five and six the patients received treatment for wet AMD, photodynamic therapy (PDT) in study Five and antiangiogenic drugs in study Six respectively Enrolled patients were followed up for at least one year post-operatively. Fluorescein angiography (FA) was performed: at base line either before surgery or within one week after surgery in cases where cataract precluded visualization of the macula, between 0.5 and 3 months (F1), between 4-6 months (F2) and between 7-12 months (F3). The fellow non-operated eyes served as control in studies One, Three and Four. The eyes were classified into 2 groups. Group A where retinal status remained unchanged was defined as the “No Change” group. Group B where maculopathy progressed from dry to wet AMD was defined as the “Progression” group.
Results: Out of 47 eyes undergoing ECCE in Study One no change of retinal status was observed in 38 operated eyes (80.9%) and progression was been in 9 eyes (19.1%). In non-operated eyes, no change maculopathy status was seen in 45 eyes (95.7%) and progression in 2 eyes (4.3%). Soft drusen were found to be a risk factor for progression in Study One. With phacoemulsification surgery (Study 4) out of 22 eyes, "no-change" in retinopathy was observed in 19 eyes operated eyes (86.4%) and progression was seen in 3 eyes (13.6%). No change in maculopathy was seen in all 22 control eyes (100%). Study Five described the response of 13 operated eyes with wet AMD to PDT. Six out of 13 eyes had completed PDT treatment with disease stabilization for at least one year and then underwent phacoemulsification with IOL implantation, Visual acuity improved from 0.32 before cataract surgery to 0.35 after surgery. Seven eyes developed AMD after cataract surgery. These eyes required more treatments with PTD 3.5 versus 3.2 treatments on average and more adjuvants such as kenalog and bevacizomab 0.9 0n averages than non-operated eyes 0.2 on average
In Study Six the mean number of anti-angiogenic injections for 24 phakic patients and 19 pseudophakic patients with wet AMD respectively was 6.5 (95% CI 5.2-7.8) and 5.6 (95% CI 4.1-7.1) [p=0.39]. Mean BCVA change for phakic patients and pseudophakic patients respectively was +4 letters (95% CI -2 thru +11) and -4 letters (95% CI -11 thru +3) [p=0.07]. For the seven patients diagnosed with wet AMD within the first 2 years after cataract surgery the mean BCVA change was -10 letters (95% CI -22 thru +3) [p=0.05 compared with phakic patients with wet AMD].
Conclusions: These studies describe an acceleration of the course of dry AMD progression after cataract surgery. A thorough pre- and postoperative assessment of maculopathy including FA and/or OCT may be recommended. Informing the patient of the risk of AMD progression and the need for further postoperative treatments may be considered. In the small retrospective Studies Five and Six, pseudophakic eyes with wet AMD tended to respond less favourable to anti-angiogenic treatment than their phakic counterparts. The most substantial difference was seen in patients converting to wet AMD within 2 years of cataract surgery in study Six.


THE EFFECT OF CATARACT ON MACULAR DEGENERATION
S. Bressler

USA

Abstract: Both cataract and macular degeneration are common age-related diseases. Many individuals simultaneously manifest both conditions. The literature contains inconsistent findings describing adverse relationships between performance of cataract surgery and development and progression of AMD. These studies will be explored in detail highlighting inherent strengths and weaknesses in study design and conclusions. The case will be made that there is no significant risk of AMD progression following cataract surgery.


SHOULD WE BUCKLE OR PERFORM VITRECTOMY? YES, BUCKLING IS THE PROCEDURE OF CHOICE
J. Nawrocki

Poland

Different surgical approaches are used in the treatment of retinal detachment. Intuition and surgeon’s experience frequently play an important role in the choice of procedure. Recently we have observed a trend toward more frequent use of pars plana vitrectomy. Should we therefore stop performing sclera buckling? The aim of this presentation is to present arguments that we still need to use scleral buckling. Analysis of this topic is multivariate and different factors have to be judged.
The incidence of simple retinal detachments (single breaks, localized detachment) remains approximately 30 % of cases. They usually continue to be treated with scleral buckling even in centres with a preference for vitrectomy. More complicated cases with multiple breaks, breaks posterior to equator or giant retinal tears are usually treated with vitrectomy. In between there is a large group of patients which may be assessed differently by different surgeons.
The majority of published papers show similar results both anatomical and functional of both methods. This may be judged as an argument for performing scleral buckling. This is an older method well established in retinology still with good results.
The SPR Study presented statistically significant advantage of scleral buckling over vitrectomy in phakic subgroup regarding the change in best corrected visual acuity and cataract formation.
Scleral buckling is an art form. But this surgical artistry has long learning curve. It requires detailed observation of vitreoretinal relationships and pathology. In reward, the surgeon gains more information and if the surgeon does not use external slit illumination some events may be not clearly visible during vitrectomy. So, even if vitrectomy will be performed later on, the knowledge and feel for the pathology persists, which may improve the quality of surgery. Scleral buckling should be taught before vitrectomy.
Vitrectomy seems very simple, everything is clearly visible and we have the feel perfectly in control of the surgery. There is a saying: “Vitrectomy is done when vitreous is gone”. Often this is not possible. Even very experienced, well equipped surgeons often leave some remnants of vitreous which may induce reproliferation and may be a cause of surgical failure. By performing scleral buckling we avoid this complication.
Most older-generation surgeons develop presbyopia. If they did not learn how to perform scleral buckling under the microscope, their trend is towards vitrectomy. Even if they would have treated similar patients with scleral buckling in the past; they now prefer vitrectomy. Microsurgical performance of sclera buckling improves the results and avoids the negative influence of presbyopia when considering the surgical method.
If scleral buckling is performed it always allows one to perform vitrectomy in the future if this is indicated. If primary vitrectomy fails, the situation is often more difficult and relaxing retinotomy may be required.
Term minimal surgery may be realized with scleral buckling only. In many eyes it may be successful. In vitreous surgery, ‘small incision’ is sometimes called ‘minimal surgery’, but in reality the surgical wound is the whole area of the inner surface of the eye so it is always maximal surgery.
Scleral buckling may induce some refractive error. However, this may decrease with time or not play an important role in the patient’s future. Anisometropia can almost always be compensated for with glasses or contact lens.


VITRECTOMY WITHOUT SCLERAL BUCKLING FOR RHEGMATOGENOUS RETINAL DETACHMENT
S. Charles

USA

Vitrectomy without scleral buckling for rhegmatogenous retinal detachment is often referred to as “primary vitrectomy”; a term which at least initially implied that scleral buckling was the standard of care and should be tried before resorting to vitrectomy. This “rescue therapy” approach is considered to be “conservative” and applied in many specialties and disease processes but can produce the unintended consequence of delaying adoption of improved therapies and putting the patient through an unnecessary procedure. Anterior segment surgeons do not try intracapsular cataract extraction before resorting to phaco or RK before LASIK. Long bone fractures were not randomized to sham therapy after casts were developed. There are few high quality clinical trials comparing vitrectomy, scleral buckling, and combined vit-buckle procedures for rhegmatogenous retinal detachment surgery. The paucity of clinical trials is presumably because there are a high number of clinical variables and many treatment options which are often used in combination. Pre-operative variables include type of breaks, size of breaks, number of breaks, lens status, refractive error, vitreous hemorrhage, vitreous traction, family history, status of the other eye, medical status, and many others. Variables in scleral buckling include: hard silicone versus sponges, subretinal fluid drainage versus non-drainage, radial versus circumferential elements, encircling versus segmental buckles, use of air or gas, paracentesis and many others. Variables in vitrectomy include air, SF6, C3F8 or silicone oil, laser versus cryo, 20, 23 or 25 gauge, use of liquid perfluorocarbons, combined lensectomy or phacoemulsification, post-operative positioning, and many others. I have heard experts say that pneumatic retinopexy causes PVR but they manage “fish-mouthing” in scleral buckling with gas; this is not rational. Some surgeons use vitrectomy only for pseudophakic eyes believing incorrectly that vitrectomy causes de novo nuclear sclerosis when, in fact, it only causes progression of pre-existing nuclear sclerosis.
Complications of Scleral Buckling: Proponents of scleral buckling often minimize the complications of scleral buckling. I have heard many experienced scleral buckle surgeons state that they “never” produce strabismus yet a high quality prospective trial reported by the late Ron Michels, an excellent surgeon, demonstrated a 50% incidence of increased tropias and phorias. Encircling buckles may result in damage to the superior oblique tendon producing problematic vertical strabismus. Fortunately, most buckle surgeons have given up the unnecessary practice of removing and reattaching extraocular muscles. Aggressive traction on retromuscle traction sutures, especially with small diameter sutures can “cheese wire” intraocular muscle tendons. Aggressive stripping of the intramuscular septum, Tenon’s capsule, and episclera combined with cautery can create adhesions.
Many surgeons use encircling bands in essentially all buckle cases. A circumferential buckle produces the same outcomes in most instances without inducing myopia or causing damage to extraocular muscles potentially causing diploplia or damage to the levator aponeurosis and Mueller’s muscle resulting in ptosis.
Patients spend substantial sums of money in the pursuit of emmetropia; first radial keratotomy, then LASIK, PRK, and refractive lens exchange have raised patient’s expectations of life without glasses or contacts. Cataract surgery patients expect emmetropia as well; substantial research, product development, and marketing efforts have been applied to toric IOLs, multi-focal intraocular lenses, and accomodative IOLs. Cataract surgeons have applied substantial effort to reduce the refractive effects of cataract surgery incisions, developed microincisional techniques and limbal relaxing incisions (LRI) to improve refractive outcomes.
More serious complications of scleral buckling include late intrusion of the buckle and buckle extrusion and infection. Intraoperative complications include a 5% incidence of retinal incarceration at the drainage site when using cut-down drainage as well as bleeding related to the drainage site. Scleral, choroidal, retinal perforation with scleral sutures is a not uncommon as well; sometimes with serious consequences.
Vit-Buckles: Many vitreoretinal surgeons usually use encircling bands in conjunction with vitrectomy for repair of rhegmatogenous retinal detachment; so called vit-buckles. I have not used this approach for two decades in order to eliminate buckling induced refractive errors, strabismus, ptosis, and pain as well to reduce operating times and therefore labor costs. Brazitikos has shown that vitrectomy without scleral buckling for retinal detachment produces better outcomes than vit-buckles. Patients would not want a vitreoretinal surgeon to automatically use encircling bands when having vitrectomy repair of retinal detachment if they were informed about outcomes and complications.
Vitrectomy Specifics: Wide-angle visualization techniques and/or scleral depression are essential if vitrectomy is to be used for retinal detachment repair. Contact-based wide-angle visualization (Volk, AVI) produces 10 degrees greater field of view than non-contact (BIOM, EIBOS) and eliminates all corneal asphericity (keratoconus, LRI, RK, PK, cataract surgery, LASIK, PRK). In addition, contact-based wide-angle visualization greatly reduces the need for ocular rotation to view the periphery which reduces flexural forces on 25 gauge tools. Just as with scleral buckling, all retinal breaks must be identified and treated with retinopexy. Traction to the flap as well as vitreous traction surrounding all breaks must be eliminated to produce achievable ~90% success rates. Internal drainage of subretinal fluid performed simultaneously with fluid-air exchange with a soft-tip cannula usually drains most of the subretinal fluid. If internal drainage is initiated prior to fluid-air exchange, posterior migration of subretinal fluid is reduced. Drainage retinotomy can be used if substantial posterior migration of subretinal fluid occurs or the retinal breaks are very small and far peripheral which can make internal drainage challenging. Another option for removal of subretinal fluid is perfluorocarbon liquids; N-perfluorooctane (PFO) is the preferred agent because the interface is visible unlike perflurodecalin. PFO will remove all subretinal fluid if the optimal techniques are utilized while internal drainage of subretinal fluid plus fluid-air exchange always leaves a thin layer of fluid which must be pumped out by the RPE. Complete removal of subretinal fluid enabled by PFO may allow use of a shorter acting gas or even air for surface tension management. Because PFO causes subretinal fluid to float anteriorly, care must be taken to remove all SRF anterior to the retinal breaks to enable surrounding all breaks with endolaser. This can be done by extending the break to the ora or making a very peripheral, small drainage retinotomy but the best approach is to slowly drain SRF through the retinal break using a 25G soft-tip cannula just when the PFO reaches the break. Care must be taken to not remove any PFO. The MedOne 25G dual-bore VFI is ideal to inject PFO while allowing infusion fluid egress to maintain appropriate IOP.
25 Gauge Sutureless Vitrectomy
The author utilizes 25G sutureless approach for all vitrectomies including rhegmatogenous retinal detachments, PVR, giant breaks, and diabetic traction retinal detachments. Just as today’s patients expect emmetropia without strabismus or ptosis as discussed above, they expect a painless procedure and a non-inflamed eye. A non-inflamed, pain-free eye is not achievable with 20G sutured wounds or vit-buckles. Contrary to what some surgeons believe, 25G vitrectomy fluidics are preferable to 23G or 20G fluidics for RD cases because port-based flow limiting due to a smaller lumen reduces pulsatile vitreoretinal traction. The author strongly recommends use of the highest possible cutting rate for all tasks and all cases; especially for giant breaks and other retinal detachment cases. The author uses only the Alcon Constellation Vision System currently with 5000 cuts/minute. In addition, the Constellation has duty cycle control; shave mode which means that the port is biased closed is ideal for working near mobile retina. Sutured-on contact lenses damage the conjunctiva, cause sub-conjunctival bleeding, and are inappropriate for sutureless, trans-conjunctival surgery.
Summary: Sutureless, trans-conjunctival microincisional vitrectomy is ideal for retinal detachment repair. In the author’s opinion, vit-buckles are no longer indicated; the focus should be on microincisional vitrectomy techniques and wide-angle visualization to repair retinal detachments without causing pain, refractive error, strabismus, ptosis, cosmetic problems and longer, more costly operating times.
References
Scleral Buckling versus Vitrectomy, Brazitikos P., Ophthalmology. 2006 Jul;113(7):1245 ; Incidence of redetachment 6 months after scleral buckling surgery. Goezinne F, La Heij EC, Berendschot TT, Kessels AG, Liem AT, Diederen RM, Hendrikse F.; Acta Ophthalmol. 2009 Apr 23. [Epub ahead of print]; Surgeon age and operative outcomes for primary rhegmatogenous retinal detachment: a 3-year nationwide population-based study. Ho JD, Kuo NW, Tsai CY, Liou SW, Lin HC. Eye. 2009 May 1. [Epub ahead of print] ; 25-Gauge sutureless vitrectomy versus 20-gauge vitrectomy for the repair of primary rhegmatogenous retinal detachment. Von Fricken MA, Kunjukunju N, Weber C, Ko G. Retina. 2009 Apr;29(4):444-50. Clinical practice. Primary retinal detachment. D'Amico DJ. N Engl J Med. 2008 Nov 27;359(22):2346-54. Review. [Primary 25- and 23-gauge vitrectomy in the treatment of rhegmatogenous retinal detachment--advancement of surgical technique or erroneous trend?]; Heimann H. Klin Monatsbl Augenheilkd. 2008 Nov;225(11):947-56. Epub 2008 Nov 17. Review. German. Primary 23-gauge transconjunctival sutureless vitrectomy for rhegmatogenous retinal detachment. Tsang CW, Cheung BT, Lam RF, Lee GK, Yuen CY, Lai TY, Lam DS. Retina. 2008 Oct; 28(8):1075-81. Primary 25-gauge sutureless vitrectomy with oblique sclerotomies in pseudophakic retinal detachment. Acar N, Kapran Z, Altan T, Unver YB, Yurtsever S, Kucuksumer Y. Retina. 2008 Oct;28(8):1068-74. Scleral Buckling versus Vitrectomy. Hedaya J, Nigam N, Freeman WR. Ophthalmology. 2008 Sep;115(9):1634-5; author reply 1635. No abstract available. Primary repair of retinal detachment with 25-gauge pars plana vitrectomy. Miller DM, Riemann CD, Foster RE, Petersen MR. Retina. 2008 Jul-Aug;28(7):931-6. Repair of primary rhegmatogenous retinal detachment using 25-gauge transconjunctival sutureless vitrectomy. Lai MM, Ruby AJ, Sarrafizadeh R, Urban KE, Hassan TS, Drenser KA, Garretson BR. Retina. 2008 May;28(5):729-34. Primary 25-guage transconjunctival sutureless vitrectomy in pseudophakic retinal detachment. Dubey AK, Dubey B. Indian J Ophthalmol. 2008 May-Jun;56(3):256-7; Re: Phacovitrectomy for primary retinal detachment repair in presbyopes. Jain R, Newland H. Retina. 2008 Apr;28(4):666; Re: Phacovitrectomy for primary retinal detachment repair in presbyopes. Zhou P, Zhao MW, Li XX. Retina. 2008 Apr;28(4):665; Primary vitrectomy without scleral buckling for pseudophakic rhegmatogenous retinal detachment. Mendrinos E, Dang-Burgener NP, Stangos AN, Sommerhalder J, Pournaras CJ. Am J Ophthalmol. 2008 Jun;145(6):1063-1070. Epub 2008 Mar 14. Surgical outcomes for primary rhegmatogenous retinal detachments in phakic and pseudophakic patients: the Retina 1 Project--report 2. Pastor JC, Fern?ndez I, Rodr?guez de la R?a E, Coco R, Sanabria-Ruiz Colmenares MR, S?nchez-Chicharro D, Martinho R, Ruiz Moreno JM, Garc?a Arumi J, Su?rez de Figueroa M, Giraldo A, Manzanas L. Br J Ophthalmol. 2008 Mar;92(3):378-82. Trends and outcomes of treatment for primary rhegmatogenous retinal detachment: a 9-year nationwide population-based study. Ho JD, Liou SW, Tsai CY, Tsai RJ, Lin HC. Eye. 2009 Mar;23(3):669-75. Epub 2008 Feb 1. [New developments in retinal detachment surgery]; Bartz-Schmidt U, Szurman P, Wong D, Kirchhof B. Ophthalmologe. 2008 Jan;105(1):27-36. Review. German. Pneumatic retinopexy, scleral buckling, and vitrectomy surgery in the management of pseudophakic retinal detachments. Ross WH, Lavina A. Can J Ophthalmol. 2008 Feb;43(1):65-72. Recent trends in the management of rhegmatogenous retinal detachment. Sodhi A, Leung LS, Do DV, Gower EW, Schein OD, Handa JT. Surv Ophthalmol. 2008 Jan-Feb;53(1):50-67. Review. Scleral buckling versus primary vitrectomy in rhegmatogenous retinal detachment: a prospective randomized multicenter clinical study. Heimann H, Bartz-Schmidt KU, Bornfeld N, Weiss C, Hilgers RD, Foerster MH; Scleral Buckling versus Primary Vitrectomy in Rhegmatogenous Retinal Detachment Study Group. Ophthalmology. 2007 Dec;114(12):2142-54. Prospective study comparing the effectiveness of scleral buckling to vitreous surgery for rhegmatogenous retinal detachment. Koriyama M, Nishimura T, Matsubara T, Taomoto M, Takahashi K, Matsumura M. Jpn J Ophthalmol. 2007 Sep-Oct;51(5):360-7. Epub 2007 Oct 5. Primary 25-gauge transconjunctival sutureless vitrectomy in pseudophakic retinal detachment.
Horozoglu F, Yanyali A, Celik E, Aytug B, Nohutcu AF. Indian J Ophthalmol. 2007 Sep-Oct;55(5):337-40. [Trans-scleral sutureless vitrectomy with a 25-G system for rhegmatogenous retinal detachment treatment]; P?rez-Gonz?lez LE, Lajara-Blesa JJ. Arch Soc Esp Oftalmol. 2007 Jul;82(7):437-42. Spanish. Vitrectomy with and without scleral buckling for retinal detachment. Siqueira RC, Gomes CV, Dalloul C, Jorge R. Arq Bras Oftalmol. 2007 Mar-Apr;70(2):298-302. Primary vitrectomy versus conventional retinal detachment surgery in phakic rhegmatogenous retinal detachment. Azad RV, Chanana B, Sharma YR, Vohra R. Acta Ophthalmol Scand. 2007 Aug;85(5):540-5. Epub 2007 Mar 9. Pars plana vitrectomy versus combined pars plana vitrectomy-scleral buckle for primary repair of pseudophakic retinal detachment. Weichel ED, Martidis A, Fineman MS, McNamara JA, Park CH, Vander JF, Ho AC, Brown GC. Ophthalmology. 2006 Nov;113(11):2033-40. Surgical management of pseudophakic retinal detachments: a meta-analysis. Arya AV, Emerson JW, Engelbert M, Hagedorn CL, Adelman RA. Ophthalmology. 2006 Oct;113(10):1724-33. Pars plana vitrectomy for RD. Gopwani R, Liu DT, Lee VY, Lam DS. Ophthalmology. 2006 Sep;113(9):1688-9; author reply 1689-90. No abstract available. Scleral buckling combined with vitrectomy for the management of rhegmatogenous retinal detachment associated with inferior retinal breaks. Alexander P, Ang A, Poulson A, Snead MP. Eye. 2008 Feb;22(2):200-3. Epub 2006 Sep 1. Tailored vitrectomy and laser photocoagulation without scleral buckling for all primary rhegmatogenous retinal detachments. Johansson K, Malmsj? M, Ghosh F. Br J Ophthalmol. 2006 Oct;90(10):1286-91. Epub 2006 Jul 12. Scleral buckling versus primary vitrectomy. Singh DV, Sharma YR, Pal N. Ophthalmology. 2006 Jul;113(7):1246-7; author reply 1247. No abstract available. Scleral buckling versus primary vitrectomy. Mart?nez-Castillo V, Espax AB, Garc?a-Arum? J. Ophthalmology. 2006 Jul;113(7):1246; Scleral buckling versus primary vitrectomy. Brazitikos P. Ophthalmology. 2006 Jul;113(7):1245; Primary retinal detachment: scleral buckle or pars plana vitrectomy? Schwartz SG, Flynn HW. Curr Opin Ophthalmol. 2006 Jun;17(3):245-50. Review.


VITRECTOMY FOR DIABETIC MACULAR EDEMA IS OF LIMITED USE
Z. Gregor

Moorfields Eye Hospital, London, UK

Diabetic retinopathy is the main cause of visual loss in the working- age population and 75% of these become blind as the result of macular edema (DME). Yet no satisfactory treatment for DME exists.
The pathogenesis of DME remains poorly understood and the effect of vitreo-macular contact has been proposed as a contributing factor in the genesis of DME. As a small number of patients who present with visible macular traction seem to benefit from vitreous surgery, it has been suggested that those without any clinical evidence of traction should undergo vitrectomy also.
This recommendation was based on retrospective reports with small numbers of patients.
We therefore undertook prospective studies investigating the effect of vitrectomy in patients with diffuse DME without any clinical evidence of vitreo-macular traction. Patients with diffuse DME and no posterior vitreous detachment were enrolled several consecutive studies. The protocols dictated clinical, laboratory and biochemical examinations by independent observers before surgery and at regular intervals thereafter for a period of one year.
We demonstrated that in the majority of patients, surgery did not result in lasting anatomical or functional improvement with or without adjunctive measures, such as the peeling of the inner limiting membrane or intraocular injection of triamcinolone. Continuing laser treatment was not inferior to surgery in a randomised pilot study.
While psychophysical tests and the levels of intraocular cytokines showed encouraging changes during the post-operative follow up, these were not mirrored by long-term clinical improvement.
Though our prospective studies of vitrectomy for diffuse DME have so far proved to be disappointing, our understanding of DME continues to evolve and new treatments and their combinations are being introduced. Hopefully they will be also rigorously investigated before their theoretical benefits are used as a basis for potentially unrewarding treatments.


WHEN TO TREAT OCULAR HYPERTENSION? PATIENTS WITH A SUFFICIENTLY HIGH RISK FACTOR SHOULD HAVE THEIR IOP LOWERED
F. Topouzis

Greece

Ophthalmologists are often troubled with cases of Ocular Hypertension (OH), in terms of whether to initiate intraocular pressure (IOP) lowering treatment or not. As it has already been shown by many studies, increased IOP has been recognized as the most important risk factor for the development of glaucoma. Moreover, IOP is at the time the only modifiable risk factor. However, not all ocular hypertensives need IOP lowering treatment, since only a small percentage of them develop glaucoma. The likelihood for conversion from OH to glaucoma varies notably among ocular hypertensives and this is related to the different risk characteristics of the patients being studied. Thus, it is very important to assess the risk for each ocular hypertensive patient individually, so as to decide whether IOP lowering treatment is needed or not.
Risk factors for conversion from OH to glaucoma have been provided by large randomized clinical trials and should be considered in the management of OH. Specifically, the results of the Ocular Hypertension Treatment Study and the European Glaucoma Prevention Study have led to the establishment of a risk calculator for the estimation of the 5-year risk of conversion to glaucoma at an individual level, allowing identification of those at increased risk for conversion to glaucoma.
In addition to the above, one should consider the effect of IOP lowering treatment on the risk for conversion to glaucoma. Clinical trials have shown that IOP lowering treatment is effective in reducing by 50% the conversion rate of OH to glaucoma. However, what should also be noted is that in our days there is still no evidence that delaying IOP lowering treatment unfavourably affects the rate of future progression of visual field damage. The Ocular Hypertension Treatment Study II (OHTS II) is to provide answer to this question in the future.
Further to that, calculations on the “number-needed-to-treat” (NNT - the number of patients that need to be treated to prevent unilateral blindness in one patient) have been made for OH. The NNT approach is based on the average risk of progression without consideration of the individual risk. If patients with the greatest risk of progression and with the greatest potential to benefit from treatment can be identified by multivariable risk assessment, NNT changes, meaning that fewer patients will need to be treated to prevent one case of blindness.
The ultimate goal of treatment is to prevent quality of life (QoL) reduction. Adults with glaucoma experience a measurable loss in health-related QoL early in the disease process. Prevention of small or early changes in visual field can have important health related QoL benefits for them. Specifically, despite the fact that the onset of visual function deterioration has been noted to occur at –3 to –4 dB of MD loss, we must recognize that by the time this amount of visual field loss is developed, a patient’s QoL has already been significantly reduced. It is therefore of great importance to treat OH early enough so as to avoid conversion to glaucoma and consequent QoL deterioration.
In addition to the above, issues of cost-effectiveness should be considered. Based on estimations on resource utilization, direct medical costs of glaucoma management appear to increase with worsening disease severity. Therefore, preventing ocular hypertensive patients from converting to glaucoma may contribute to the reduction of the overall cost of the disease management.


ALL PATIENTS SHOULD HAVE A TARGET TOWARDS WHICH THERAPY IS DIRECTED
H.D. Jampel

Department of Ophthalmology, Johns Hopkins University, Baltimore, Maryland, USA

A fundamental principle in all therapeutic endeavors is determining what the goal of one’s therapy is. One can argue about the details of the therapeutic goal in glaucoma (my favorite is reducing the rate of glaucoma cell death so that it does not become symptomatic during a patient’s lifetime), but whatever the ultimate goal is, there is only one therapy, lowering the intraocular pressure (IOP). Therefore, determining how much to lower the IOP is an exercise that we all consciously or subconsciously engage in, and should be explicated stated.
The target IOP is not a number that we determine definitively and for all time upon first encountering a patient, but is an estimate that should be periodically reevaluated. During a patient visit we should not only be asking ourselves “Has the target IOP been achieved”, but also “Given what has happened to the patient during our time together, and given what has happened since the last visit” is the target IOP appropriate, or does it have to be raised or lowered”?
There are two critical junctures in a glaucoma patient’s management when particular attention needs to be paid to the target pressure. The first is in the decision to initiate IOP lowering therapy in the first place. At that time, one is asking the question, “What is the highest IOP that I think it is safe for the patient to have”? For example, for ocular hypertensives, one may use a risk calculator to determine the 5 year risk of converting to glaucoma disk or visual field damage, and decide what 5 year risk is acceptable.
The second critical juncture is the decision for incisional surgery. At that time, the “risks” in the “risk/benefit” equation play a much more important role in the decision making process. Whereas one might readily add a medication or perform trabeculoplasty to bridge the gap between a patient’s IOP and a target 2-3 mm lower, in some eyes facing surgery, one might readjust the target IOP upwards to acknowledge one’s estimation that surgery is simply too risky.
I have seen too many examples, some of them my own, in which a review of the medical record fails to show any rhyme or reason between the IOP from visit to visit and the course of therapeutic intervention. Although the brightest and most organized among us may be able to rationally manage glaucoma patients without an explicit (but variable) target, for me it is a valuable tool for knowing where I am going.


ESTABLISHING A TARGET PRESSURE DISTRACTS FROM OUR THERAPEUTIC GOALS
A. Heijl

Sweden

Most glaucoma guidelines recommend establishing a numerical target pressure in newly diagnosed patients with glaucoma. Factors pointing in the direction of a lower target pressure are usually lower untreated IOP levels, more glaucoma damage and lower age (and thus higher life expectancy).
This might seem to make sense, but establishing a numerical target pressure is not desirable, because it distracts our therapeutic goal. There are several reasons for this:
1. There is no scientific support that lowering IOP by a certain percentage is a correct approach.
2. Progression will take place also at normal IOP levels in the majority of glaucoma patients.
3. Rate of progression is extremely variable among glaucoma patients and cannot be predicted.
4. Fighting for 1 or 2 extra mmHg of pressure reduction involves the risk of doing more harm (with side effects or complications) than good, since we do not know until in retrospect if our initial notion of target pressure was correct or not.
5. Most importantly, using a numerical target pressure makes us focus on a surrogate measurement instead of concentrating on what we need to monitor, i.e. visual function.
Instead one can take another approach:
1. Place the newly diagnosed patient in an age-function diagram and determine whether she/he has a small, moderate or large risk to ever develop serious glaucoma damage jeopardizing Quality of Life.
2. Adjust the initial level of ambition (treatment intensity) according to the risk.
3. Follow the patient carefully to determine rate of progression in a few years.
4. Evaluate after 2-3 years to see if the observed progression rate is acceptable.
5. At that time: Maintain treatment if the progression rate is acceptable (or even diminish treatment in early disease with no progression), but step up treatment intensity a little if progression rate is borderline, and drastically if progression rate is alarming.


SELECTIVE LASER TRABECULOPLASTY (SLT): A VIABLE FIRST-LINE THERAPY FOR THE MANAGEMENT OF OPEN ANGLE GLAUCOMA
M. Latina

USA

a) Learning Objectives: Participants will gain an understanding of the role of selective laser trabeculoplasty in the management of open angle glaucoma and the use of SLT in the office setting. The basic mechanisms of SLT and the differences between SLT and ALT will be discussed. Studies on use of SLT as primary, adjunctive, replacement and repeat therapy will be presented.
b) Presentation Abstract: Selective Laser Trabeculoplasty (SLT) represents a new approach to the treatment of open angle glaucoma. SLT utilizes a short-pulsed Q-switched Nd: YAG laser emitting at 532 nm which preserves the Trabecular Meshwork architecture and functionality by selectively targeting pigmented trabecular meshwork cells without inducing collateral thermal damage. The lack of thermal damage to the TM by SLT has important clinical implications. Because compliance with the use of topical ocular medications for the treatment of glaucoma is poor, especially when more than one medication is necessary to control IOP, SLT offers a better alternative as primary treatment of glaucoma in many cases. Clinical studies demonstrating the role of SLT as primary therapy and its efficacy as compared to the Prostaglandins as primary therapy will be presented. Adjunctive, replacement and repeat therapy will be discussed. Results of the multi-center SLT-MED study comparing SLT to Medications as Primary Therapy will be reported.


NYSTAGMUS SURGERY
N. Miller

USA

This presentation will debate the safety and effectiveness of a new surgical procedure to correct congenital nystagmus-a disorder of eye muscle-vision-brain coordination characterized by rapid to and fro eye movements (oscillation). Patients with congenital nystagmus sometimes have other eye problems as well, such as cataracts, glaucoma, astigmatism or strabismus (cross-eyes). When these patients have eye muscle surgery to correct a problem, such as strabismus, their nystagmus also improves. Researchers think that simply cutting the muscles might produce this beneficial effect. This study will test this hypothesis-the horizontal muscles of the eye will be cut and then reattached in the same position. Our debate
Will focus on the safety of the surgery and its effect on eye oscillation and vision.


MANAGEMENT OF THE UNHAPPY PATIENT
J. Alio

Spain

Patients undergoing presbyopia surgery (phakic and pseudophakic), might not be satisfied with the outcome because of complications, inadequate expectations or lack of neuroadaptation to the multifocal or atypical visual image which is created by different techniques. During this debate, the patient selection criteria, how to inform the patient about the outcome, how to handle postoperative visual complications and how to stimulate neuroprocessing will be highlighted to convert the unhappy patient into a successful outcome.


CLEAR LENS EXTRACTION IS ETHICAL
S. Arshinoff

Canada

Purpose: To show that progress in cataract surgery to include judiciously chosen cases of slear lenses for surgery is ethical.
Study Design: This paper is a historical review of progress in cataract surgery.
Methods: cases are presented to demonstrate that there are more reasons to perform lens surgery that an opacifying human lens.
Results: Criteria for human lenticular surgery can no longer be looked at simplistically by the optical opacity of the lens to be removed. Instead the potential surgeon must assess whether the difficulty being suffered by the patient would be satisfactorily corrected by the proposed surgery, and that the benefits of surgery considerably outweigh the risks. In other words, clear lens surgery should be regarded in the same cautious fashion as any other surgical procedure.
Conclusion: Clear lens surgery should not be cavalier, but there are many indications for lenticular surgery beyond an opaque human lens. These indications will gradually change as new information and technologies emerge, as with any other surgical procedure.


BIMANUAL TECHNIQUES MICS
J. Alio

Spain

Microincisional cataract surgery is the cutting edge of cataract surgery today. Minimizing the incision has been always a way in cataract surgery to maximize outcomes. Today, the available phaco technology, improvements in instrumentation, better knowledge of the fluidics inside the eye and adequate intraocular lenses, make it possible to perform a most successful cataract outcome through incisions of less than 1.8 mm. Bimanual techniques have the added value of eliminating surgically induced astigmatism, eliminating changes in corneal aberrations, improving corneal biomechanical changes following surgery and a safer immediate postoperative evolution. Fluidics works in MICS like instruments. Fluidics jointly with a reduction in phaco power creates a safer environment with less energy used for the purpose of cataract removal. Microincision cataract surgery (MICS) both coaxial (2.2mm-1.8mm) or biaxial (1.6mm-1mm) is the last evolution of today’s small incision cataract surgery trend which was initiated in the seventies. Further evolution of cataract surgery will be made through the postulates of today’s MICS.


TRI-MICS: THREE PORT MICRO-INCISION CATARACT SURGERY
E. Assia

Department of Ophthalmology, Meir Medical center, Kfar-Saba & Ein-Tal Eye Center, Tel-Aviv, Israel

Purpose: To describe a 3-port micro-incision phaco technique using a modified anterior chamber maintainer (ACM).
Methods: A large pore, thin-walled ACM is inserted through a 1.1 mm inferior incision to provide a continuous irrigation throughout surgery. Sleeveless phaco tip and a second-hand instrument are inserted through additional 2 superior incisions.
Results: The modified ACM serves as the sole fluid source and provides flow comparable to or grater than conventional co-axial or bi-manual instruments. Any phaco machine can be used without modifications of the machine or surgical techniques. IOLs are implanted through a 1.8 mm incision even without viscoelastic substances. No corneal thermal burn was seen in any of the cases.
Conclusions: The tri-port MICS using a large pore ACM is an effective alternative for micro-incision phacoemulsification.


IFIS: SURGICAL OPTIONS: STRETCH AND OVDS WORK BEST
D. Sachs

Israel

Floppy Iris is a condition encountered in Flomax (or related drugs) patients. Mid dilated pupil despite application generous amounts of mydriatics suggests the presence of either PXF or Flomax treated condition. Slit lamp examination and anamnesis can confirm the proper diagnosis.
Intraoperative miosis, prolapse and billowing of the iris endanger the surgery.
1% Atropine drops are applied for 5 days prior to surgery in every case of eventual IFIS.
A mixture of Lidocaine 1% and preservative free epinephrine (Epi-Sugar-Caine) is injected into the anterior chamber for 1 and a half minute right after performing the paracenthesis. The next step is to fill the anterior chamber with Healon 5 in order to maintain a good dilatation allowing the performance of a large capsulorhexis. The hydrodisection, hydrodelineation and nucleus rotation are followed by the reinjection of a large amount of Healon 5. This step is sufficient to keep the pupil dilated to more than 6.0 mm in most of the cases. Small amount of regular Healon is injected beneath it, over the crystalline lens (soft shell technique). Healon 5 has to be added as long as needed over the iris. It prevents prolapse and billowing of the iris during all phaco stages.
Wide pupil allows a safe surgery. If the mydriasis is not maintained with Healon 5 the pupil has to be stretched. This is done bimanually with a Kuglen hook and a spatula. It should be done in a horizontal plane in all the directions with anterior chamber filled with OVD. The Phaco parameters, vacuum and flow rate must be modified and lowered, minimizing the hazardous anterior chamber turbulence and aspiration of the efficacious Healon 5.
OVDs and stretching are the first and best options in managing IFIS. It simplifies the surgery that can be exercised by the majority of surgeons without outstanding skill, and is cost-effective comparing to other pupil extending devices.


ASTIGMATIC CORRECTION DURING CATARACT SURGERY: YES, CATARACT SURGERY IS REFRACTIVE IN ANY EVENT
W.J. Stark

USA
Advanced cataract surgery can be the most frequently performed refractive surgery procedure now, especially with high patient expectations of excellent uncorrected visual acuity. Adding astigmatism management to the case, at a minimal cost, can be very rewarding for the patient.
Astigmatism up to 0.75 diopters can be managed by operating along the steep axis. If additional correction is needed, astigmatic keratotomy and /or toric IOLS can be used.
Data submitted to the FDA for approval of toric IOLs, as well as my own personal experience will be presented. Up to approximately four diopters of corneal astigmatism can be corrected using a combination of astigmatic keratotomy and toric IOL.


SIMULTANEOUS BILATERAL CATARACT EXTRACTION UNDER GENERAL ANESTHESIA
E. Assia, T. Yokrat, A. Abulafia, J. Raz

Department of Ophthalmology, Meir Medical center, Kfar-Saba & Ein-Tal Eye Center, Tel-Aviv, Israel

Purpose: to evaluate the safety and benefits of simultaneous bilateral cataract surgery under general anesthesia in adults and children.
Methods: Medical records of patients who had simultaneous bilateral cataract surgery from June 1999 to December 2008 were reviewed. All procedures were managed as 2 separate consecutive surgeries. Outcome measures included intra-operative and postoperative complications and post operative visual acuity.
Results: Forty three adults (86 eyes) and 19 children (38 eyes) were operated simultaneously on both eyes. Intra-operative complications occurred in 6 eyes: posterior capsule rupture in 5 patients and zonulysis in 1 patient. Post-operative complications were temporary wound leak, cystoids macular edema and intraocular lens subluxation in one eye each; and posterior capsular rents in 3 eyes. Postoperative fibrinoid reaction (TASS) was diagnosed in 3 eyes. Uncorrected visual acuity improved in 76.7% of operated eyes in adults and in all children's eyes, except for one amblyopic eye.
Conclusions: Bilateral ocular surgery is safe and effective. Intra-operative and postoperative complications rate was low and not attributed to the bilateral intervention. Avoiding a second general anesthesia justifies the potential risk of simultaneous binocular surgery.


EXTERNAL BEAM RADIATION (TELETHERAPY)
J. Pe'er

Israel

Radiation therapy, in its various forms, is a highly effective method of treatment for retinoblastoma, and until the early 1990s was the first choice of non-surgical modalities for treating this malignancy. In eyes with low staging of retinoblastoma, the success rate of external beam radiation (EBR) exceeds 95%, but even in very progressive stages it can reach 50%, with globe preservation.
Studies published in the early 1990s of large groups of patients with long follow-up showed unequivocally that EBR causes serious side effects such as orbital (mid-facial) hypoplasia, and more important, second malignant neoplasms, mainly sarcomas. These side effects were shown to be more prominent if the child with retinoblastoma was irradiated in the first year of life. Retinoblastoma oncologists shifted their treatment, in those cases in which enucleation was avoidable, toward first-line treatment with chemotherapy and local complementary treatments using brachytherapy, cryotherapy, laser photocoagulation and transpupillary thermotherapy.
In Groups D and E of the international retinoblastoma classification, the retinoblastoma is diffusely disseminated in the eye, usually with vitreous and subretinal seeding of tumor cells. These tumors are very difficult or impossible to treated using chemotherapy and local complementary treatment. Whenever one eye is normal or at least at a lower stage which enables treatment with globe preservation, the eye with the advanced disease should be enucleated. The challenge is when the "good" or sometimes the only eye belongs to Group D or E. In such cases we should make the utmost efforts to save at least one eye.
Since EBR is an effective treatment for retinoblastoma, and can cure also tumors with vitreous and subretinal seeding, it should be seriously considered as an optional treatment over enucleation of an only eye. In such cases, in order to try and prevent the major adverse side effects, the radiation should be delayed until after the [child's] first birthday. Other measures that can be considered are a lower dose of irradiation, such as 36 Gy instead of the conventional 45 Gy, and using new techniques such as three-dimensional conformal radiation therapy and intensity-modulated radiation therapy, which affect the eyeball more but with less effect on the surrounding orbital tissue. Proton beam radiation with its precise dose of irradiation to the target, reducing the dose to the normal tissue, is becoming more popular in treating advanced retinoblastoma, in centers where it is available.


TREATMENT OF ADVANCED (GROUP D AND E) RETINOBLASTOMA: ENUCLEATION
T. Kivela

Department of Ophthalmology, Helsinki University Central Hospital, Helsinki, Finland

Group D retinoblastoma comprises tumours that have spawned diffuse vitreous or subretinal seeds or both, distant from the solid tumour foci (1). Visual prognosis is guarded and depends on tumor size and location. Morbidity from focal therapy can be high.
Group E retinoblastoma includes extensive tumours occupying more than half of the globe, typically associated with secondary complications such as neovascular glaucoma, haemorrhage in the anterior chamber, vitreous or subretinal space, invasion of the postlaminar optic nerve, massive choroidal invasion, or invasion of the anterior chamber, sclera or orbit (1).
Patients with group D and E retinoblastoma have a much lower chance of saving their eye with chemoreduction, transpupillary thermotherapy, cryocoagulation and brachytherapy alone, without reverting to external beam radiotherapy (EBRT) or secondary enucleation. Of group D and E eyes, 53% to 75% eventually require either EBRT or enucleation (2,3,4). Even though 25% to 47% of group D eyes can be salvaged anatomically with systemic chemotherapy and focal treatment only, visual potential of the salvaged eyes is guarded. Few studies have documented that these salvaged eyes would retain meaningful vision compared with the uninvolved fellow eye or a fellow eye with a later onset, typically group A retinoblastoma, with up to 100% eye retaining rate (2).
The enucleated eye in group D and E retinoblastoma is also generally blind or nearly so, so that enucleation does not lead to significant further loss of vision in unilateral retinoblastoma.
When a child has unilateral Group D or E retinoblastoma and a normal fellow eye, enucleation is most often the treatment of choice (2,5,6), especially when the child is over one to two years of age at the time of diagnosis. In these cases, the tumour is likely to be nonhereditary and the normal fellow eye consequently is safe. If so, enucleation provides immediate and, if the optic nerve, choroid and anterior chamber are uninvolved, also permanent cure (5).
Even if the child with unilateral group D or E retinoblastoma is younger, rising the chances of the tumour being hereditary, or if genetic testing reveals that the tumour indeed is inherited, close follow-up of the initially uninvolved eye and prompt focal therapy of any later foci will almost guarantee retained vision. When the worse eye is enucleated, there is no need to start chemotherapy or radiotherapy with their systemic and focal complications, respectively. One can rest assured that the risk of second cancers will be unaffected.
When the child has bilateral retinoblastoma with group D or E tumour in the worse eye and a group B or C retinoblastoma that would require chemoreduction rather than focal therapy only, it may be reasonable to defer enucleation of group D and E eyes and wait for treatment response. In these cases, there is a change that the initially worse eye is the one eventually retained.
However, once the better eye is stabilised, one should critically consider enucleation of the worse eye in case recurrences develop and they can not be managed with reasonable focal treatment. This is because prolonged time to enucleation after attempting salvage of the eye with chemoreduction is predictive of extraretinal extension to the choroid and ciliary body (7). Such an extension will in turn increase the chances of extraocular spread and metastasis.
In summary, enucleation is generally the best option when there is poor potential for useful vision that moreover could be achieved only with prolonged and expensive therapy with many potential short-term and long-term side effects, including infertility from systemic chemotherapy or vascular occlusion from intra-arterial treatment. Enucleation will reduce the risk of metastasis and death from undetected high-risk pathology (5,7). It will also enable quick return to normal life, unburdened by frequent follow up visits (7).
References:
(1) Novetsky DE, Abramson DH, Kim JW, Dunkel IJ. Published international classification of retinoblastoma (ICRB) definitions contain inconsistencies - an analysis of impact. Ophthalmic Genet. 2009;30:40-4. (2) Shields CL, Mashayekhi A, Au AK, Czyz C, Leahey A, Meadows AT, Shields JA. The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology 2006;113:2276-80. (3) Shields CL, Ramasubramanian A, Thangappan A, Hartzell K, Leahey A, Meadows AT, Shields JA. Chemoreduction for group E retinoblastoma: comparison of chemoreduction alone versus chemoreduction plus low-dose external radiotherapy in 76 eyes. Ophthalmology 2009;116:544-551. (4) Cohen VM, Kingston J, Hungerford JL. The success of primary chemotherapy for group D heritable retinoblastoma. Br J Ophthalmol 2009;93:887-90. (5) Mallipatna AC, Sutherland JE, Gallie BL, Chan H, H?on E. Management and outcome of unilateral retinoblastoma. J AAPOS 2009;13:546-50. (6) Lin P, O'Brien JM. Frontiers in the management of retinoblastoma. Am J Ophthalmol 2009;148:192-8. (7) Balaguer J, Wilson MW, Billups CA, Mancini J, Haik BG, Qaddoumi I, Khoury JD, Rodriguez-Galindo C. Predictive factors of invasion in eyes with retinoblastoma enucleated after eye salvage treatments. Pediatr Blood Cancer 2009;52:351-6.


SUPER-SELECTIVE INTRA-ARTERIAL CHEMOTHERAPY FOR RETINOBLASTOMA
F. Munier

Switzerland

Since the 1990s, chemotherapy has been the systematic first-line treatment in the management of retinoblastoma, in order to reduce tumor volume (chemoreduction) and render it accessible to focal treatments. This approach has enabled globe preservation with no external radiotherapy in the large majority of less-advanced tumors (Group A-C of the International Classification of Intraocular Retinoblastoma), and in only 19-60% of more advanced cases (Group D). Selective chemotherapy of the retina consisting of direct intra-arterial injection via catheterization of the ophthalmic artery not only offers a promising alternative to systemic intra-venous chemotherapy in advanced intra-ocular retinoblastoma (Group D) but also may significantly improve the success rate in terms of globe preservation. Infusion of Melphalan into the ophthalmic artery via the carotid artery was pioneered already 20 years ago in Japan by Kaneko et al. Recently Abramson et al. in New-York provided evidence supporting the anti-tumoral effect of this approach, with no major side-effects. This therapeutic modality was introduced in Lausanne in 2008. We will present our experience with first line and salvage intra-arterial chemotherapy in group D eyes.


BRACHYTHERAPY FOR THE TREATMENT OF RETINOBLASTOMA: 125I APPLICATORS
T. Kivela

Department of Ophthalmology, Helsinki University Central Hospital, Helsinki, Finland

Brachytherapy for retinoblastoma currently is used as consolidation or salvage treatment after chemoreduction of larger, group B to D retinoblastomas, and to manage local recurrences after failed transpupillary thermotherapy and cryotherapy for group A to D retinoblastoma with a 95% success rate (1). It is rarely used as sole primary treatment for retinoblastoma (2) any more. Special uses include treating the bony orbit and eyelids after extraocular spread of retinoblastoma (3).
When brachytherapy is needed, 125Iodine applicators are often more versatile or otherwise superior in managing retinoblastoma as compared to 106Ruthenium/106Rhodium applicators.
First, 125Iodine applicators are composed of a gold plaque to which an arbitrary number of radioactive iodine seeds can be glued with silicon glue. Consequently, these plaques can be crafted to any size and shape desired; in our case, the crafting is done by a local goldsmith who will produce plaques of desired shape on short order. In contrast, 106Ruthenium/106Rhodium applicators are sold in predefined sizes and shapes by the manufacturer, and they can not be altered.
Consequently, the physician managing retinoblastoma can either choose a 125Iodine plaque that matches, or is conformal with, the tumour or tumours treated. An example is a bow or girdle shaped plaque which can cover one or two quadrants of peripheral retina with subretinal seeds. He or she may also use a larger 125Iodine plaque as a carrier for seeds which need to be placed posteriorly over a small tumour that would be difficult to target using a small conformal plaque. An example is a small tumour located adjacent to the optic disc, which can easily be managed with a plaque notched to accommodate the optic nerve, which carries only two or three seeds adjacent to the notch. A 106Ruthenium/106Rhodium applicator of corresponding size will radiate over its entire surface area, leading to unnecessary irradiation of normal surrounding retina.
Second, only a fairly small number of iodine seeds need to be purchased every six months, because these can be moved from plaque to plaque. One can have a wide array of different unmanned plaques in stock, making 125Iodine economical to use even when the number of patients is small. In contrast, all 106Ruthenium/106Rhodium plaques needed must be kept in stock and replenished every 2 years, even if a particular plaque may be needed only rarely during its life time.
Third, 125Iodine applicators emit gamma rays which can traverse longer distances in the eye. They can be used to treat thick retinoblastomas if needed, although this is rarely required in these days of systemic and intra-arterial chemotherapy. More often deeper penetration is useful when one has to manage a tumour with adjacent vitreous seeds. In contrast, 106Ruthenium/106Rhodium applicators, which emit beta rays, have a more limited treatment depth. This is less of a limitation in managing retinoblastoma vs. treating uveal melanoma, because of the smaller 40 Gy vs. 80 Gy apical dose required to destroy the former as compared to the latter.
The same apical dose can be achieved using 125Iodine applicators with a much lower dose to tumour base (4) and consequently with less choroidal and retinal atrophy, as compared to a 106Ruthenium/106Rhodium applicator (5) of similar size and shape. On the other hand, lateral scatter of radiation from a 125Iodine applicator will reach wider than that from a 106Ruthenium/106Rhodium applicator, which sometimes increases the risk of collateral damage from the former.
In summary, 125Iodine applicators are easy to make and cheap to stock in different sizes and shapes, allowing conformal therapy of various retinoblastomas by moving a small number of seeds between various plaques or targeted irradiation of awkwardly located tumours. They provide a more uniform depth dose curve and penetrate deeper, which can be used either to limit collateral damage or to manage adjacent vitreous seeds, respectively.
References:
(1) Shields CL, Mashayekhi A, Sun H, Uysal Y, Friere J, Komarnicky L, Shields JA. Iodine 125 plaque radiotherapy as salvage treatment for retinoblastoma recurrence after chemoreduction in 84 tumors. Ophthalmology 2006;113:2087-92. (2) Merchant TE, Gould CJ, Wilson MW, Hilton NE, Rodriguez-Galindo C, Haik BG. Episcleral plaque brachytherapy for retinoblastoma. Pediatr Blood Cancer 2004;43:134-9. (3) Stannard C, Sealy R, Hering E, Hough J, Knowles R, Lecuona K, Reddi VB. Postenucleation orbits in retinoblastoma: treatment with 125I brachytherapy. Int J Radiat Oncol Biol Phys 2002;54:1446-54. (4) Wilkinson DA, Kolar M, Fleming PA, Singh AD. Dosimetric comparison of 106Ru and 125I plaques for treatment of shallow (<or=5 mm) choroidal melanoma lesions. Br J Radiol 2008;81:784-9. (5) Bacin F, Amara S, Kemeny JL, Rozan R, Bard JJ, Donnarieix D. Etude comparative de l'irradiation beta (106Ru/106Rh) et de l'irradiation gamma (125I) sur l'oeil du lapin. Ophthalmologica 1998;212:429-38. (6) Shields CL, Shields JA, Cater J, Othmane I, Singh AD, Micaily B. Plaque radiotherapy for retinoblastoma: long-term tumor control and treatment complications in 208 tumors. Ophthalmology 2001;108:2116-21. (7) Lumbroso-Le Rouic L, Aerts I, L?vy-Gabriel C, Dendale R, Sastre X, Esteve M, Asselain B, Bours D, Doz F, Desjardins L. Conservative treatments of intraocular retinoblastoma. Ophthalmology 2008;115:1405-10.


RUTHENIUM106 BRACHYTHERAPY FOR INTRA-OCULAR ETINOBLASTOMA
F. Munier

Switzerland

Conservative treatment of intra-ocular retinoblastoma requires a vast platform of therapeutic means. Among them, one has to distinguish first and second line treatments from salvage therapy. Classically the first line treatments aim at partial response so that tumors are amenable to second line therapies in a de-escalating mode, which are usually more focal. Inversely, salvage therapy will proceed in a re-escalating mode to overcome a recurrence. Remarkably, Ruthenium106 brachytherapy can be efficiently used at any time for tumors up to 5 mm in thickness. With a dosimetry of 50Gy at apex, tumor control is obtained in 87.5% if used as first or second line treatment, and in 68.1% in case of salvage. With such a dose, the radio-induced side effects are very limited and no non-ocular second primaries were reported. Therefore a prescription of 60 Gy at apex is expected to significantly increase tumor control with no additional toxicity.


PROTON BEAM VS EXTERNAL BEAM RADIOTHERAPY FOR RETINOBLASTOMA: EXTERNAL BEAM RADIOTHERAPY
T. Kivela

Department of Ophthalmology, Helsinki University Central Hospital, Helsinki, Finland

External beam radiotherapy for retinoblastoma is mostly used as salvage treatment after failed chemoreduction (1) and, sometimes, as primary treatment of international classification group D retinoblastomas with diffuse vitreous seeding which is unlikely to respond to chemoreduction alone and which can not be managed with focal therapies.
The wisdom has been that external beam irradiation is best avoided because it is associated with increased risk of later second cancers, especially sarcomas in the treated volume, and with delayed growth of the bony orbit, leading to more or less disfiguring asymmetric growth of the face and the irradiated orbit.
However, much of the underlying data derives from times when external beam radiotherapy was administered with high doses and crude treatment plans. Subgroup analysis suggests that the risk for second cancers in the field of radiation is heavily dependent on the age at which treatment is given and may not be significantly different after the age of 12 months as compared to no external beam therapy (2).
Today it is possible to use multiple fields or, better still, stereotactic methods of delivery of external beam radiotherapy to target selected foci of retinoblastoma in the posterior pole (3). This modality will minimize the cosmetic effects of external beam irradiation on the growth of the bony orbit to a great extent.
External beam radiotherapy is effective when used as primary treatment for advanced retinoblastoma equivalent to group D, the ocular survival rate being 81% at 1 year and 53% at 10 years after treatment (4). Likewise, up to 77% of eyes that are treated with external beam radiotherapy for recurrence of retinoblastoma following failed chemoreduction can be salvaged (1).
External beam radiotherapy is preferably given from multiple fields so that the lens will be spared and orbital growth will be less affected. However, if the need be, the whole eye can be irradiated. In the latter instance one has to be prepared for a future cataract extraction at a later date.
A potential new application is routine external beam irradiation given 2 months after completion of chemoreduction at a lowered dose of 26 Gy, a modality which may have a future role in the special instance in which one is trying to save an eye with group E retinoblastoma. By 2 years, 91% of such eyes were salvaged with chemoreduction and adjuvant external beam therapy as compared to 53% of eyes salvaged with chemoreduction alone (5). The difference narrowed but was retained at 5 years,
In summary, external beam irradiation remains a useful part of our armamentarium in managing retinoblastoma because, in a number of patients, it is the only treatment modality that has a fair chance of saving the eye when conservative treatments fail. Also, it is now understood that most severe complications of external beam irradiation possibly occurred because the dose earlier was unnecessarily high or the child happened to be very young at the time of irradiation, typically less than a year old. With smaller modern doses and by avoiding treatment of very young children whenever possible, the complications mentioned have become much less disturbing.
References:
(1) G?nd?z K, G?nalp I, Yal?inda? N, Unal E, Ta?yildiz N, Erden E, Geyik PO. Causes of chemoreduction failure in retinoblastoma and analysis of associated factors leading to eventual treatment with external beam radiotherapy and enucleation. Ophthalmology 2004;111:1917-24. (2) Abramson DH, Frank CM. Second nonocular tumors in survivors of bilateral retinoblastoma: a possible age effect on radiation-related risk. Ophthalmology 1998;105:573-9. (3) Sahgal A, Millar BA, Michaels H, Jaywant S, Chan HS, Heon E, Gallie B, Laperriere N. Focal stereotactic external beam radiotherapy as a vision-sparing method for the treatment of peripapillary and perimacular retinoblastoma: preliminary results. Clin Oncol (R Coll Radiol) 2006;18:628-34. (4) Abramson DH, Beaverson KL, Chang ST, Dunkel IJ, McCormick B. Outcome following initial external beam radiotherapy in patients with Reese-Ellsworth group Vb retinoblastoma. Arch Ophthalmol 2004;122:1316-23. (5) Shields CL, Ramasubramanian A, Thangappan A, Hartzell K, Leahey A, Meadows AT, Shields JA. Chemoreduction for group E retinoblastoma: comparison of chemoreduction alone versus chemoreduction plus low-dose external radiotherapy in 76 eyes. Ophthalmology 2009;116:544-551.


PENETRATING KERATOPLASTY IS THE BEST TREATMENT
J. Alio
Spain

Fuchs endothelial corneal dystrophy patients are usually elderly, affected by a problem that many times is precipitated by inadequately performed cataract surgery. Penetrating keratoplasty is still today, in spite of the recent progress of lamellar techniques, the state of the art in the management of endothelial cell dysfunction. The faster recovery, the lack of postoperative complications, the reduction of the immunological burden created in the elderly patient by a corneal graft, makes penetrating keratoplasty the most conservative but the best approach for the rehabilitation of the chronic edema that follows Fuchs dystrophy associated to corneal decompensation. The arguments in favour of penetrating keratoplasty outweigh the potential benefits created by posterior lamellar grafts. During this presentation the main pitfalls of posterior lamellar grafts and descemet endothelial transplantation will be highlighted against the advantages of penetrating keratoplasty.


DESCEMET’S STRIPPING AUTOMATED ENDOTHELIAL KERATOPLASTY (DSAEK) OR DESCEMET’S MEMBRANE ENDOTHELIAL KERATOPLASTY (DMEK) SHOULD ALWAYS BE TRIED FIRST
W.J. Stark

USA

Fuchs’ corneal dystrophy1 is a dominantly inherited, progressive disorder that affects corneal endothelium. It is usually ?rst observed in patients older than 50 years of age but can be seen in some patients in childhood. There is a progressive loss of endothelial cells with a secretion of an abnormally thickened basement membrane, leading to guttata formation. These guttata are often best seen by retro illumination but can be seen by direct illumination of the slit lamp.
Cataract surgery in patients with Fuchs’ corneal dystrophy presents a challenge, because the intraocular surgery can result in an 8%-10% loss of the endothelial cells. The use of dispersive viscoelastics may lessen endothelial cell loss during surgery.
The decision as to whether to perform cataract surgery alone or cataract surgery plus Descemet stripping automated endothelial keratoplasty (DSAEK) or Desemet Membrane Endothelial Keratoplasty (DMEK) is often complex and depends on the assessment of endothelial cell health. It is debated whether the best assessment is by endothelial cell counts or central corneal pachymetry. In our practice we have found endothelial cell counts to vary significantly and not be helpful in determining when a cornea with Fuchs’ endothelial dystrophy might decompensate with a cataract surgery. Therefore, we rely on clinical appearance of the cornea (epithelial edema vs. no edema), the pachymetry measurements of the cornea, and the visual needs of the patient.
Past publications, including the Preferred Practice Pattern2 and Basic and Clinical Science manual3 for ophthalmologists, have indicated that a preoperative corneal thickness of >0.60 mm (600 µm) may be predictive of corneal decompensation, and indicates that an initial penetrating keratoplasty may be required in these patients in combination with cataract surgery. Our experience at the Wilmer Eye Institute indicates that many patients with a preoperative corneal thickness of >600 µm, as measured by pachymetry, do very well after cataract surgery and do not require postoperative penetrating keratoplasties or DSAEK.
We recently published in “Ophthalmology”4 a twelve year review of 136 patients with Fuchs’ dystrophy who underwent phacoemulsi?cation and intraocular lens implantation. The average preoperative corneal thickness in these was 580 µm, and fifty eyes (36.8%) had preoperative corneal thickness ?600 µm. postoperatively the average visual acuity of our patients 20/33. None of the eyes with a preoperative corneal thickness of <600 µm decompensate within two years after cataract surgery. Of the fifty patients with preoperative pachymetry measurements of greater than or equal to 600 µm, only 5 (10%) progressed to penetrating keratoplasty and 90% of the fifty eyes did not need a corneal transplant at least within the first one to two years after cataract surgery. These patients had an average visual acuity of 20/35 postoperatively. Based on these results, we have suggested that the preferred practice pattern for ophthalmologists extend the indications for cataract surgery in patients with Fuchs’ dystrophy without obvious epithelial edema to undergoing cataract extraction without keratoplasty if the corneal thickness is ?640 µm. Patients should be counseled that they have an approximately 10% chance of needing a keratoplasty within the first one to two years after surgery and if they live long enough they may eventually need a PK or DSAEK or DMEK, because this is a progressive disorder. We modify our viscoelastic use during surgery in patients with Fuchs’ dystrophy to use a dispersive viscoelastic such as Viscoat or Healon 5 to offer better protection of the endothelium during the phacoemulsification portion of the surgery. No study has been performed to definitively show that this is beneficial, but it is our belief that a dispersive viscoelastic helps protect the endothelium. One disadvantage of the dispersive viscoelastic is that it may trap small nuclear fragments in the peripheral angle that are not removed during phacomulsification and/or irrigation-aspiration of the remaining viscoelastic. The retention of small nuclear fragments in the anterior chamber angle after cataract surgery can be damaging to endothelium and cause decompensation of the cornea. Therefore, one must be very careful to remove all nuclear chips during the cataract extraction and/or irrigation-aspiration.
Our teaching in the past has been to perform cataract extraction alone inpatients with a Fuchs’ dystrophy and a central corneal thickness of ?640 µm. We realize that an increase in corneal thickness does lead to increase in light scatter and have found in our studies that as the corneal thickness goes above 640 µm, visual acuity begins to deteriorate. We also reported on 12 patients who had a corneal thickness between 640 µm to 680 µm, who underwent very careful cataract surgery. These were elderly and/ or one eyed patients whom we thought penetrating keratoplasty was not warranted. Ten of the 12 cases (86%) maintain clear corneas at two years after surgery, with a median visual acuity of 20/40. There seems to be a correlation of increased corneal thickness of over 640 µm with a decrease in visual acuity, and currently we are evaluating this in a large number of Fuchs’ dystrophy patients after cataract surgery.
Certainly if a patient has a corneal thickness between 550 µm and 640 µm with epithelial edema that cornea has decompensated and a PK or DSAEK or DMEK is indicated. One can determine epithelial edema by retro illumination view and/or applying a cotton tip applicator to the cornea epithelium after using anesthesia to see if it is detached indicating epithelial edema.
The recent developments and popularization of DSAEK by Mellis5, Terry6,7,8,9 and Price10 will certainly decrease the number of PK’s for Fuchs’ corneal dystrophy. We still recommend a simple cataract operation if there is no epithelial edema and central corneal thickness is <640 µm. This in many of our patients has provided 20/20 visual acuity with a 90% chance of not needing a corneal transplant. If there is epithelial edema, and when the corneal thickness goes above 640 µm there will be decreased visual acuity due to light scatter from the stroma and epithelial edema. In these cases we are now recommending a combination of phacomulstification removal of the cataract and DSAEK. If the case is borderline, or in a patient with one eye where cataract surgery might provide an improvement but possibly not a perfect visual acuity due to mild corneal edema, then we have suggested cataract extraction alone to see what visual acuity is obtained. If it is adequate for the patient’s needs, a DSAEK or DMEK can be avoided. If visual acuity is not adequate then the patient can be treated with a DSEAK or DMEK. Although DSAEK is becoming more popular, there are complications of the procedure. A recent eye bank presentation in Toronto, Canada, June 2005, indicated that possibly 20% of DSAEK’s dislocate. Our percentage of dislocation is less then 10%. Terry has recently reported about a 1% dislocation rate (personal communication). We have seen two cases in forty with rejection, and both of these have cleared.
In summary, we have extended the indications for cataract surgery without simultaneous corneal surgery in eyes without epithelial edema to a corneal thickness of ?640 µm and possibly to 680 µm. The ability to perform DSAEK or DMEK, which is less debilitating to the patient than PK, has encouraged us to extend the indications for cataract extraction in patients with moderate Fuchs’ dystrophy but without epithelial edema, realizing that DSAEK or DMEK can be performed later if the patient does not achieve adequate visual acuity with cataract surgery alone. Since the DSAEK operation induces about -1.50 diopters hyperopic shift we aim for a postoperative spherical equivalent of -1.50 to 1.75 diopters in patients undergoing combined DSAEK and cataract extraction or in Fuchs’ patients who are undergoing cataract surgery and may need a later DSAEK.
References:
Vogt A. Weitere Ergebnisse der spaltlampenmikroskopie des vorden bulbusabschnittes. Albrecht Von Graefes Arch Klin Exp Ophthalmol. 1921;106:63-103; American Academy of Ophthalmology Anterior Segment Panel. Preferred practice pattern. Cataract in the adult eye. San Francisco: American Academy of Ophthalmology; 2001. Available at: http//www.aao.org/aao/education/library/ppp/index. cfm. Accessed Oct 1, 2002; Basic and Clinical Science Course Section 11. Lens and Cataract. San Francisco: American Academy of Ophthalmology; 2001; Seitzman GD, Gottsch, JD, Stark WJ. Cataract Surgery in Patients with Fuchs’ Corneal Dystrophy. Ophthalmol. 2005;112:441-446; Melles GR, Wijdh RH, Nieuwendaal CP. A technique to excise the descemet membrane from a recipient cornea (descemetorhexis). Cornea 2004;23(3):286-8; Terry MA, Ousley PJ. Corneal endothelial transplantation: advances in the surgical management of endothelial dysfunction. Contemporary Ophthalmol. 2002;1:1-8; Ousley PJ, Terry MA. Stability of vision, topography, and endothelial density from 1 to 2 years after deep lamellar endothelial keratoplasty. Ophthalmology 2005; 112:50-57; Terry MA. Endothelial Keratoplasty: Current Techniques and Results. Current Insight, Volume 1, Number 3, Summer 2006 (AAO Web article); Terry MA. Management of Corneal Endothelial Dysfunction. [AAO Specialty Clinical Update]. 2005. Available online at:
http://www.aao.org/vp/edu/ced_cornea/v1m5 ; Price FW, Price MO. Descemet’s stripping with endothelial keratoplasty in 200 eyes: Early challenges and technique to enhance donor adherence. J. Cataract Refract Surg 2006; 32: 411-418


NEW APPROACHES FOR THE TREATMENT AND KERATOCONUS AND KERATECTASIA - CROSSLINKING AND INTRACORNEAL RINGS: WHAT IS THE BEST CHOICE?
J. Murta

Portugal

Keratoconus and keratectasia are included in a group of noninflammatory corneal thinning disorders characterized by a tectonic corneal weakness leading to an ectasia of the cornea, irregular astigmatism and, consequently, loss of vision. The principal approaches to the management of theses diseases have been limited, until recent years, to the use of rigid gas permeable contact lens and, in more severe cases, to corneal surgery namely penetrating keratoplasty. Several alternative surgical techniques had been proposed such as thermal keratoplasty, epikeratoplasty, photorefractive keratectomy, laser in situ keratomileusis, with non consistent anatomical and functional results, or deep anterior lamellar keratoplasty. In recent years, two procedures have been designed to manage these ectatic corneal disorders: collagen cross-linking and intrastromal corneal rings.
These diseases are associated with reduction of the biomechanical strength of the cornea, possibly related to reduce interfibrillar crosslinks. The concept of corneal collagen cross-linking treatment (CXL) aims to address this pathogenic mechanism, utilizing ultraviolet A (UVA) at 370 nm to activate riboflavin and generating reactive oxygen species that increase the formation of intra and interfibrillar covalent bonds between collagen fibrils.
The insertion of intracorneal ring segments into the stroma of the cornea enhance or restore corneal rigidity and achieve refractive adjustment by flattening the cornea in a direct proportion to the thickness of the implant and in inverse proportion to its diameter. Different models of polymethyl methacrylate (PMMA) intracorneal rings, different diameters of channel sizes, different number of normograms as well as different channel dissection methods have been used.
We will evaluate, compare and discuss long term anatomic and functional results of the insertion of intracorneal rings (Intacs), with Keraring using different channel sizes, different channel dissection techniques and new normograms as well as combination of corneal crosslinking treatment with intrastromal rings insertion to attain stability in keratoconus and in post-LASIK keratoectatic disease.


ENDOSCOPIC OR EXTERNAL DCR, WHICH IS PREFERABLE FOR NASOLACRIMAL DUCT OBSTRUCTION IN ADULTS?
N. Rosen

Israel

Although the classic external DCR is still the most popular procedure used by most ophthalmic lacrimal surgeons and especially by the occasional lacrimal surgeon. Endonasal DCR has grown and is still growing in popularity since the establishment of the technique almost 20 years ago.
The advantages of the endonasal technique are quite obvious. It does not leave a scar or other deformities such as webbing in the medial canthal area. The recovery period after internal DCR is shorter than after external DCR there is usually less bleeding and less discomfort for the patient.
Initially there was marked skepticism in the ophthalmic community regarding the success rate of this procedure and almost all published works stressed the steep learning curve of this technique. Recently published statistics of the success rate of internal DCR show similar success rate to the external approach.
It is true that internal DCR require mastering a special technique of operating in the nose but once this technique is mastered the operation becomes routine.
Initial temporary partnership with an ENT specialist is a good way to attenuate the steep learning curve.
In conclusion, the internal DCR has obvious advantages over the external approach; its drawbacks can be overcome with special and planned training thus rendering it to become the preferred modality of surgery.


EXTERNAL DCR: IT IS CHEAPER AND THE SUCCESS RATE IS HIGHER
D. Verity

UK

Both endoscopic and external DCR approaches seek the same end, that is, reduction of overall lacrimal outflow resistance. However, external DCR, in the hands of an experienced clinician and surgeon, remains both the most cost-effective and functionally successful surgical approach to distal lacrimal outflow insufficiency.
(a) The external approach is cheaper: Although external DCR surgery generally takes a few minutes longer than endoscopic surgery, it remains the more cost-effective option for the following reasons. Firstly, the endoscopic approach is often undertaken by both ENT and ophthalmic surgeons – this being an inefficient use of medical expertise. Secondly, the higher rate of external revisional surgery following endoscopic surgery entails additional outpatient and preoperative assessments, and further surgical time (by a highly experienced surgeon, with surgery being potentially longer than for primary DCR) Finally, in those cases where a glass bypass tube is required due to unrecognised proximal resistance or true ‘functional’ epiphora, a revisional external approach (with adequate anterior ethmoidectomy) is required before the tube can be placed. Thus, taking these aggregate factors into account, day case external approach DCR surgery is less expensive than endoscopic DCR surgery.
(b) The success rate of the external approach is higher: The reason that external DCR surgery has an undisputedly higher success rate is that it is able predictably to overcome anatomical and viscous outflow resistance, this achievable with adequate anterior ethmoidectomy and suturing of anterior and posterior flaps. The latter are not amenable via an endoscopic approach, this accounting for the lower success rate of the endoscopic approach. If satisfaction with the external scar is considered a further measure of ‘success’, then an appropriately placed incision and meticulous attention to diathermy and wound closure yields a scar which is typically of no concern whatsoever in all but a miniscule fraction of patients.


MANAGEMENT OF CHILDHOOD EPIPHORA: PROBING, INTUBATION OR DCR?
D. Paridaens

The Netherlands

Background: In the management of childhood epiphora, most clinicians would wait until 12 months before probing unless there is acute dacryocystitis or a congenital dacryocoele. In cases of mild epiphora one may wait another 6 to 12 months before probing, especially if the parents are reluctant for their child to have a procedure under general anaesthesia.
For failed probing there is an ongoing debate on how to proceed: should we re-probe or should we additionally use balloon catheter dilation or silicone intubation? Or even do a DCR?
What is our preferred treatment: In our practice we re-probe all children who underwent probing elsewhere, but we perform re-probing combined with silicone intubation in all children who earlier underwent probing at our hospital. Only in case of failure of this intervention we will proceed with DCR.
Using this approach in more than 12 successive years we have been able to adequately treat childhood epiphora with very few cases which eventually required DCR.
Discussion: Only a prospective trial comparing re-probing without intubation versus re-probing with intubation would yield an answer to the question: Is additional intubation really necessary? The low incidence of DCR in our institution versus the higher incidence of DCR in a center where intubation is not routinely performed at reprobing seems to point at a beneficial role of intubation.
It is acknowledged that intubation may be complicated by usuration of the canaliculi and infection, but if DCR can be avoided, most parents will take the risk of these side-effects.


INTUBATION HAS NO PROVEN ROLE IN FAILED PROBING: REPROBE, DCR OR NOTHING
G. Rose

Moorfields Eye Hospital, London, UK

Except for agenesis of the lacrimal passages, childhood lacrimal drainage problems are almost exclusively due to stenosis or failure of canalisation of the nasolacrimal duct at its lower end; secondary to this obstruction, the proximal system (namely the lacrimal sac and upper duct) may undergo enlargement with retention of debris in this compartment – producing “volume” symptoms and signs. Canalicular disease is generally iatrogenic in this age group.
Obstructions at the lower end of the nasolacrimal duct may be overcome with gentle probing of the membrane-like obstruction and subsequent firm lacrimal sac massage to ensure passage of fluid through the new opening (until the epithelial anastomosis has healed). The majority (about 75% at the typical age of probing) of cases of membranous block will be cured by this technique, with minimal risk of collateral injury. Persistence of symptoms after probing continues due to several mechanisms.
In children where a passage is successfully created, “flow” symptoms due to nasolacrimal duct stenosis may persist (the parents often noting symptomatic improvement, but still a tendency to water under challenge); reprobing will only cause further stenosis during healing and risk worsening the problem. In other such children, “volume” symptoms persist due to markedly enlarged lacrimal sacs and this immediately curable with DCR; intubation only places a foreign body within an infected system, with a significant risk of dacryocystitis, with only a small chance of curing this problem.
In children where a probing has failed to produce a satisfactory passage, this will either be due to reformation of a membranous block (in which case reprobing has a good chance of success), or due to marked stenosis of the bony nasolacrimal canal – in which case reprobing or intubation will not succeed, whereas DCR will provide immediate relief of symptoms.
The risks of reprobing are almost nil and there is only a small risk of complication with open DCR, performed under general anaesthesia as a daycase admission, by an experienced lacrimal surgeon. Most methods of intubation tend to be quite violent in their manipulation of the canalicular system, and this places the canaliculi at risk of permanent damage – canalicular disease being very much harder to treat and often giving unsatisfactory outcomes.


DEBATE ON MANAGEMENT OF UNILATERAL SEVERE CHILDHOOD PTOSIS: UNILATERAL SURGERY IS BEST AS IT AVOIDS DAMAGE TO THE GOOD SIDE
J. Dickinson

UK

Surgery to prevent amblyopia: In very young children, the first priority in the management of unilateral severe childhood ptosis is to prevent amblyopia. This may be due to stimulus deprivation if ptosis is severe, but is much more commonly due to other causes of amblyopia: astigmatism or anisometropia, but particularly strabismus. These must be addressed prior to surgery but if stimulus deprivation is present then unilateral surgery is always indicated. Note that correction of ptosis can influence astigmatism. At this stage, it may be more challenging to measure both the degree of ptosis and the levator function, and while photographs can help with the former, surgery is not necessarily seen as definitive. Non-autogenous materials are generally used as autogenous fascia lata is not available until about the age of 4 years and although Palmaris longus is theoretically a good alternative it is only present in 80% of the population and is still in relatively uncommon use (Wong et al). Hence, prolene or silicone are more commonly used in the setting and have the advantage that they cause no granulomatous reaction and can easily be both adjusted or removed as necessary. In time their effect tends to fade and definitive surgery with autogenous material is likely to be required. There is no indication to subject very young children to bilateral surgery when the reason for surgery is to treat or prevent unilateral amblyopia.
Surgery for aesthetic improvement: This is usually performed around the age of 4-5 years for three reasons. It allows time for the development of fascia lata which remains the ‘gold standard’ material for treatment; it is easier to measure eyelid function and therefore plan appropriate surgery; it is easier to measure and monitor vision at this age. In children with poor levator function of 6mm or less then the crucial question is whether unilateral surgery can provide a good aesthetic outcome and the evidence strongly supports that it can. Naturally this avoids damage to the other eyelid and the loss of its levator muscle, but it also avoids the risk of corneal ulceration which, although rare, has been reported (e.g. Fogagnolo et al).
So what is the evidence in support of unilateral surgery? There have been almost no formal trials comparing unilateral and bilateral surgery, but in 1984 Epstein compared 8 patients undergoing bilateral brow suspension plus extirpation of the normal levator with 8 undergoing maximal levator resection. Of the group undergoing unilateral surgery, 6/8 achieved good cosmesis in comparison to only 4/8 in the bilateral group who remained ptotic. Unbiased observers thought the unilateral group were better overall.
The type of procedure chosen will depend on the degree of levator function and most surgeons will rely on a maximal or supra-maximal levator resection or Whitnall’s suspension before considering a unilateral brow suspension unless there is evidence that the brow on the ptotic side is held significantly higher than the other side (Cordere). Mauriello compared a series of patients undergoing maximal or supra-maximal levator surgery with 145 historical controls undergoing brow suspension and found that the levator surgery patients tended to do better. However patients receiving unilateral brow suspension with either autogenous fascia lata or synthetic materials appear to do as well as bilateral patients in other studies (Salour et al; Morris et al, Kersten et al). Parents of young children are loathed to consider surgery to the normal side unless it is strictly necessary and the evidence suggests that we can generally support them in this respect.
References:
Wong Long-term results of autogenous palmaris longus frontalis sling in children with congenital ptosis. Eye 2005;19:54; Epstein Ophthal Surgery 1984; 15: 971; O’Donnell, Codere et al Congenital Unilateral and Jaw-Winking Ptosis Orbit 2006; 25: 11; Mauriello Ophthalmol 1986; 93: 466; Salour Comparison of Mersilene mesh and autogenous fascia lata in correction of congenital blepharoptosis: A randomized clinical trial European Journal of Ophthalmology 2008; 18: 853; Morris Safety and Efficacy of Silicone Rod Frontalis Suspension Surgery for Childhood Ptosis Repair J Pediatr Ophthalmol Strabismus 2008; 45: 280; Kersten Unilateral frontalis sling for the surgical correction of unilateral poor function ptosis. Ophthal Plast Reconstr Surg 2005; 21: 412

DEBATE: MANAGEMENT OF UNILATERAL SEVERE CHILDHOOD PTOSIS
Unilateral surgery is best, as it avoids damage to the good side:
J. Dickinson

UK
Bilateral procedures should always be performed, to achieve symmetry
C. Hintschich

Germany

Childhood ptosis usually is due to a dysgenetic levator muscle. The striated muscle fibres are interspersed with fat and fibrous tissue causing different degrees of malfunctioning. Such a dysgenetic levator muscle does tend to stretch with time once under tension, causing the ptosis to recur after ptosis surgery. Congenital dysgenetic childhood ptosis is characterized by occurrence at birth with a unilateral or bilateral "hanging" of the upper eyelid, a decreased levator function, lid lag on down gaze and often a missing skin crease.
If the eyelid covers the pupillary axis, amblyopia develops fast. The high incidence of amblyopia in children with less severe unilateral ptosis usually is attributed to refractive errors and squint. However, there is increasing evidence to show that even if a ptosis only partially occludes the pupil, there is a risk of amblyopia.
Ptosis is managed by surgical ptosis repair, which is performed, when reliable measurements can be obtained, which is usually when the child is between 3 and 5 years of age and before the child goes to school. If there is a risk of amblyopia, early surgery has to be performed.
The choice of operation depends primarily on the levator function. Both direct procedures working on the levator complex or indirect procedures such as frontalis sling operations are available. A unilateral severe ptosis always presents the surgeon with a difficult choice between a maximal levator resection, if necessary with an internal sling, or a brow suspension procedure. A large levator resection as a unilateral procedure usually does not correct the ptosis completely, causes severe lid lag on down gaze and even lagophthalmos and has a high risk of recurrence due to the fact, that the muscle is dysgenetic. To avoid these disadvantages, a brow suspension procedure can be performed. To achieve symmetric results, this has to be done bilaterally after having weakened the levator on the unaffected side. Finally, bilateral brow suspension procedures give the best symmetric results in severe unilateral dysgenetic ptosis. However, problems of the sling material have to be considered. At very early age nonautogenous materials have to be used with typical risks inheritent to any alloplastic material. And last not least, the idea of having surgery to both eyelids in a unilateral condition interfering with a healthy eyelid is not generally accepted by parents and patients.


DECOMPRESSION: IT CORRECTS MORE ABNORMALITIES
D. Verity

UK

Central to all medical intervention is correction of the primary pathology. In the case of thyroid eye disease (TED), where thyroid control is achieved and active inflammatory disease suppressed, the gold standard for surgical management is a sequential triad of orbital decompression, squint surgery and surgery for eyelid height and contour.
A ‘natural’ periocular facial appearance is governed by upper lid height and contour, upper lid skin ‘show’, lower lid displacement, scleral exposure, and an even degree of fullness in the upper sulcus. In TED, correction of exophthalmos will address many of these abnormalities, thus restoring natural symmetry. Conversely, eyelid surgery alone, without restoration of globe position, at best may disguise these abnormalities, but at worse may accentuate these changes. Thus, lower lid tightening may accentuate inferior scleral show, upper lid blepharoplasty enhance the apparent proptosis and lacrimal gland proptosis, upper lid lowering increase the upper lid show, and so on. Thus, correction of the primary structural abnormality – the position of the globe relative to the bony orbit – does indeed correct more abnormalities than eyelid surgery alone.


EYELID SURGERY: IT IS SIMPLER AND HAS FEWER COMPLICATIONS
G. Rose

Moorfields Eye Hospital, London, UK

In the vast majority of patients with thyroid eye disease, the staring appearance and most of the symptoms (such as burning, grittiness, redness and watering) are due to the eyelid retraction, this mainly affecting the upper lid, but also the lower lid. These patients are well served, with relief of symptoms in most cases, by eyelid surgery: where upper lid retraction predominates, retractor recession (when done well) produces a very satisfactory eyelid level with good contour and much-improved eyelid closure; lower lid retraction, when present (occurring much less frequently than upper lid retraction), may also be addressed by appropriate retractor release, with placement of a suitable spacer material -- such as hard palate mucosa or donor sclera.
As these various techniques for eyelid lengthening are well established, there is little reason – logically --for them not to be applied in those patients who have proptosis as well as eyelid signs. In these patients, it is merely necessary to apply a rather more vigorous lid lengthening (often with lower lid hard palate mucosal grafting) and it may be necessary to augment the upward vector on the reconstructed lower lid by performing a lateral and/or medial canthoplasty. Many of these procedures can be performed under local anaesthesia as an outpatient, with low morbidity.
Orbital decompression is a much more “aggressive” procedure, with a much higher risk (especially of diplopia) and does not address the problem of upper eyelid retraction. Why take a significant risk of diplopia and possible visual loss when eyelid surgery can successfully “camouflage” the proptosis?


EVISCERATION OR ENUCLEATION FOR BLIND EYES WITHOUT TUMOR
D. Paridaens

The Netherlands

Background: Enucleation has been the traditional and worldwidely most frequently performed procedure to remove an eye. However, in recent decades there has been a shift towards evisceration as the treatment of choice in the management of painful, blind eyes without tumor. This was demonstrated by a recent survey among consultant ophthalmic surgeons in the UK, where over 70% of surgeons prefer to perform evisceration for this indication.
What reasons underlie this shift towards evisceration as the preferred method for eye removal? Criticasters of evisceration have warned for the risk of sympathetic ophthalmia. However, in practice the cases of sympathetic ophthalmia were found to be associated to previous trauma, rather than the evisceration procedure. Another reported risk is the fact that malignant tumours may go unnoticed prior to evisceration. However, careful examination prior to evisceration may help to avoid this rare problem. Recently there have been important improvements in evisceration techniques. Various ways of scleral modification allow for implantation of fairly large implants with low postoperative risk of implant exposure. Besides, it is a fast and easy technique.
What is our preferred treatment: In our practice we eviscerate all (painful) inflamed or atrophic blind eyes without evidence of tumour. We have used various scleral modification techniques and now routinely place 20 mm acrylic balls in the scleral modified cavity in case of sufficient conjunctiva. The procedure can be done in less than 30 minutes, also under local anesthesia.
We have seen very few postoperative implant exposures. In our tertiary practice we have encountered no sympathetic ophthalmia following evisceration.
Enucleation with placement of 22 mm acrylic balls in donor sclera is our preferred method to remove eyes with an intra-ocular malignant tumour.
Discussion: On the basis of our experience with eye removal in a large practice with two of such procedures per week and the reported experience in the literature we conclude that the preferred treatment for blind eyes without tumour is evisceration using a scleral modification technique. This technique is considered safe, easy and quick, allows for placement of relatively large implants and is associated with a low complication rate.


DEBATE: EVISCERATION OR ENUCLEATION FOR BLIND EYES WITHOUT TUMOR?
Evisceration: The damage to orbital structures is less and rehabilitation is faster:
D. Paridaens

The Netherlands
Enucleation: A procedure without risk to the other eye:
C. Hintschich

Germany

The principle of evisceration is the removal of the ocular content leaving the scleral envelope and adjacent structures intact. In the case of primary implants, nowadays they are inserted beyond the scleral shell into the orbital fat after dividing the posterior sclera. Enucleation is the complete excision of the intact eyeball. For volume replacement and restoration of orbital architecture, an orbital implant or transplant usually is inserted. Many different types of alloplastic orbital implants have been in use, however, like with any alloplastic material, typical problems can arise. This is true for both enucleation and evisceration. Probably one of the safest and aesthetically most appealing procedures in enucleation is the use of primary autologous dermofat grafts. Evisceration does seem to produce good aesthetic results; however, its superiority over enucleation has not yet been proved. On the other hand, evisceration does have three significant disadvantages over enucleation. First, histological examination of the specimen is not feasible and unsuspected malignant disease can be spread, secondly, the use of autologous grafting, i.e. dermofat implantation, is impossible, and thirdly, sympathetic opthalmia (SO) to the unaffected and single eye can be induced. Reports in the literature about SO are uncommon, however, they are ongoing. Under these assumptions, enucleation truly is a procedure without risk to the other eye. Once suggesting evisceration to the patient, at least these considerations should be mentioned towards the patient.


BIOPSY MUST BE PERFORMED BEFORE TREATING ALL INFILTRATIVE ORBITAL LESIONS: BIOPSY ALL LESIONS OR DIAGNOSTIC ERRORS ARISE
U. Schaudig

Department of Ophthalmology, University Medical Center Eppendorf, Hamburg, Germany

Infiltrative orbital diseases can be a diagnostic challenge. Systemic treatment with corticosteroids or immunosuppressive agents might be necessary to treat and control orbital inflammatory disease. Biopsies of diffuse infiltrating lesions can be sometimes frustrating, since histological results can be undecisive at times. The clinical pictures of malignant lesions can mimick a benign inflammatory disease and even a biopsy taken at the edge of a malignant lesion can be misdiagnosed for inflammation.
There are, however, several reasons supporting a “biopsy first” strategy.
The response to anti-inflammatory medication can be positive, even in the presence of a malignancy, because of the surrounding inflammation and swelling. Positive response therefore is no proof for the lack of malignancy.
In case of malignant disease, treatment shall not be postponed since it leaves the patient at a higher risk for metastatic disease.
Orbital inflammatory disease can be treated not only by corticosteroids but by an increasing number of various available monoclonal antibodies and antimetabolites. It is curcial that the diagnosis is made at the highest possible histological level.
In orbital lesions, it is mandatory that all efforts are made to make a precise diagnosis. Despite the improvement in imaging techniques, this is only possible by a biopsy.


BIOPSY MUST BE PERFORMED BEFORE TREATING ALL INFILTRATIVE ORBITAL LESIONS: ORBITAL INFLAMMATION SHOULD BE GIVEN A TRIAL OF STEROIDS, AS SURGERY CAN CAUSE MAJOR EXACERBATION OF ORBITAL INFLAMMATION
J. Dickinson

UK

Orbital biopsy can cause significant orbital scarring, enophthalmos and permanent diplopia from dysfunction of extraocular muscles. In rare cases biopsy can cause visual loss which may be both profound and permanent. As well as having a potential adverse impact on the patient’s clinical course, biopsy can also confuse the interpretation of subsequent imaging. Therefore there are times in the management of presumed orbital inflammation when a trial of steroids without biopsy is appropriate. These include patients in the following groups:
i) Typical features on imaging coupled with typical signs and symptoms suggestive of idiopathic orbital inflammatory disease (IOID) and no features of other pathology
ii) Position of inflammation within orbit e.g. certain apical masses where morbidity of biopsy outweighs benefit
iii) Age of patient: e.g. very young children may warrant a trial of steroids for presumed inflammation if there is no suspicion from bloods / imaging of other pathology: in particular infection
iv) Patient co-morbidity makes the risks of biopsy unduly high
Steroids without biopsy can be justified if there are typical features of IOID especially its myositis variant: pain 70%; periorbital oedema 75%; red eye 60%; diplopia 30-50%; chemosis 30%; proptosis 30-60%; especially a single episode. A previous similar episode does not exclude the initial use of steroids.
Meticulous history taking, examination and investigations should have been done to positively exclude the following:
1) infection
2) trauma ( + retained foreign body)
3) specific inflammatory conditions that require very specific treatments such as Graves’ orbitopathy / Wegeners/ Sarcoidosis etc.
4) malignancy
5) Arteriovenous fistulas
References:
Kitei D, and DiMario FJ, Childhood Orbital Pseudotumor: Case Report and Literature Review Journal of Child Neurology 2008 23: 25-30; Mottow-Lippa L, Jakobiec F, Smith M. Idiopathic inflammatory orbital pseudotumor in childhood II. Am Acad Ophthalmol. 1981;88: 565-574; Ahn Yuen SJ; Rubin PAD. Idiopathic Orbital Inflammation Distribution, Clinical Features, and Treatment Outcome. Arch Ophthalmol. 2003; 121: 491-499; Yeh S Foroozan R Orbital Apex Syndrome Current Opinion in Ophthalmology. 2004; 15(6):490-8.


SCLERITIS: HOW SHOULD IT BE TREATED? REGIONAL STEROIDS
S. Lightman

UK

Scleritis may or may not be associated with a systemic disease and may or may not be sight threatening. It is classified into types based on location and clinical form – anterior and posterior and anterior scleritis is divided into diffuse, nodular and necrotising in format. Posterior scleritis cannot be visualised in the same way so that distinguishing necrotising from non-necrotising posterior scleritis is not currently possible. The major reason for treatment is pain when sight/ integrity of the eye is not threatened or there is no underlying systemic disorder which is active. Although scleritis may affect both eyes at the same time it is more often unilateral when active. Systemic NSAIDs /corticosteroids/other immunosuppressive agents are the usual mode of treatment and are very effective but with a significant side effect profile on an individual patient basis. Patients ideally would like to be offered treatment centred on the affected eye and one way to do this is with regional steroids. For the local treatment of scleritis, use of both orbital floor depomedrone and sub-conjunctival triamcinolone have been reported. All reports are of small numbers of patients with non-necrotising scleritis and all report high efficacy in scleritis resolution with the usual local steroid side effects such as raised intraocular pressure and cataract with one report of scleral thinning occurring. However others have reported severe scleral necrosis occurring as a result of local steroid therapy in the treatment of scleritis and suggest that the risks of such a serious outcome however small greatly outweigh any potential benefit. The size of the risk is unknown but any risk would be cumulative given that local corticosteroids are relatively short acting and may need to be given repeatedly. Many ocular procedures are very beneficial but can rarely have a severe complication - an example of this is cataract surgery and endophthalmitis. All is in the balance of risks and benefits and this will be debated in this session.


SCLERITIS: HOW SHOULD IT BE TREATED? SYSTEMIC TREATMENT
J. Heissigerova

Department of Ophthalmology, Charles University, Prague, Czech Republic

Scleritis is an uncommon painful inflammatory condition of the sclera that may involve adjacent ocular tissues (cornea, uvea or the episclera) and poses significant threat to vision. Its spectrum of intensity covers range from trivial self-limiting episodes to severe necrotising disease. Majority of scleritis is of non-infectious aetiology and more than 50% of cases are associated with systemic diseases such as rheumatoid arthritis, Wegener’s granulomatosis, relapsing polychondritis, polyarteritis nodosa, polymyositis and systemic lupus erythematosus. Scleritis is in 50% bilateral.
The severity of the disease, the bilaterality and the strong association with systemic diseases all designate scleritis for systemic treatment. Some patients with scleritis respond well to treatment with NSAIDs. The more aggressive forms of non-infectious scleritis (posterior and necrotizing scleritis), however, require the use of systemic corticosteroids and often further immunosuppression. Well recognized is scleritis treatment with cyclophosphamide, azathioprine, methotrexate and other immunosuppressive drugs. Among the new biologic agents, which have been used as treatment for scleritis, are TNF-alpha blockers (ethanercept, infliximab or adalimumab), rituximab (anti-CD20 monoclonal antibody) and daclizumab (anti-IL-2 monoclonal antibody), so the choices of immunointervention therapy expand considerably.
Lesser part of scleritis cases can be identified as infectious and the clinical picture varies according to a type and amount of the noxious agent (bacteria, virus, fungi or parasites). Identification of the aetiology leads to specific antimicrobial treatment, which is mostly both systemic and local. Topical and systemic steroids may also be used to reduce the inflammatory reaction.
In conclusion: Scleritis can manifest as a severe sight-threatening disease that requires early diagnosis, and prompt and intensive systemic treatment.


THE OPTIMAL MANAGEMENT INITIALLY SHOULD BE REGIONAL CORTICOSTEROIDS
N. Acharya

Department of Ophthalmology, Ocular Inflammatory Disease and Uveitis Clinic, University of California, San Francisco, California, USA

Corticosteroids are the mainstay of initial therapy for uveitis because of their potency as well as their rapid onset of action in suppressing inflammation. In particular, regional corticosteroids such as injections and sustained release implants allow for local delivery to the eye, sparing the body from the adverse effects of systemic steroids. While corticosteroid-sparing agents such as immunosuppressive therapies and biologic therapies have demonstrated potential in controlling inflammation, they may be limited by their delayed onset of action, their intolerability, and the occurrence of adverse effects. Furthermore, the long-term consequences of biologics are unknown, but there is concern about malignancy and an increased risk of opportunistic infections. Frequent laboratory monitoring is also required.
Active ocular-infiltrating T cells are thought to contribute to the perpetuation of ocular inflammation, and both activated T cells and antigen-presenting cells have been observed in the eyes of uveitis patients. Therefore, local therapies which target these cells may be successful in achieving control of inflammation. Periocular and intravitreal injections of corticosteroids have been shown to be effective in controlling inflammation and reducing macular edema in uveitis patients, but there is a risk of flare-ups and cumulative damage to the eye as the medication effect wanes. Sustained-delivery systems such as the fluocinolone acetonide implant FDA-approved for the treatment of uveitis obviate the need for repeated corticosteroid injections. The National Eye Institute-funded Multicenter Uveitis Steroid Treatment (MUST) trial is an ongoing randomized controlled clinical trial in patients with noninfectious uveitis comparing the efficacy of the 0.59-mg fluocinolone implant to standard systemic immunosuppressive therapy. Study outcomes include change in visual acuity, ocular and systemic complications, and quality of life assessments. The MUST trial results are expected to provide insight into the pros and cons of both approaches. Other studies of the fluocinolone acetonide implant indicate high success in reducing the rate of uveitis recurrences and reducing the need for systemic immunosuppressive therapies. Although over 3 years 90% of patients required cataract surgery and 40% of patients required glaucoma filtration surgery, these procedures were successful in most patients. Because of the lack of comparative data on local vs. systemic therapy for uveitis, clinicians must weigh the pros and cons of each choice and consider a personalized approach to each patient.


THE OPTIMAL MANAGEMENT OF UVEITIS: THE OPTIMAL MANAGEMENT INITIALLY SHOULD BE SYSTEMIC THERAPY
D.A. Jabs

Departments of Ophthalmology and Medicine, The Mount Sinai School of Medicine, New York, New York, USA

Most cases of anterior uveitis can be managed with a topical corticosteroid therapy. However, intermediate, posterior, and panuveitis require either regional corticosteroid injections or systemic therapy with corticosteroids supplemented with immunosuppressive agents as appropriate. Approximately 20% of patients with intermediate uveitis do not need therapy due to good vision and absence of macular edema. Approximately 30% of patients with intermediate uveitis can be managed with infrequent regional corticosteroid injections. However, 50% of patients with intermediate uveitis require oral corticosteroids in order to control the inflammatory process. Patients with posterior and panuveitis, who require therapy, typically are treated with oral corticosteroids with or without immunosuppressive drugs. The fundamental problem with regional corticosteroids is the relapse which occurs as the drugs wear off, typically at approximately 90 days. With each relapse there is incremental damage to the eye and ultimately a “saw-tooth” decline in visual acuity. Conversely, systemic corticosteroid therapy can be titrated to maintain suppression of the disease, to prevent relapse, and to preserve vision in patients who have a chronic, often life-long disease. Available data suggests that systemic corticosteroid therapy reduces the odds of visual impairment in patients with sarcoid uveitis by over 90%. Similarly, the use of immunosuppression for many types of posterior and panuveitis, including serpiginous choriditis, birdshot chorioretinitis, multifocal choroiditis with panuveitis, and Vogt-Koyanagi-Harada disease in chronic phase, demonstrate marked reduction of structural complications and improvement in visual outcome. Side effects of these drugs typically are reversible (except for alkylating agents), but do require monitoring. With appropriate immunosuppressive drugs, an acceptably low-dose of corticosteroids can be found, and the side effects of chronic low-dose (? 7.5 mg daily prednisone) corticosteroids are minimal. Recent data from the Systemic Immunosuppressive Treatment for Eye Disease (SITE) demonstrates the long-term safety most classes of immunosuppressive drugs. Therefore, the initial therapy of most cases of intermediate, posterior, and panuveitis should be systemic, given the superior control and absence of long-term side effects.


BIOLOGICAL VS CONVENTIONAL IMMUNOSUPPRESSION FOR UVEITIS: CONVENTIONAL IMMUNOSUPPRESSION
D.A. Jabs

Departments of Ophthalmology and Medicine, The Mount Sinai School of Medicine, New York, New York, USA

Initial treatment of approximately 50% of patients with intermediate uveitis, and nearly all patients with posterior and panuveitis requires oral corticosteroids, supplemented with immunosuppressive drugs as necessary. Available data have suggested that immunosuppression improves outcomes in patients with many types of posterior and panuveitis, including serpiginous choriditis, birdshot chorioretinitis, multifocal choriditis with panuveitis, and Vogt-Koyanagi-Harada disease. Conventional immunosuppressive drugs include the antimetabolites agathioprine, methotrexate, and mycophenolate; the T cell inhibitors cyclosporine and tacrolimus; and the alkylating agents cyclophosphamide and chlorambucil. A substantial database demonstrates the efficacy of these drugs including randomized clinical trials, (cyclosporine and tacrolimus) longitudinal data analysis (cyclophosphamide) and large databases from multiple referral center practices (azathioprine, methotrexate, mycophenalate, cyclosporine, cyclophosphamide). Most side effects from these agents (except alkylating agents) are reversible but require a monitoring. The Systemic Immunosuppressive Treatment for Eye disease (SITE) studies have demonstrated the long-term safety of these agents. Conversely, information regarding efficacy of biologic agents largely comes from small uncontrolled case series, which although suggestive, does not provide an adequate level of evidence for recommending biological therapy as the primary form of immunosuppression. Furthermore, the long-term safety of these agents remains uncertain. Therefore, conventional immunosuppression is the appropriate approach for immunosuppression in patients requiring such therapy for uveitis.


SERPIGINOUS CHOROIDITIS
J. Forrester

Unversity of Aberdeen, King's College, Scotland, UK

Serpiginous choroiditis (SC) is boxed in the ophthalmologist’s imagination as a discrete entity, as one of the white dot syndromes which themselves are a set of rather obscure entities, defined by clinical manifestations only. SC has a typical clinical pattern, emanating as an inflammatory choroiditis from a peripaillary distribution and progressing slowly around the posterior pole in the regions of the large vessel arcades to encroach on the fovea and cause visual loss with severe macular involvement. Sometimes this includes a subretinal neovascuar membrane but this is not essential to cause foveal destruction. Variants of this clinical pattern are well recorded and although the clinical condition became well defined by previous experts such as Gass, in fact this form of choroidal disease had been described much earlier.
Initially, it was not clear that it was an inflammatory disease, and at one time there was a substantial school of thought that this condition was a defect in choroidal blood flow. Subsequent studies including therapeutic trials of anti –inflammatory and immunosuppressive drugs lent credence to the idea that SC was an autoimmune disease. However, proponents such as Gass continued to consider SC as a disease caused by infection, in particular herpes simplex virus, and indeed the clinical progression has certain similarities to epithelial herpetic infections (the words “herpetic” and “serpiginous” are semi-synonymous etymologically).
Recently, Gupta at al. suggested that some forms of SC were caused by M. tuberculosis and further studies by Mackensen and others provided evidence that tuberculosis might be a cause for SC. In particular, more sensitive TB tests such as the Qauntiferon test supported this view.
The notion that SC might be due to TB is not new and was originally suggested in the late 1950’s. The serpiginous behaviour of mycobacterial infectiosn has been described in skin lesions and in lymph node infections and so this possibility can reasonably be entertained. TB infection however can be the great mimicker as can other infections such as syphilis and Lyme disease, and definitive evidence is difficult to obtain for a mycobacterial cause for SC. This presentation will discuss the evidence and solicit comment as to the most pertinent views on the etiology of SC.
References:
(1) Cordero-Coma M, Benito MF, Hernandez AM, Antolin SC, Ruiz JM: Serpiginous choroiditis. Ophthalmology 115:1633, 1633 e1631-1632, 2008. (2) Gupta V, Gupta A, Arora S, Bambery P, Dogra MR, Agarwal A: Presumed tubercular serpiginouslike choroiditis: clinical presentations and management. Ophthalmology 110:1744-1749, 2009. (3) Mackensen F, Becker MD, Wiehler U, Max R, Dalpke A, Zimmermann S: QuantiFERON TB-Gold--a new test strengthening long-suspected tuberculous involvement in serpiginous-like choroiditis. Am J Ophthalmol 146:761-766, 2008.


USING OPTICAL COHERENCE TOMOGRAPHY (OCT) TO MANAGE DME: SPECTRAL DOMAIN SHOULD BE USED WHENEVER AVAILABLE
U. Schmidt-Erfurth

Austria

Diabetic macular edema (DME) is a frequent complication in the course of diabetic retinopathy causing severe vision impairment. It is characterized by focal or generalized retinal thickening due to fluid accumulation in the presence of leaking microaneurysms or generalized capillary leakage. It frequently induces formation of hard exudates and has a poor long-term prognosis. The etiology of DME is complex and not completely understood, but several mechanisms leading to an impairment of the blood retinal barrier and a subsequently increased fluid discharge into retinal tissue could be identified in recent years.
Optical coherence tomography (OCT) has become an important tool over the last decade in the diagnosis of DME because the retinal morphology can be evaluated in detail similarly to in vivo histology. Advances in OCT technology provide novel insight into in vivo changes that occur in the human retina secondary to DME or treatment, such as retinal cysts, lipid exudates, subretinal fluid or diffuse edema. The fourth-generation OCT, SD-OCT, uses a fast spectral domain technique and performs scans in a raster pattern throughout the entire macular area at a resolution of 5um in the axial and 20um in the transverse direction. This fourth-generation system can also be combined with an eye tracking system allowing the observation of morphological changes at the exact same retinal location over time. The fifth-generation OCT, the polarization sensitive OCT (PS-OCT), enables to detect retinal tissue due to its different qualities of polarization and allows specifically the detection of microexudates. Microexudates are precursors or parts of hard exudates typically seen in diabetic macular edema. Previously, we could show that these sub-clinical signs of lipid and/or lipo-protein exudation can be detected in spectral domain OCT and in polarization sensitive OCT due to their polarization changing properties. These findings give a new insight into patho-morphology and patho-physiology of DME even if hard exudates are not yet present.
In diagnosis of DME, OCT is a still new and helpful tool correlating to findings in fluorescein angiography. Apart from morphological analysis it offers valuable possibilities to measure the amount of DME in reproducible manners, even if there are significant differences in between retinal thickness values of OCT machines of different companies.
During therapy of DME, OCT offers new information about the therapeutical mechanisms. The exact intra-retinal changes secondary to laser therapy can be determined in detail. Be it macular grid or panretinal photocoagulation, for the first time it is possible to visualize intra-retinal morphological changes secondary to laser treatment in the human retina in vivo and to observe their changes over time. Further, micro-exudates show characteristic changes in intra-retinal distribution according to the individual therapy. They can dissolve or accumulate in the outer retinal layers becoming fundoscopically visible as hard exudates. The time-course of this accumulation is significantly influenced by the nature of the individual therapeutic agent. During anti-VEGF therapy of DME for instance, hard exudates formation can be observed in only a few days, whereas following laser therapy this response can be expected to last several weeks.
All in all, OCT still is a new diagnostic tool improving the insight in the nature of DME and therapeutically induced effects on retinal morphology. Information about the amount and the location of DME, the extent of retinal damage and the level of lipid exudation visualized by OCT is important to diagnose and manage this complex disease. Together with fluorescein angiography it enables the clinician to choose and follow-up the ideal treatment option in each individual patient, be it surgery, laser therapy or an intravitreally administered agent.


USING OPTICAL COHERENCE TOMOGRAPHY TO MANAGE DME: TIME DOMAIN IS GOOD ENOUGH
M. Goldstein

Tel Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv

Optical Coherence Tomography has become in the last years the most effective non invasive imaging modality for objective assessment of retinal thickening, as well as accurate information on the change in retinal edema in general and particular Diabetic macular edema. The OCT helps us in the evaluation of DME development, progression, and response to the various available treatments.
DME diagnosis: Time Domain OCT is definitely good enough for early detection, and quantitatively diagnose and measure DME. It has been shown that the OCT is superior to biomicroscopy in detecting minimal thickening or small changes in retinal thickness. DRCR study demonstrated the superiority of the TD OCT over Fundus pictures in detection and examination reproducibility at baseline and following 1 year. TD OCT has high rate of intrasession repeatability, meaning accurate measurments.
DME follow up and progression: Time Domain OCT can demonstrate the extension of the retinal thickening towards the macula, can measure the thickness difference between consecutive exams, and can imply the development of retinal and subretinal anatomical changes.
DME patterns easily visualized TD OCT:
1. Diabetic Macular Edema (DME) - Diffuse retinal thickening- areas of reduced intraretinal reflectivity.
2. Cystoid Mcular Edema (CME) - Cystoid macular edema- large, ovoid areas of low reflectivity which reflect intraretinal cystoid-like cavities, Separated by highly reflective septae.
3. Vitreomacular Traction (VMT) - Posterior hyaloidal traction- tangential traction identified as a highly reflective band over the retinal surface.
4. CME + Sub Retinal Fluid (SRF) – in long standing CME, serous retinal detachment not associated with posterior hyaloidal traction- dark accumulation of subretinal fluid beneath the highly reflective dome-like elevation of the retina.
5. Traction Retinal detachment (TRD) - area of low signal underlying the highly reflective border of detached retina (peaked-shaped).
6. Diabetic ERM
7. OCT Hyperreflective Foci- Morphologic evidence of intraretinal lipids extravasation in DME


CONTROVERSIAL CASES IN PROLIFERATIVE DIABETIC RETINOPATHY
S. Bressler

USA

Panretinal photocoagulation (PRP) has been the gold standard means of addressing proliferative diabetic retinopathy since the mid 1970’s. Since then studies have evaluated different ways of performing the treatment- and outcomes associated with these various techniques will be reviewed. More recently, anti-VEGF therapies have been shown to foster transient regression of neovascularization. Illustrative cases will be used to explore this concept and debate whether PRP should be placed in patients with PDR who are receiving these agents to manage macular edema. Finally, anti-vegf agents have been used as adjuvants in severe cases of PDR requiring vitrectomy surgery- useof these agents with and without PRP and/or vitrectomy will be explored.


AVASTIN IN ROP
N. Miller

USA

Retinopathy of Prematurity (ROP) is a leading cause of blindness in children in developed countries around the world, and an increasing cause of blindness in developing countries.
The Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) Study demonstrated that ablation of the peripheral avascular retina reduced the risk of poor structural and visual outcome due to retinal distortion or detachment in ROP (1980's). The ablated retina is not functional and is not amenable to regeneration.
Peripheral retinal ablation is not universally effective in fostering regression of ROP. This is particularly true for an aggressive form of ROP (aggressive posterior ROP, or APROP) which typically afflicts profoundly premature and infirm neonates. In this subset of infants, progression of ROP to bilateral retinal detachment and blindness occurs despite timely and complete peripheral retinal laser ablation.
The debate will focus on the role of the vascular endothelial growth factor (VEGF) on the development of ROP. When an infant is born prematurely the relatively hyperoxic environment the baby is introduced to shuts down the production of VEGF. Retinal maturation is delayed. Subsequently, at a time when intraocular VEGF levels would normally be declining late in the third trimester of pregnancy, abnormally high levels of VEGF are seen due to large areas of avascular retina and associated tissue hypoxia.
The availability of FDA-approved drugs for anti-VEGF treatment renders it possible to treat such eyes off-label. Available drugs include pegaptanib sodium (Macugen) for partial blockage of VEGF-A, or drugs such as ranibizumab (Lucentis) and bevacizumab (Avastin), which cause complete blockage of VEGF-A.
As VEGF is required in the developing retina for normal angiogenesis, and our goal is not to penetrate tissue, but to block the excessive levels of VEGF trapped within the overlying vitreous which is responsible for the abnormal vasculature in ROP.
some studies are now on going on the effect of bevacizumab (Avastin), which will: a) attain complete blockage (vs. Macugen) of intravitreal VEGF-A, and; b) which is limited in its ability to penetrate tissues because it is a full antibody (vs. Lucentis, an antibody fragment specifically designed for better tissue penetration), and is more likely to restore VEGF homeostasis within the developing retina.


RANIBIZUMAB MONOTHERAPY FOR ALL LESIONS MONTHLY AND AT LEAST TWO YEARS
N. Bressler

Wilmer Eye Institute, Johns Hopkins University School of Medicine, USA

Results from large-scale, randomized clinical trials, such as MARINA and ANCHOR, which provide the strongest evidence to support the initiation of anti-VEGF therapy for neovascular AMD, are based on monthly treatments for 2 years. One of the challenges to this therapy is to try to determine whether a regimen can be identified that may allow less frequent treatments and less frequent visits without compromising visual acuity outcomes. The PIER study tested a reduced frequency; fixed dosing regimen of ranibizumab every 3 months after 3 monthly treatments had been given was shown to be superior to sham treatment. However, the improvement in mean visual acuity through month 3 was not sustained to month 12. Thus, this reduced frequency, fixed-dosing schedule was much more likely to avoid substantial vision loss than sham treatment, but not more likely to result in substantial vision improvement. A subsequent randomized trial, the EXCITE study, presented at the Euretina 2009 Meeting 2009, May 16, Nice), confirmed superior outcomes with respect to mean improvement in visual acuity from baseline for monthly compared with less frequent treatment.
Yet another study, utilizing OCT to guide retreatment decisions, the SUSTAIN study, presented at: Association for Research in Vision and Ophthalmology 2009, May 5, Fort Lauderdale.), again showed a loss in the mean visual acuity gain from month 3 to month 12 in the group randomized to a regimen that considered OCT information to guide retreatment after month 3 compared with monthly treatments through month 12.
Another study, PRONTO, using both monthly OCT and occasional FA, suggested similar outcomes with respect to vision improvement, but the confidence intervals around the results with _45 subjects were wide so that one could not state confidently that the chance of substantial improvement was similar. Furthermore, there was no comparison group with monthly treatment to know how these subjects would have done with monthly treatment. In addition, these results have not been confirmed in a subsequent, similarly designed study. An additional study, HORIZON (Singer M. HORIZON extension trial of ranibizumab for neovascular age-related macular degeneration: two-year safety and efficacy results. Presented at: Association for Research in Vision and Ophthalmology 2009, May 5, Fort Lauderdale); evaluated whether investigators could sustain improved visual acuity results beyond 2 years of monthly treatment using clinical judgment and whatever imaging the investigator judged was appropriate to make retreatment decisions. Among 481 subjects 2 years after entry into MARINA, ANCHOR, or FOCUS trials, median visual acuity had improved by approximately 10 letters (from 20/80 to 20/50); in addition, the median visual acuity had been relatively stable from 1 to 2 years after initiating monthly treatment. However, 1 year after entry into HORIZON, when monthly treatments were replaced by retreatment decisions by the investigator, median visual acuity decreased by 5 letters to 20/63; 2 years after entry into HORIZON, median visual acuity decreased by another 3 letters.
In summary, although treatments that occur less than monthly seem to increase the chance of avoiding substantial visual acuity loss, the chance of substantial visual acuity gain seems less likely than with monthly treatment, regardless of whether a reduced frequency fixed-dosing schedule is used, or a retreatment decision based on OCT alone or OCT and other parameters such as FA. Even if a regimen can be determined that can sustain the chance of substantial visual acuity improvement attained with monthly treatments, frequent visits to assess whether treatment is given seem to be needed, and OCT alone, as performed in the studies described (usually consisting of time domain OCT), does not seem to be sufficient to identify the need for treatment that results in a sustained chance of visual acuity improvement.
Adapted from Ophthalmology 2009;116:S15-S23© 2009 by the American Academy of Ophthalmology.


PRN monotherapy is the optimal treatment for AMD
A. Loewenstein

Department of Ophthalmology, Tel Aviv Medical Center, Sackler Faculty of medicine, Tel Aviv, Israel

Background: Many clinical trials have already shown the significant treatment benefit with monthly anti VEGF injection in neovascular AMD. However as we all know from our daily clinical practice, the clinical treatment regimen cannot always be applied to our patients. Firstly some of our patients have CNV baseline characteristics different than those included in the trials
Secondly a fixed planned regimen for a period of 2 years is very hard to follow outside the set of a clinical trial.
Methods: We will review the evidence from the multicentered trials implicating monthly treatment and from multicentered trials and other regimens using PRN treatment.
Results: As evident from these trials, most visual improvement occurred within the first 3 months. Considering the burden, the risk of infection, and the results, flexible dosing is feasible but with monthly monitoring of active disease
Conclusion: Flexible, PRN dosing may be a good feasible treatment for CNV secondary to AMD.


Combination therapy other than standard PDT
A. Augustin, J. Kirchhof

Department of Ophthalmology, Klinikum Karlsruhe, Germany

All relevant available therapies for CNV have drawbacks as monotherapies. These therapies include photodynamic therapy (PDT) with verteporfin (Visudyne®; Novartis AG) and anti-VEGF therapies (ranibizumab [Lucentis®, Genentech], bevacizumab [Avastin®, Genentech], and pegaptanib [Macugen®]), which have primarily been evaluated in patients with CNV due to AMD (i.e. patients age 50 years or older).
Vision improvement of 1-2 lines, as demonstrated on average with ranibizumab, is the current expectation for treatment benefit in CNV due to AMD. However, the vision improvement with ranibizumab is associated with monthly intravitreal injections. If these injections are not continuously administered, vision appears to decline and then stabilise at pretreatment levels or even below.
Widespread use of intravitreal bevacizumab to treat patients with CNV due to AMD began approximately a year before ranibizumab was commercially available, after ranibizumab trial results were announced. A systemic anticancer drug, bevacizumab is not approved for intravitreal use in ophthalmic practice, but for use in combination with chemotherapy for metastatic carcinoma of the colon or rectum. Bevacizumab is derived from the same source antibody as ranibizumab, so it is believed to have similar effects, and published case series appear to confirm this belief.
The current viable monotherapies available to treat CNV (verteporfin PDT and the anti-VEGF therapies) were conceived as cancer treatments, to arrest the neovascularisation that feeds tumours, before these treatments were developed and applied to ocular diseases. Similarly, combination therapy for ocular CNV derived from the combination therapy concept in oncology. In both therapeutic areas, the goal of combination therapy is to disrupt the multiple stimuli that lead to pathologic cellular proliferation. In cancer, tumours and the neovasculature that feeds the tumours are targets, while in ocular CNV, the neovasculature itself is the target.
Several known factors (and certainly many as yet unknown ones) contribute to pathologic CNV. The cascade of subretinal changes that leads to neovascularisation appears to occur as follows: inefficient metabolic activity (i.e. nutrients blocked from receptors and cellular waste clogging the tissue) leads to hypoxia; hypoxia leads to choroidal vascular atrophy; choroidal vascular atrophy leads to inflammation; inflammation leads to angiogenesis; and angiogenesis, mediated by vascular endothelial growth factor (VEGF), leads to neovascularisation. Neovascularisation may be the choroid's attempt to optimise its metabolic activity and preserve its essential function. This degenerative cascade is nuanced and has been described, although new findings that refine the cascade continue to be reported.
Most notably, the role of inflammation and genetic predisposition to inflammation is being elucidated. Complement factor H polymorphism appears to be associated with AMD pathogenesis.
The three main therapeutic targets of CNV development and proliferation, from the cascade described above, are neovascularisation itself, angiogenesis, and inflammation. A therapy is available for each of these targets: verteporfin PDT eradicates CNV, anti-VEGF therapies block angiogenesis, and anti-inflammatory drugs stop inflammation.
Combination therapy has been used for several years to treat patients with CNV due to AMD. Initially, verteporfin PDT was combined with intravitreal triamcinolone acetonide (TA). Many case series confirm good vision results for the PDT + TA combination. Most of these studies, however, noted glaucoma or increases in intraocular pressure, as well as cataract formation, due to the intravitreal injection of TA.
In a case series our group evaluated 104 patients with CNV due to AMD who were treated with a combination of PDT + intravitreal bevacizumab (1.5 mg) and dexamethasone (0.8 mg). Reduced fluence PDT (42 J/cm2 given at the standard fluence rate of 600 mW/cm2 for a reduced time of 70 seconds) was administered 16 hours before bevacizumab and dexamethasone injections. A significant increase in VA and a significant reduction in treatment numbers could be achieved. These results were the basis of several randomized trials and case series.
The multicenter, randomized, single-masked RADICAL trial is comparing V-PDT+ranibizumab±dexamethasone with ranibizumab monotherapy. A total of 162 patients/eyes were randomly assigned to one of four treatment groups: quarter-fluence PDT (15 J/cm2) followed within 2 hours by ranibizumab and then dexamethasone; half-fluence PDT (25 J/cm2) followed within 2 hours by ranibizumab and then dexamethasone; half-fluence PDT (as just described) followed within 2 hours by ranibizumab; or ranibizumab alone.15 Entry criteria included age ?50 years, no previous treatment for AMD, VA letter score 73 to 25 (approximately equivalent to Snellen scores of 20/40 to 20/320), and <9 DA lesion size. Patients randomly assigned to combination treatment groups received one initial treatment and those randomly assigned to ranibizumab monotherapy received 3 initial treatments (baseline and months 1 and 2). Patients were assessed for retreatment on a monthly basis with OCT and fluorescein angiography (FA). Best corrected VA and safety were assessed throughout.
One-year results show that vision results appear similar in all treatment groups, although wide confidence intervals were noted. There was less need for retreatment with combination therapy vs monotherapy and no new safety concerns. As noted, these are 1-year results of a 2-year trial, and as with the MONT BLANC and DENALI trials, we must await final results.
In the multicenter CAVE Study, reduced-fluence V-PDT + bevacizumab + triamcinolone acetonide triple therapy was compared with bevacizumab monotherapy and with V-PDT + bevacizumab dual therapy, with data from 103 patients evaluable at 1 year. All patients were treated at baseline and returned for follow-up every 6 weeks, with retreatment as needed based on FA and OCT criteria. Retreatment rates were highest with bevacizumab monotherapy and lowest with triple therapy. There were no significant between-group differences in VA gains. Interestingly, the greatest extension in treatment-free interval was with dual therapy, leading the investigators to conclude that addition of triamcinolone did not produce additional benefit.
In treatment-na?ve patients, Hughes and Sang gave reduced duration V-PDT + dexamethasone + ranibizumab and compared outcomes with monthly ranibizumab monotherapy (n=30 in each group). A single “booster” ranibizumab injection was given 1 month after triple therapy and patients were followed monthly. At 1 year, 19 (63%) of triple therapy patients had received only 1 retreatment. No patient received more than 2 cycles of triple therapy or 2 additional ranibizumab injections. Compared with monotherapy, triple therapy produced a greater mean reduction in center point thickness and greater improvement in mean VA.
Triple therapy has also been studied as rescue treatment. Sang and Hughes administered reduced duration V-PDT (42 seconds, 66 mW/cm2), dexamethasone, and bevacizumab to 40 patients who did not respond to previous therapy. After initial triple therapy, if central thickness increased by >75 ?, subretinal fluid was seen on OCT, or hemorrhage occurred, retreatment with bevacizumab was given within 1 to 2 months or with triple therapy at 3 months. At 1 year, 31 (77% ) patients required additional treatment, with mean time to retreatment, 4.8 months. Mean VA improved by 8 letters, center point thickness decreased by 126 ?, and no adverse events were noted.
The greatest challenge for combination therapy is the number of variables associated with it. The number of available and emerging therapies for the treatment of patients with CNV is rapidly increasing. With different therapies, doses, timing, and treatment sequences possible, conducting definitive large, randomised trials to determine the best therapy or combination therapy becomes infeasible. The multiplicity of therapy for CNV is both a blessing and a curse; that is, we have many options to offer patients, but we do not know which option is most effective and safe.
Furthermore, the issues surrounding multiplicity of therapy are compounded by patient differences, such as the disease manifesting CNV (AMD, pathologic myopia, ocular histoplasmosis syndrome, etc.), disease stage, vision at diagnosis, previous treatment status, lesion morphological characteristics (size and composition), and lesion location, to name just a few. These different patient characteristics contribute to the outcome and safety of treatment. It would be ideal to administer individualized doses; for example, to treat each patient with a dose of anti-VEGF therapy based on the amount of VEGF expressed in the patient's retinal tissue.
It is evident, then, that combination therapy for CNV due to AMD and other ocular neovascular disease is a rich area for additional research. Additional clinical studies are required both to determine the patient and disease characteristics that affect outcomes and to narrow the scope of treatment variables to ultimately establish the combination of therapies that provides the best outcomes


IS THERE ADEQUATE EVIDENCE TO RECOMMEND BEVACIZUMAB OVER RANIBIZUMAB WHEN FINANCES ARE NOT AN ISSUE? - YES
U. Schmidt-Erfurth

Austria

Avastin (Bevacizumab) is an anti-VEGF antibody, which was approved by the FDA in 2004 as an intravenous treatment for patients with advanced colorectal cancer and has been used soon after approval as an off-label treatment for neovascular AMD.
Ranibizumab is an antibody-fragment derived from bevacizumab. Due to its smaller size and targeted development for the treatment of neovascular age-related macular degeneration (AMD) it supposedly shows better penetration through the retina and higher affinity to VEGF.
The short answer to the above question is: „It depends.“ Following the guidelines for evidence based medicine (EBM), there is level 1 evidence available for ranibizumab, while the highest available level of evidence for bevacizumab is level 2a. Therefore, Avastin does not offer the same level of evidence and cannot be evaluated side by side. This may be possible as soon as the results of the CATT trial become available. CATT (Comparisons of Age-Related Macular Degeneration Treatments Trials) is a multi-centered trial organized with the help of the National Institutes of Health (NIH) in the USA to determine the safety and efficacy of intravitreal bevacizumab compared with ranibizumab. The prospective, randomized and masked clinical trial will offer a head-to-head comparison of ranibizumab and off-label intravitreal bevacizumab used in 1200 patients. It comprises monthly ranibizumab and bevacizumab treatment arms as well as PRN treatment arms with both drugs.
Only then may there be direct comparisons of the efficacy and potential adverse events of off-label intravitreal bevacizumab versus ranibizumab.
Until then the available evidence is limited to small series and larger but still short-term and uncontrolled series of patients with neovascular AMD treated with off-label intravitreal bevacizumab.
Although developed at the same company, Genentech, there are some critical differences between these drugs: ranibizumab is an anti-VEGF antibody fragment, while bevacizumab is a humanized, full-length anti-VEGF antibody. The size of the bevacizumab molecule is of course larger than that of the fragment, ranibizumab. It has therefore been postulated that the penetration through the retinal layers is inferior to ranibizumab, which has already been refuted by histologic penetration studies. Several studies using RPE cell lines and bovine, rabbit, pig, and monkey models did not demonstrate evidence of ocular toxicity at the dose commonly administered. However there is an increasing number of reports of sterile endophthalmitis after intravitreal bevacizumab. This might be attributed to differences in the vehicle used for the drug and differences in the production process. But there is of course always a risk for endophthalmitis with every injection into the eye, even when strictly sterile conditions are adhered to. The risk for serious ocular adverse events such as endophthalmitis, uveitis and retinal detachment was 1.7% and lower in the large ranibizumab multicenter trials MARINA, ANCHOR and PIER. These rates were even lower for the use of intravitreal bevacizumab, although these numbers are based on self-reported events and hence the reliability may be questioned. Again, the CATT Study might contribute a reliable comparator for the available data regarding ranibizumab.
Another effect, which has been observed in equal rates for both drugs, is the rise of intraocular pressure, which was not a mere volume effect but a sustained rise. This effect was observed in patients who received multiple injections of either drug with and without a prior history of glaucoma.
The durability of the effect of bevacizumab appears comparable to ranibizumab with apparent intravitreal concentrations up to one month after injection.
Intravenous anti-VEGF blockade is known to be associated with increased rates of thromboembolic events and consecutively the systemic absorption of these agents following intraocular injections may increase these rates in patients treated with intravitreal anit-VEGF. The half-life of intravitreal ranibizumab is 3 days as confirmed by animal studies. And although the molecule is larger, bevacizumab has a similar half life of just over 4 days. Both ranibizumab and bevacizumab are absorbed into the systemic circulation, but there is a difference in the time for clearance from the system: ranibizumab’s half life is just 12 hours while it is at 20 days for bevacizumab. However the rates of systemic adverse events such as hypertension and stroke are similar for both drugs.
The functional and anatomical results are quite satisfying for bevacizumab, although these are based on smaller sample sizes and mostly uncontrolled studies.
The level of evidence for intravitreal bevacizumab is sufficient for the use in the treatment of neovascular AMD although it is inferior to the level-one evidence available for ranibizumab. So in the unlikely scenario of financial insignificance of the therapeutic approach, the evidence clearly points towards ranibizumab. But in real life with financial constraints everywhere and especially in health care systems around the world, the evidence available for bevacizumab merits its use in the treatment of neovascular AMD.


IS AUTOFLUORESCNECE NEEDED IN THE MANAGEMENT OF NEOVASCULAR AMD OR GEOGRAPHIC ATROPHY? YES
U. Schmidt-Erfurth

Austria

Age-related macular degeneration (AMD) affects an estimated 30 to 50 million individuals worldwide. It is the most common cause of legal blindness in developed countries among elderly individuals. AMD is typically divided into two clinical subgroups: the “wet” neovascular form affecting the retinal pigment epithelium (RPE) and Bruch´s membrane and the “dry” atrophic type predominantly related to RPE alteration and loss.
Geographic atrophy (GA), known to be a late stage development of AMD occurs in 20% of patients with preexisting clinical hallmarks of this degenerative disease. The natural course of GA, unlike the aggressive neovascular form of AMD, progresses slowly and usually involves visual loss, primary due to retinal pigment epithelium (RPE) degeneration and retinal atrophy resulting in absolute and relative scotoma affecting the central vision field.
There is neither an evidence-based preventive therapy nor a cure for both categories. Intravitreal anti-angiogenic agents, as well as photodynamic therapy and thermal laser represent palliative treatment options which have been shown to partially reverse visual impairment in a portion of patients affected by neovascular AMD.
Routine imaging modalities in patients with choroidal neovascularization (CNV) consist of fundus fluorescein angiography (FA), optical coherence tomography (OCT) and color fundus photography (FF). The clinical use of FA serves to assess location, extent and nature of the lesion in AMD. The enhanced visualization of retinal structures and their pathological changes in OCT provide an improved understanding of retinal disease and more adequate patient management strategies. Currently the benefit of OCT-imaging particularly applies to a realistic analysis of the anti-exudative effect of intravitreal anti-angiogenic drugs in neovascular AMD, even if histopathological findings concerning CNV have been replicated in OCT.
Common imaging modalities used in patient management with geographic atrophy is fundus autofluorescence derived by confocal scanning laser ophthalmoscopy (cSLO) and increasingly optical coherence tomography.
The cSLO device uses blue light at a wavelength of 488 nm to illuminate the fundus and captures the fluorescence signals from cellular elements of retinal and RPE layers. Delori et al described that fundus autofluorescence (FAF) is based on the fluorescent characteristics and distribution of LP within the RPE layer. RPE cell death may result from the accumulation of lipofuscin (LP), a toxic by-product of photoreceptor shedding, which accumulates in the lysosomal compartment of the RPE cell. In healthy eyes, LP is continuously cleared by RPE and choriocapillaris. As a part of the aging process the clearing ratio diminishes over time and an excess of intracellular LP impairs the normal cell metabolism and eventually leads to cell death by induction of a reductive chronic inflammatory condition involving complement factor H. Since complete RPE loss, as in GA, results in absence of fundus autofluorescence (FAF), and metabolically altered RPE has different fluorescent properties than physiological RPE, autofluorescence patterns may therefore be potentially used to identify pathophysiologic mechanisms in AMD and delineate the area and the progression of GA.
Compared to the diagnostic breakthrough in neovascular AMD, the role of OCT/ SD-OCT concerning GA in AMD is presently not entirely clear. Several studies have been performed comparing FAF and SD-OCT with a specific focus on morphologic features. However, only limited data is available assessing the potential of SD-OCT regarding lesion size determination and clinical reproducibility of planimetric measurements, as well as the predictive value of SD-OCT features in GA progression.
Then again FAF imaging in neovascular AMD is a less well studied topic. This is not only reflected in few scientific contributions, but also in missing FAF imaging in routine clinical practice or multicenter trials, when it comes to choroidal neovascular disease. This can be explained by controversial results found in clinical studies concerning this topic. A study by Spaide showed that FAF in fellow eyes of patients with exudative AMD had a larger amount of FAF than eyes without history of exudative AMD. Whereas a study by McBain et al. found that a homogenous FAF pattern in fellow eyes of patients with CNV was the most common. Nevertheless a consistent finding in FAF with patients with CNV was that visual acuity prognosis when treated with anti-angiogenic drugs was better when FAF seemed less altered in comparison to background FAF.
In summary, neither the role of OCT in GA nor the meaning of FAF in CNV is entirely understood. Therefore the question should be: “Of which use can the available imaging modalities (FAF, OCT, FA and FF) be in AMD patient management?” or “Which use can we make out of the available imaging modalities in AMD patient management?”


IS AUTOFLUORESCENCE NEEDED IN THE MANAGEMENT OF NEOVASCULAR AMD OR GEOGRAPHIC ATROPHY
S. Bressler

USA

Autofluecvence is a new image modality that provides information about the health and well being of the retinal pigment epithelium. Areas of geographic atophy often have a characterisitic appearance on these images. Some authors have suggested there are features in the autofluoresence images of eyes with geographic atrophy GA) that demonstrate varying risk profiles for GA progression. The debate will focus on whether this is a diagnostic test with utility for research purposes or one that is important for the practicial clinical management of patients in 2010.


MANAGEMENT IN BRANCH VEIN OCCLUSION: LASER TREATMENT
D. Finkelstein

USA

In the mid 1980's, the Branch View Occlusion Study report that argon laser photocoagulation successfully reduced vision loss from perfused macular edema in patients with visual acuities of 20/40 or worse who were treated with laser photocoagulation applied in a "grid" pattern throughout the leakage area (demonstrated by fluorescein angiography). Coagulations were extended no closer to the fovea than the edge of the capillary free zone and no farther into the periphery than the major vascular arcade. After three years of follow-up, about two-thirds of patients treated with laser photocoagulation gained an average of two or more lines of vision, in contrast to about one third of patients in the control (untreated) groups.
For neovascularization, the BVOS data showed that scatter photocoagulation treatment of new vessels on the disc (NVD) and/or new vessels elsewhere (NVE) reduced the likelihood of vitreous hemorrhage by approximately 50%. The technique used involved application of treatment throughout the non-perfused segment of the fundus no closer to the macular than the major macular arcade. The photocoagulation had no affect on visual acuity.
The BVOS Group reported in the mid 1980's that argon laser scatter photocoagulation should be applied after, rather than before, the development of neovascularization, because 50% of ischemic BVOs with large areas of ischemia (more than five disc diameters in diameter) will not develop neovascularization. Since the treatment technique used reduced the frequency of vitreous hemorrhage, the study group recommended that only BVO patients with prior neovascularization be treated with laser photocoagulation.
Both for grid laser treatment for perfused macular edema and scatter treatment for management of neovascularization and reduction of vitreous hemorrhage, complications of laser treatment, when applied with this methodology in experienced hands, is only quite rarely associated with complications such as puncture into the choroid with resultant retinal fibrosis and traction.
It is important to recognize that there is no evidence that laser treatment for branch retinal vein occlusion be initiated promptly after the occlusion has occurred. For example, there is no evidence that perfused macular edema needs to be treated promptly and it has not been recognized that an occlusion with an ischemic quadrant be treated with scatter photocoagulation prior to the development of neovascularization. Laser treatment, either grid of scatter, is, therefore, rarely recommended prior to one year after the occlusion has occurred. During this period of wait time, patients will often become accustomed to using vision with one eye, especially when supported by frequent conversation with a compassionate ophthalmologist. It is important to a clinician's empathy, therefore, that attention be given to the patient's value system as these conversations proceed during the first year. One area of particular importance to most patients in the United States has been demonstrated to be that patient's spirituality; I emphasize this particular support system and we have published information in particular regarding this area of interest and importance.


INTRAVITREAL ANTI-VEGF: ALONE OR WITH LASER?
F. Bandello, M. Battaglia Parodi

Italy

Branch retinal vein occlusion (BRVO) is a frequent cause of visual loss, which is mainly related to the development of macular edema, macular ischemia, and vitreous hemorrhage secondary to retinal or optic disc neovascularization. Some studies have shown that intravitreal levels of VEGF are significantly increased after BRVO. Moreover, ischemia-induced upregulation of VEGF causes a loosening of tight junctions, which can lead to vascular leakage and macular edema formation. The Branch Vein Occlusion Study demonstrated the beneficial effects of grid laser photocoagulation in the treatment of macular edema associated with BRVO. Unfortunately, the multicentre trial confirmed that visual acuity improvement is limited. Thus, several approaches have been attempted to significantly increase the functional gain. Intravitreal anti-VEGF injection can achieve a substantial visual acuity and macular edema improvement in a considerable portion of patients affected by macular edema secondary to BRVO. The rationale of the combined treatment of anti-VEGF intravitreal injection with grid laser treatment is based on the hypothetical greater effect that grid laser photocoagulation could achieve acting on a thinner macular area. Initial studies seem to confirm this theory. Bearing in mind the acute features of BRVO manifestation in contrast to chronic diseases, such as diabetic macular edema, it is plausible that a more aggressive therapeutic strategy can accomplish greater and sustained effects. Moreover, the combined treatment can avoid the severe and rather frequent ocular side effects typical of intravitreal triamcinolone administration, including rise in intraocular pressure and cataract formation. Further studies are warranted to confirm that the combined approach can lead to a good outcome in the long-term follow-up.


Management of central retinal vein occlusion by intravitreal steroids
A. Loewenstein

Department of Ophthalmology, Tel Aviv Medical Center, Sackler Faculty of medicine, Tel Aviv, Israel

Background: Occlusion in the central retinal vein typically occurs at the lamina cribosa or just posterior. Local factors such as compression of an atherosclerotic central retinal artery or primary occlusion of the central retinal vein as a result of inflammation may be risk factors for CRVO. Anti-VEGF therapies target only one component of the pathogenesis of CRVO. Underlying inflammation is not treated.
Corticosteroids target the underlying inflammation in CRVO.
Methods: Triamcinolone acetonide, Fluorocinolone, and dexamethasone are a few steroids investigated in contorlled trials as treatment for CRVO.
Results: In the score trial, the efficacy of triamcinolone acetonide was shown, in the Retisert trial, the efficacy of Fluorocinolone was studied, and in the Geneva trial, that of dexamethasone. These results, regarding both efficacy and safety will be presented.
Conclusions: Central vein occlusion I an inflammatory disease and steroids should be part of its management.


MANAGEMENT IN CENTRAL VEIN OCCLUSION
S. Bressler

USA

Retinal venous occlusive disease is the 2nd most common retinal vascular abnormality seen by retina specialists. Central vein occlusions commonly lead to macular edema and until recently there has not been an efficacious treatment to manage this complication. Randomized trials comparing observation to intravitreal triamcinolone or to ranibizumab have recently been completed. Each agent led to improved outcomes relative to the natural course of this condition. The outcomes with anti-VEGF treatment appear to be more substantial in termsof vision improvement than those associated with steroids. The use of the two classes of agents will be debated- focusing on relative risks and benefits.


IOL IN THE PATIENTS WITH WEAK OR ABSENT ZONULES: AC IOL IS AN EXCELLENT OPTION
D. Sachs

Israel

AC IOLs are generally implanted in primary intention when the posterior capsule is broken during phacoemulsification or in a secondary procedure when capsular support is insufficient or absent. PC IOL is an inadequate option in the presence of weak or absent zonules because of the risk of decentration and late dislocation.
Skilled and experienced surgeons are capable to stabilize and secure a posterior 3 piece IOL on only few remnants of a ruptured posterior capsule. They can also suture it to the sclera or to the iris if needed but the procedure is complicate, time consuming and there is uncertainty about the long term suture endurance.
The actual Kelman Multiflex AC IOL is the best option in case we need to implant a lens in an alternative location. This type is the ultimate Anterior Chamber lens. The previous AC IOL generations experienced severe complications due to their deficient rigid design. The new generation is entirely pliable which allows full flexibility. The insertion of the IOL chosen to fit the anterior chamber diameter requires a certain practice but is quite easy. If inserted with precaution there is no risk of dislocation or excessive loss of endothelial cells.
We have a responsibility toward our patients and must choose to implant this type of IOL in every case of severe phacodonesis due to weak or absent zonules.


EXCHANGE OR REPOSITION BY IRIS FIXATION, BEST METHOD
W.J. Stark

USA

Inadequate capsule support is a rare but potential complication associated with cataract surgery. Options include leaving the patient aphakic, placing an anterior chamber (AC) intracocular lens (IOL), or suture-fixating a 3 piece foldable acrylic IOL in the ciliary sulcus or the peripheral iris. We now prefer suturing the IOL to the peripheral iris using a modified McCannel technique.
The technique can be accomplished through a 3.5mm central incision. The pupil is constricted with acetylcholine to facilitate papillary capture of the IOL optic. The IOL is folded in a “moustache fold” and inserted through the corneal wound, placing the haptics within the sulcus and positioning the optic above the plane of the iris. A Barraquer sweep is passed through the paracentesis and placed beneath the optic as the lens is unfolded. Additional viscoelastic material is injected into the AC, pushing the iris posteriorly against the haptics. The Barraquer sweep is used to elevate the optic. Both maneuvers facilitate visualization of the haptics, simplifying passage of the suture. Using a modified McCannel-type iris-fixation technique, a 10-0 polypropylene (Prolene®) suture is passed on a needle Ethicon CTC-6 through clear cornea and the iris, under the peripheral aspect of the inferior haptic, then out through the iris and clear cornea. A paracentesis is created over the inferior haptic, and two ends of the suture are pulled through this site. The superior haptic is secured in a similar manner. The sutures are loosely tied with a single throw and are not locked. The optic is placed posterior to the iris. Using a Sinskey hook, the iris is manipulated to produce a round pupil. Miochol is injected again to ensure a round miotic pupil. The sutures are securely tied.
If there is no capsular support the sutures are tied tight before the optic is placed in the posterior chamber. If necessary, a vitrectomy through pars plana incision or an anterior vitrectomy through the corneal wound is performed. The retained viscoelastic material is removed from the AC.
Air is injected into the AC and checked for unidentified strands of vitreous. If vitreous is present, a Barraquer sweep is used to break the strands or a more extensive vitrectomy is perfomred. Then a repeat injection of air is made into the AC, again inspecting for vitreous. A balanced salt solution is injected in to the AC, bringing the eye to a more normal physiologic pressure. The wound is tested for leaks.
Results: The results of suture fixation of IOL's in eye with no capsular support will be presented.
Conclusions: The ability to insert and suture-fixate an IOL through a 3.5 mm incision gives the surgeon greater flexibility in treating patients with no capsule support. This technique permits secondary IOL insertion in aphakic patients who are contact lens intolerant, facilitates the management of IOL problems after surgery that require IOL exchange, and allows the surgeon to properly treat patients who develop loss of capsule support at the time of cataract surgery.


CLOSED- SYSTEM SCLERAL FIXATION OF DISLOCATED CAPSULAR FIXATED PC-IOLS
E. Assia

Department of Ophthalmology, Meir Medical center, Kfar-Saba & Ein-Tal Eye Center, Tel-Aviv, Israel

Purpose: To describe a technique for repositioning malpositioned PC-IOLs while still in the capsular bag.
Methods: A 10-0 or (preferably) 9-0 polypropylene suture with a long (16mm) strait needle is inserted 0.5-1.0 mm from the limbus behind the IOL loop. The needle is guided out through a side port incision using a 27G needle, rotated 180o and reinserted through the same paracenthesis. Passing above the IOL loop to the needle is externalized though the scleral wall. The knot of the ring suture is buried and no scleral flaps are required. The same is done on the opposite side to complete a symmetrical fixation.
Results: Subluxated or dislocated PC-IOLs are effectively repositioned and fixated though two 1mm side-port incisions and 4 needle holes in a relatively closed system. This avoids removal and exchange the IOL through a large incision and recovery is almost instantaneous. Complication rate is low and usually includes vitreous hemorrhage and transient pressure elevation.
Conclusions: The closed system scleral fixation is relatively simple and very efficacious for treatment of malpositioned capsular PC-IOLs


THE BEST ANTIBIOTIC FOR INTRACAMERAL USE IS MOXIFLOXACIN
S. Arshinoff

Canada

Purpose: To review current intracameral antibiotic data and attempt to draw conclusions.
Study Design: This paper is a review of current intracameral antibiotic methods, and studies available illustrating the efficacy of each.
Methods: Data was collected from all available intracameral antibiotic studies, and analyzed.
Results& Conclusion: Although intracameral cefuroxime was shown by the ESCRS study to be effective in reducing the risk of endophthalmitis 5 fold, the more recent iSBCS study has shown better results with intracameral moxifloxacin or vancomycin. Of these 2 agents, intracameral moxifloxacin enjoys a broader spectrum of antimicrobial activity and is much more safe and simple to prepare.


THE IMPORTANCE OF PREOPERATIVE, NON-STEROIDAL ANTI-INFLAMMATORY DRUGS
W.J Stark

USA

The exact pathogenesis and optimal regime for the prevention and treatment of clinically significant cystoid macular edema (CME) has yet to be clearly elucidated. Variability in the definition of CME, diagnostic criteria, ancillary testing are factors that contribute to the heterogeneity and the prevalence, disease course in response to medical prevention and therapy have been reported. This talk will present the summary of the available literature regarding the use of non-steroidal anti- inflammatory drugs (NSAIDs) for the prevention and treatment of CME associated with cataract surgery. In the United States these drugs are approved for reduction post-operative inflammation when compared to placebo, and no drug to date has been approved for the prevention or reduction in the incidence of CME.
The rational and economic implications for the use of NSAIDs associated with selected cataract surgery case will be presented.


EPISCLERAL BRACHYTHERAPY (PLAQUE RADIOTHERAPY)
J. Pe'er

Israel

Episcleral brachytherapy using radioactive plaques was the first "conservative" method of treatment of uveal melanoma, mostly in the posterior location. Stallard introduced the Co-60 plaque in the 1950s. In the 1970s the Co-60 was replaced by the I-125 plaque (emitting ?-radiation), mainly in the U.S., and by the Ru-106 plaque (emitting mostly ?-radiation), mainly in Europe. Other radionuclides used for episcleral brachytherapy in some centers are: Strontium-90, palladium-103, gold-198, and iridium-192. Currently episcleral brachytherapy is the most commonly used modality for treating patients with posterior uveal melanoma.
The episcleral plaques are placed over the tumor base in surgery under local or general anesthesia, and left there – according to calculations – for several days, and are removed in another short surgery after radiating the desired dosage. The usual dose to the uveal melanoma tumor apex is 80 – 100 Gy, while the tumor base gets several times more radiation, particularly if the tumor is thick. Radiation of up to 1500 Gy has been reported without causing scleral necrosis. The currently-used plaques are relatively safe to the patient, the medical staff and the surrounding people. Episcleral brachytherapy is used sometimes in combination with transpupillary thermotherapy and trans-scleral local tumor resection, and rarely in combination with more than one radionuclide.
The main side effects of episcleral brachytherapy are: cataract – more frequently after treatment of anterior tumors, radiation retinopathy, radiation optic neuropathy, retinal and vitreous hemorrhage, neovascular glaucoma, and scleral melting. Cataract can be treated by the usual procedures for cataract extraction. The vascular complications are treated as other retinal vascular diseases, and recently more often by intraretinal injections of corticosteroids and anti-angiogenic agents.
About half of the patients treated by brachytherapy maintained functional vision. Local tumor recurrence happens in 5 – 10% of the patients; many of them can be re-treated by brachytherapy or other "conservative" methods. About 10 – 15% of the eyes have to be enucleated after brachytherapy. The main reasons for secondary enucleation are: tumor recurrence, recurrent vitreous hemorrhage, and painful neovascular glaucoma. No significant difference in survival was found between episcleral brachytherapy and primary enucleation in patients with uveal melanoma.
Ocular oncologists prefer to conserve the eye, avoiding enucleation whenever it is possible. Episcleral brachytherapy using radioactive plaques with one of the nuclides can be performed in every medical institute, without the need for special equipment such as a proton beam accelerator. It is also less expensive than proton beam radiotherapy. Brachytherapy is less invasive than local resection, where general anesthesia must be administered by an experienced team of anesthesiologists. Unlike local resection, the danger of losing the eye during surgery is practically zero. Experienced teams can place the radioactive plaque over almost any part of the sclera, without much difficulty, achieving tumor control as good as with proton beam radiotherapy. Episcleral brachytherapy was shown to be effective also in many cases of "extra-large" uveal melanomas. The adverse effects of brachytherapy are usually only intraocular, not damaging the eyelids, lacrimal system and ocular surface as in proton beam radiotherapy.
Episcleral brachytherapy using radioactive plaques that are readily available, is easy to perform even under local anesthesia, is relatively inexpensive, non-invasive, and with comparable local and systemic results to other methods yet with only intraocular side effects that are usually manageable. It can be used also as an adjunctive form of treatment. These are the reasons that brachytherapy is and will continue to be the first line of treatment of small, medium and even large-size uveal melanomas in most ocular oncology centers.


DEBATE: WHAT IS THE BEST CONSERVATIVE MANAGEMENT OF UVEAL MELANOMA? PROTON BEAM IRRADIATION
E. Gragoudas

USA

Patients diagnosed with uveal melanoma are at risk of vision loss, loss of the eye and death from metastasis. Enucleation, once the standard therapy for these tumors, has been replaced by more conservative therapies including proton beam irradiation.
The physical properties of protons permit highly localized and uniform dose distributions. Specifically the manner in which protons lose energy in tissue, with minimal scatter due to its mass, low LET (linear energy transfer), and deposition of most energy at the end of their range (Bragg peak), allows the design of a beam that covers the target volume with a uniform dose and reduces or eliminates the dose proximal and distal to the target. The radiation can be delivered to the entire tumor with a sharp reduction of the dose outside the treated area, thereby sparing normal ocular structures. By varying or modulating the beam energy, the Bragg peak can be broadened to conform to any tumor. This ability to control the placement and energy of protons should lead to improved local control rates and a reduction in the incidence of radiation-induced damage to normal ocular tissue. Other advantages of proton therapy include a treatment planning system with the ability to design an aperture that approximates the shape of the tumor and to choose a fixation angle that minimizes radiation exposure to critical structures. As a result, large tumors can be treated because the overall irradiated volume of the eye is reduced, with the possibility of fewer untoward radiation effects. Additionally, tumors located near the optic nerve and macula can be treated, with preservation of the eye and, in some cases, retention of visual function.
Tumors touching or contiguous to the disc, ineligible for treatment in the Collaborative Ocular Melanoma Study (COMS), can be treated with proton therapy. Radiation papillopathy developed in 57% and maculopathy in 60% of 573 patients treated with proton irradiation for tumors located within 1 disc diameter of the optic nerve. Although visual acuity is compromised (approximately 20% retain useful vision (at least 20/200) 5 years after treatment), eye conservation is possible in most patients (>80% 10 years after proton therapy compared to 23% of eyes treated with iodine 125 plaques). In the majority of cases, some vision is retained (5 year rate of visual acuity of counting fingers or better was 67%).
Similar to other conservative therapies, high rates of local control are achieved and survival rates are similar to those observed after enucleation. The 15 year melanoma-related mortality rate in the series of patients with tumors located near the optic nerve was 24%, similar to rates observed in our larger cohort of patients. Tumor recurrence rates are very low after proton irradiation; the 5 year cumulative rate is 3% compared to approximately 10% after plaque therapy with iodine 125.
Proton irradiation should be the preferred therapy for patients with tumors contiguous to the optic disc. Plaque radiotherapy may be a poor choice in these cases because the radioactive plaque cannot be placed accurately to completely cover the tumor. As a result, recurrences may develop. Complete loss of vision or loss of the eye, once thought to be inevitable in cases of parapapillary and peripapillary tumors may be avoidable with proton therapy.


MELANOMA: SHOULD WE PERFORM SYSTEMIC EVALUATION?
J. Pe'er

Israel

Despite the success of treatment of primary uveal melanoma in most cases, 30 – 50% of the patients develop metastases within 15 years, most of them to the liver, and die within 6 – 12 months. Currently there is no cure for this metastatic disease. However, some methods of treatment, including surgical hepatectomy, various types of chemotherapy and immunotherapy, may extend the survival significantly, sometimes in years. An earlier diagnosis of liver metastases may enable a more successful treatment.
Prof. Damato and Prof. Gragoudas will present their points of view for and against routine systemic evaluation for metastatic uveal melanoma.


DEBATE: SHOULD WE PERFORM SYSTEMIC EVALUATION? NO
E. Gragoudas

USA

Background: Up to 50% of patients diagnosed with uveal melanoma eventually die from metastasis. Liver involvement is common (approximately 90% of cases) in metastatic uveal melanoma, and effective therapies for hepatic metastasis are lacking. Thus the value of early diagnosis and intervention for patients with disseminated disease remains controversial, with limited data available to assess this issue.
Most ocular oncologists in the United States perform biannual liver function tests to monitor for metastasis. If liver enzymes are elevated, further evaluation is performed, with an abdominal CT scan, MRI, or ultrasonography. Eventually, liver biopsy is performed to confirm the presence of metastasis. These surveillance methods were employed by investigators in the Collaborative Ocular Melanoma Study (COMS). Recently, newer diagnostic imaging tools, e.g., positron emission tomography /computer tomography have begun to be evaluated, but the impact of these more sophisticated imaging tools on survival is not known.
Investigators in the COMS Trials found no differences in survival between patients who received treatment for metastatic disease and those who did not, but they did not evaluate the effect that early versus late diagnosis of metastasis may have had on survival.
An assessment of patients with metastatic melanoma enrolled in a Finnish Registry determined that, of those who had annual examinations, metastasis was diagnosed in 74%, with the remaining 26% diagnosed after developing symptoms. A nonsignificant increase in median survival after diagnosis of metastasis was observed in patients having annual examinations compared to those who did not (8.9 months versus 4.3 months; p=.08) but there was no difference in survival from the time of initial tumor diagnosis (p=.25).
It is unclear from these limited data whether earlier diagnosis through routine screening and treatment of metastatic disease is associated with improved survival. Although there appears to be some suggestion of a benefit, lead time bias may account for these findings.
Systemic evaluation: The MEEI experience: An assessment of patients with metastatic uveal melanoma enrolled in the Ocular Melanoma Registry at the Massachusetts Eye and Ear Infirmary revealed no difference in median survival (time from initial diagnosis of the tumor to death from metastasis) between patients diagnosed by routine surveillance testing (n=259, “asymptomatic” or “early diagnosis” group) and those who were diagnosed after developing symptoms (n=90, “symptomatic” or “late diagnosis” group). Although median survival time after the diagnosis of metastasis was longer in the early diagnosis group than the late diagnosis group (6 months versus 3 months; p<.001), the lack of similar effect on median survival time after diagnosis of the primary tumor, suggests that this finding is due to lead time bias. Additionally, there were no meaningful differences between these groups in the proportion of patients undergoing treatment for metastasis (67% of the asymptomatic patients vs. 60% of the symptomatic patients) or the types of treatment that patients received (The most common treatment was chemotherapy, received by 53% of asymptomatic patients and 47% of symptomatic patients).
The present data suggest that early diagnosis and treatment of metastasis are not beneficial in prolonging survival. The time from diagnosis of the primary tumor to death is similar between the early diagnosis group and late diagnosis group. Currently, extensive and frequent work-ups may be unreasonable since few advances in the treatment of hepatic metastases have been made. Early diagnosis of metastasis may lead to a decision to treat the metastasis with therapies that are largely ineffective and associated with serious toxicities. However, annual liver function tests may be worthwhile as improved therapies are discovered.


STRABISMUS SURGERY
P. Nucci

Italy

In this session the advances in strabismus and nystagmus surgery will be discussed. Three main areas are of particular interest, Nystagmus surgery, Strabismus surgery and Thyroid related eye disease.
The advent of a relatively new procedure for nystagmus has caused much controversy in the ophthalmology world. IN a point counter point discussion the merits of different surgical approaches for Nystagmus including 4 muscle tenotomies are discussed. Perhaps no new surgical procedure has divided the ophthalmology world as tenaciously as this procedure. Who is right? Perhaps more importantly is this procedure, its rationale and intended benefits fully understood?
Minimally invasive strabismus surgery has increasingly become a popular method of surgery. It is suggested that this technique aids faster recovery and results in less conjunctival scarring. Does it make a difference however to the final outcome 12 months post operatively? A proponent of minimally invasive surgery argues the point that it does. Again a point counter point approach will allow the audience a chance to make up their own minds
When to operate in a patient with thyroid related eye disease resulting in severe strabismus is a frustrating conundrum. Should you wait for the earliest time of stabilisation of the deviation angle or should you wait much longer to allow the disease to ‘burn out’. Point-counter point discussion exposes the thought patterns of leading experts in this field. There may well be many correct answers to this conundrum but the rationale and logic between them will help the audience decide which the superior approach is.


THYROID RELATED STRABISMUS
Early surgery is preferable
D. Granet

USA
We should postpone surgery as much as possible
D. Mojon

Switzerland

Early strabismus surgery allows fast patient rehabilitation and, therefore, prevents from social isolation, accidents related to double vision, long occupational and driving disability. The risk of further strabismus surgery after early surgery because of disease relapse is nowadays reduced by the use of intravenous corticosteroids, orbital irradiation, and better treatment options to normalize thyroid hormones levels. Late strabismus surgery will, on the average, be associated with a lower number of surgical procedures and will minimize the risk for reinterventions of the same muscle. Furthermore, in some patients delaying surgery will result in no need for surgery if, for example, involvement of the second inferior rectus muscle will spontaneously normalize a vertical deviation.
Multiple Choice Questions:
Which is an advantage of early strabismus surgery in thyroid endocrine orbitopathy?
A) Less intraoperative bleeding
B) On the average less surgeries for patient rehabilitation
C) Faster rehabilitation
Which spontaneous clinical course in a patient with mainly unilateral thyroid endocrine orbitopathy may avoid performing strabismus surgery?
A) Involvement of second inferior rectus muscle
B) Involvement of second superior oblique muscle
C) Involvement of second inferior oblique muscle
Which modification allows performing minimally invasive rectus muscle recessions in thyroid related strabismus if motility is strongly restricted?
A) Muscle reattachment sutures after desinsertion
B) Posteriorly longer keyhole cuts
C) Performing ipsilateral antagonist reinforcement before recession


THE TIMING OF INTERVENTION IN POSTERIOR SEGMENT TRAUMA: EARLY VITRECTOMY
F. Kuhn

USA

“When” is just an important question in the surgical intervention of eyes with posterior segment injury as is the “what”. Timing (staging) of vitreoretinal surgery is thus crucial as the management strategy is contemplated. Delaying posterior segment surgery beyond two weeks risks the development of irreversible retinal damage; performing it concomitant to wound repair (primary comprehensive reconstruction) is able to treat/prevent many retinal complications but exposes the eye to the threat of major intraoperative hemorrhage.
Early vitreoretinal surgery in eyes with posterior segment injury in the hands of an experienced surgeon who has proper logistical support (well-equipped operating room and adequate, knowledgeable support staff) is especially crucial in cases of high risk for endophthalmitis or proliferative vitreoretinopathy.


DELAYED VITRECTOMY
W. Mieler

Chicago, Illinois, USA

In the setting of an open-globe injury with damage to the retina, there has been long-standing debate as to the most appropriate timing of surgical repair. Repair of the sclera/corneal/corneoscleral wound is generally taken care of within several hours of the injury, in order to restore the integrity of the eye, and to potentially limit the risk of infection and other associated complications. The precise timing of the retinal repair however, is quite controversial. It can be repaired concurrently with the laceration repair, or deferred for a week or two. Repair is generally not deferred beyond two weeks, in view of the concern regarding development of sympathetic ophthalmia. It should be pointed out however, that in select situations such as endophthalmitis or even with retained intraocular foreign bodies (IOFBs), it is recognized that there is need for prompt surgical intervention, as otherwise, the function of the eye may be lost.
In trying to determine the most appropriate timing to surgically repair a retinal detachment in the setting of an open-globe injury, no definite answer can be obtained upon a thorough review of the experimental animal literature. Various eye trauma models in monkeys and rabbits, performed by Cleary and Ryan (1979), Topping, Abrams, and Machemer (1979), and Gregor and Ryan (1983), did not yield a clear result. There was no statistical difference comparing surgery performed at day one versus day fourteen, in terms of preventing or removing vitreous proliferation, though surgery performed at day one was technically more difficult and challenging.
In a similar fashion, a review of the clinical literature does not yield a definitive answer. Several studies in the early 1980s (Coleman 1982, deJuan 1984) did suggest a possible better prognosis with early intervention, though the cases were not matched between the groups in regard to diagnoses nor severity of injuries. The early intervention group had more patients who had injuries with generally recognized, better prognoses.
In 1988, there was an attempt to answer this timing issue with a clinical study, called the Vitrectomy for Trauma Study (VTS), spearheaded by Sternberg. After several submissions of a grant proposal to the National Eye Institute (NEI), it was recognized that a study of this type would most likely never be funded, due to the complexity of issues when dealing with open-globe injuries. While timing is one potentially very important factor, many other factors may be of equal or even greater significance (location and size of laceration, choroidal hemorrhage, subretinal hemorrhage, retinal incarceration, etc).
The issue of timing of surgical intervention therefore comes down to the individual preference of the surgeon. Operating in a delayed timeframe, which is generally defined as between 7 and 14 days post-injury, is my preferred option. Potential beneficial factors for a delayed approach include operating in a more controlled environment (day time, with OR personnel who are trained as ophthalmic technicians and assistants). There is less uveal congestion, and less risk of significant intraoperative hemorrhage. Waiting for a week or so post-injury, may allow time for development of a posterior vitreous separation, though since most patients with injuries are quite young, there is no guarantee that this will occur. If anterior segment hemorrhage is present as part of the initial injury, waiting a week or so for the blood to clear, may allow for sparing of the lens. To summarize, the decision regarding timing of surgical repair cannot be made solely on scientific data, and the issue is generally left to the discretion of the individual surgeon.


SHOULD FAITH PLAY A ROLE IN THE MANAGEMENT OF OPHTHALMIC DISEASES
D. Finkelstein

USA

An important principle of medical ethics, with respect to the relationship of the physician to the patient, is that the physician always should be particularly concerned with the values of the patient in determining management considerations for that patient. Ethical medical practice includes physician behavior, beyond technical competence, that promotes healing and optimizes that patient’s welfare. A growing body of literature draws attention to the importance of physician behavior that acknowledges the patient’s status as a whole person beyond the person’s disease. The physician who respects the patient as a person with dignity must acknowledge the patient’s value system to establish a relationship that permits conversation that merits trust for joint therapeutic decision making.
For many patients, religion and spirituality is important to their value system and may represent a unique source of motivation and coping with life events, including the experience of personal illness, where illness refers to the response to a disease. The physician who knows little about a patient’s family status, occupation, and religion/spirituality beliefs may provide inadequate therapeutic guidance despite being technically competent. Knowing a patient as a whole person, including his or her religion/spirituality beliefs, may allow a physician to aid better in the adjustment , coping, and healing process in the face of disease.
In a small research investigation, we assessed the prevalence of religion and spirituality as a component of ophthalmology patients’ value systems. We distributed a brief questionnaire to over 100 consecutive patients to evaluate the prevalence of spiritual and religious belief and behaviors in ophthalmology patients. It is interesting to note as a result of that study that over 80% of patients reported, for example, that prayer was important to their sense of well being and 45% reported weekly attendance at religious services.
Attention to religion and spirituality is one aspect of acknowledging and respecting a patient’s value system and in establishing a relationship that promotes trust for making joint therapeutic decisions.


Early detection is important in AMD management
A. Loewenstein

Department of Ophthalmology, Tel Aviv Medical Center, Sackler Faculty of medicine, Tel Aviv, Israel

Background: Anti VEGF treatment has dramatically improved the outcome for patients who developed CNV, but still, monitoring of patient at risk for developing CNV is of limited efficacy. Studies have shown, the close follow up can find the lesions at an earlier stage. Data from multicentered invterventional studies, showed that patients who are diagnosed early have a better final visual acuity.
Methods: We will present a developed technology, the preferential hyperacuity perimeter, PHP, it's ability to early detect the development of CNV. We will show (1) the sensitivity/specificity of a single ForeseeHome test in detection of CNV among intermediate AMD patientws; and (2) the long-term compliance in usage frequency of the ForeseeHome among intermediate AMD patients.
Methods: (1) Single encounter part- retrospective and multi-centered: patients with newly diagnosed CNV or intermediate AMD patients were recruited. Inclusion criteria included experience with a computer mouse and best corrected visual acuity better than 20/200. Participants underwent an Amsler grid examination and then a brief ForeseeHome tutorial followed by a single encounter ForeseeHome test. (2) Longitudinal part- prospective and single center: only intermediate AMD patients were enrolled. These patients received a packed device at home, with instructions to use it daily in an unsupervised manner. Frequency of usage was evaluated for a follow up of 6 months
Results: Results: (1) Single encounter part- Sensitivity and specificity of the ForeseeHome were 85% and 84%, respectively, irrespective of lesion location, type, size. This result stands in contrast with the Amsler grid test, for which sensitivity was low (57%) and dependent on location of the lesion (subfoveal vs. non subfoveal: 86% and 36% respectively). Specificity of the Amsler test was 85%. (2) The longitudinal part- Usage frequency was persistent
Conclusion: Asingle encounter with the ForeseeHome yielded a high specificity and sensitivity in detection of newly diagnosed CNV, with sensitivity being independent on anatomical characteristics of the lesion Along with a high frequency of usage, these findings hold promise for early detection of CNV while keeping a low false positive alarm rate.


MUTATION SCREENING OF PATIENTS WITH INHERITED RETINAL DYSTROPHIES: WHICH METHOD, AGAINST WHAT COSTS, AND WHO WILL PAY?
F. Cremers

Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

Inherited retinal diseases constitute the major cause of visual impairment and blindness in children and young adults in the western world. Their aggregate prevalence is 1 in 2,000 individuals. They have an enormous impact on the quality of patients’ lives. Educational and occupational options decrease. With the emergence of novel gene- or mutation specific therapies, it becomes increasingly important for patients to know their exact molecular defects. Furthermore, knowing the causative genetic defect is a prerequisite for adequate genetic counseling of patients and their families. More accurate information on prognosis can be provided based on the clinical outcome in patients with mutations in the same gene.
Molecular genetic studies in the last two decades have revealed the defective genes underlying approximately 65% of inherited retinal diseases. For some of these diseases, such as choroideremia, Norrie disease, and Stargardt disease, a single gene is implicated. For other diseases, such as X-linked retinitis pigmentosa (RP), and achromatopsia (ACHM), mutations in a few genes explain the far majority of the cases. In these examples, Sanger sequencing is cost-effective which renders DNA diagnostics straightforward.
However, many of the prevalent inherited retinal diseases, among which Leber congenital amaurosis (LCA), autosomal recessive (ar) and dominant (ad) RP, ar cone-rod dystrophy (CRD), and Usher syndrome (USH), display an enormous degree of allelic and genetic heterogeneity. Thus far 26 genes have been found to be mutated in patients with arRP, explaining ~50% of all cases, and the 20 known adRP genes contain ~50% of the causative mutations. Most progress was made for LCA, in which mutations in 16 genes underlie ~70% of the cases. Ten genes have been implicated in USH, explaining the majority of the cases. There also is a sizeable group of retinal diseases which are more difficult to classify, often show relatively mild clinical features, or show a late-onset. Several pattern and macular dystrophies belong to this group.
Using classical approaches as well as novel strategies, we can expect that the majority of the remaining causal genes will be identified in the next 5 years. In view of the substantial allelic and genetic heterogeneity displayed by many inherited retinal diseases, molecular diagnostics is challenging. Which techniques can be used to cost-effectively identify the underlying genetic defects?
i). Detection of frequent variant(s)
Conventional Sanger sequencing of relatively frequently occurring variants is warranted for the CEP290 c.2991+1655A>G mutation which is found in 20% of Caucasian LCA patients, and the CNGB3 p.T383fsX variant that is found in 50% of ACHM patients.
ii). Sequence analysis of main disease gene(s)
Sanger sequencing is also preferred for diseases for which the far majority of mutations can be found in one or a few genes encompassing a total maximum of ~50 exons/amplicons, such as achromatopsia (CNGB3, 18 exons; CNGA3; 8 exons), Stargardt disease (ABCA4, 50 exons), and X-linked RP (RPGR; 19 exons; RP2; 5 exons).
iii). High throughput detection of known variants
The analysis of all known LCA mutations can be performed cost-effectively using allele-specific primer extension (APEX) analysis, which yields pathologic variants in ~60% of patients. APEX is a mini-sequencing method. It is relatively cheap and flexible, but requires the amplification of each individual genomic sequence containing a mutation. This technique is less cost-effective for arCRD and arRP for which 25-35% of alleles can be found. An alternative technology based on resequencing (Affymetrix) in principle can detect all sequence variants, but will miss deletions and duplications which can represent up to 15% of variants. It also requires parallel or multiplex PCR amplification of genomic fragments, which renders it time consuming and thereby costly.
iv). Next generation sequencing
Next generation sequencing (NGS) represents a major breakthrough in cost-effective sequencing. NGS makes use of microarray-based enrichment of target sequences followed by massive parallel sequencing. Compared to conventional Sanger sequencing, the costs per basepair has dropped 100-1000 fold. To identify novel retinal disease genes, all the exons from a sizeable genomic region (e.g. established via linkage analysis or by identity-by-descent mapping) can be sequenced. Alternatively, all exons of the human genome (the exome) can be sequenced for less than € 10,000. NGS has been developed for large-scale sequencing projects. Studies are in progress to tailor NGS technology for diagnostic purposes, e.g. to sequence the exons of all (~180) human retinal disease genes, or a subset of these genes, for less than € 1,000,-.
The ultimate goal of many studies performed in the field of ophthalmic genetics is to provide novel treatments for these devastating diseases. In view of the enormous genetic heterogeneity for some diseases, it will be a challenge to identify enough patients eligible for some gene or mutation specific therapies. To achieve this, we need to raise awareness among general practitioners, clinical geneticists and ophthalmologists on the current status and future outlook of novel therapies. More importantly, we need to inform the patients in a well-balanced way. We should not oversell the potential of novel therapies as knowledge regarding safety and the effects of over-expression of introduced genes is still being gathered in different animal models in the coming years. On the other hand, once therapies become available, patients eligible for treatments should be known as otherwise valuable time may be lost in view of the progressive nature of many inherited retinal diseases.
The question that follows is who can make use of the techniques mentioned above and who will pay for the considerable costs? Only in a few western countries, health insurance companies will cover the costs involved in molecular diagnostics. In the developing countries, the medium or high throughput techniques listed above are too expensive for routine molecular diagnostics. Cheap, comprehensive, and efficient techniques need to be developed that also can be used by non-western countries.
Money will also be an issue regarding the development of novel therapies as industry is not inclined to invest in these ‘orphan disease’ studies that cannot be applied to large numbers of patients. Both private and government funding will be needed to translate the therapeutic studies from the laboratory to the clinic.


THE PHENOTYPIC FOLLOW-UP: HOW CRUCIAL IS THE KNOWLEDGE OF DISEASE PROGRESSION IN GENE THERAPY?
B. Lorenz

Germany

Leber Congenital Amaurosis (LCA) describes a group of retinal dystrophies with infancy onset. A broader definition is early onset severe retinal dystrophies (EOSRD). Recently, encouraging results have been published concerning gene therapy of LCA2 caused by mutations in the RPE65 gene (1-5). However, the functional results in humans are controversial to the data obtained from the large animal model, the Briard Dog. In young animals at the age of 8-10 months, Ganzfeld electroretinography ERG showed significant improvements well correlating to the area of the retina treated with a single subretinal injection of AAV vectors carrying the normal gene copy. In contrast, in humans, no objective ERG recordings were obtained following gene transfer, and only some patients really improved in light sensitivity, notably the very young children. Interestingly, in 20 months old dogs, no such improvement was seen (6).
This paper aims at shedding some light on the controversial results in humans compared to the canine data obtained in clinical and preclinical trials in RPE65 deficiency; and at defining parameters that can be measured in vivo to help identify individuals that will likely take advantage of gene therapy of the RPE65 phenotype in particular, and of pediatric retinal dystrophies in general.
Pediatric retinal dystrophies summarize a wide spectrum of diseases that starts with complete non-functioning of the retina from birth on, and includes diseases with progression to blindness over about two decades of life. Patients with mutations in the RPE65 gene can have severe phenotypes with blindness before the end of the first decade or occasionally much milder forms (7). Especially in the case of extremely early blindness not only the retinal morphology but also the complex neuronal network of the central visual pathways plays a crucial role when it comes to possible therapeutic benefits.
It is known from functional MRI studies that in the case of early blindness cortical areas originally reserved for visual processing will be taken over by other cognitive circuits such as auditive processing. Therefore, it appears unlikely that in conditions of extremely early onset of blindness gene therapy will be effective beyond the toddler age. One example is LCA1 associated with mutations in the retinal guanylatcyclase (GUCY2D), in which retinal function is severely reduced from birth on but funduscopic disease progression is extremely slow. In such a case very early gene therapy may well be effective.
Mutations in the RPE65 gene are associated with early changes in the photoreceptor outer segments due to the lack of rhodopsin formation as the major component of the discs. This observation can also be made in the Briard dog model (8). Gene therapy was proven to be effective in these animals (6;9;10) and demonstrates that normal morphology as seen by transmission electron microscopy and optical coherence tomography (OCT) is not an absolute prerequisite for functional rescue. However, the presence of photoreceptor cells in the retina is absolutely necessary for gene therapy to be effective, as this treatment strategy can only restore function to cells that are still present. Therefore, the interpretation of the results of clinical examinations such as OCT, fundus autofluorescence (FAF) and fundus imaging needs to be performed with great care.
Another major factor influencing the positive outcome of gene therapy is the type of mutation in the corresponding gene, and can explain interspecies differences. For example, the Briard dog model for RPE65 deficiency carries a naturally occurring stop mutation in this gene, while most human patients carry at least one missense mutation, which may be associated with the production of a defective protein. Such a protein may compete with the normal protein for correct function or localization within the cell or may even block expression of the transgene following gene transfer. Such a mechanism has already been shown for autosomal dominant traits such as a.d. Retinitis pigmentosa associated with heterozygous mutations in the Rhodopsin gene, but may also happen in autosomal recessive traits like most forms of LCA.
In recent years, imaging techniques have significantly improved our potential to describe the retinal morphology in a spatially and time resolved manner. Modern high resolution (spectral domain) OCT techniques allow local analysis of most of the retinal layers. In the near future, even higher resolution and combinations with functional analyses will further improve our capacity of in vivo phenotyping. In contrast, objective functional tests such as Ganzfeld ERG are of lower resolution, and often already below threshold at the time of diagnosis. Psychophysical methods for subjective testing of vision can be used in patients with very low levels of residual vision but are prone to variation. However, the combination with fundus-controlled perimetry can overcome some of the drawbacks of subjective testing as it allows the monitoring of involuntary eye movements in a very precise way.
The FAF is an indirect functional test and visualizes the accumulation of debris in the RPE such as lipofuscin. It can be increased in case of increased debris formation (i.e. Stargardt disease), or increased cell death (various forms of retinal dystrophies). On the other hand, it can be decreased in case of disturbed chromophore recycling (i.e. the RPE65 phenotype (11)) or in case of severely diseased RPE cells (RPE atrophy).
Conclusion: The combination of high resolution OCT, FAF, ERG and psychophysics allows not only a good phenotypic description but is also crucial for monitoring the effect of gene therapy. Definition of treatable stages of pediatric retinal dystrophies will only be possible with a combination of all these methods. Imaging methods can be applied in young children, whereas psychophysics will in general be only possible from school age on. As the functional effects of the different mutations differ, and apparently other genetic as well as environmental factors also influence the phenotype as is evident from familial cases, monitoring of the disease course is desirable in each individual case in preparation of any therapeutic intervention.
References
Bainbridge,J.W., et al 2008. Effect of gene therapy on visual function in Leber's congenital amaurosis. N. Engl. J. Med. 358:2231-2239.; Cideciyan,A.V., et al 2009. Vision 1 year after gene therapy for Leber's congenital amaurosisN. Engl. J. Med. 361:725-727; Cideciyan,A.V., et al 2009. Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at 1 year Hum Gene Ther 20:999-1004; Maguire,A.M., et al 2008. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N. Engl. J. Med. 358:2240-2248; Maguire,A.M., et al 2009. Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial Lancet 374:1597-1605; Le Meur,G., et al 2007. Restoration of vision in RPE65-deficient Briard dogs using an AAV serotype 4 vector that specifically targets the retinal pigmented epithelium. Gene Ther 14:292-303; Lorenz,B., et al. 2008 A comprehensive clinical and biochemical functional study of a novel RPE65 hypomorphic mutation IOVS 2008; 49 (12):5235-5242; Wrigstad,A., et al. 1992. Ultrastructural changes of the retina and the retinal pigment epithelium in Briard dogs with hereditary congenital night blindness and partial day blindness Exp Eye Res. 55:805-818; Acland,G.M., et al 2001. Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 28:92-5; Narfstrom,K., et al. 2003. Functional and structural recovery of the retina after gene therapy in the RPE65 null mutation dog. Invest Ophthalmol Vis Sci 44:1663-72; Wabbels,B., et al. 2005. Longitudinal and cross-sectional study of patients with early-onset severe retinal dystrophy associated with RPE65 mutations. Graefes Arch Clin Exp Ophthalmol. 2005 May;243(5):417-26.


ACCESSIBILITY OF RETINAL DEGENERATIONS TO GENE THERAPY
K. Stieger

Department of Ophthalmology, Justus-Liebig-University Giessen, Giessen, Germany

During the last decade, the transfer of genes by recombinant Adeno-Associated Virus vectors (rAAV) has allowed for the treatment of retinal degenerative disorders in a variety of animal models and, two years ago, results of the first human clinical trials have been reported. Especially with the use of large animal models, such as the dog, it has been possible to test and refine new strategies in pre-clinical evaluations, thus bringing close to the reality a clinically relevant treatment. The naturally occurring RPE65-/- briard dog model has been successfully treated by several research groups, with therapy persisting for up to 8 years. Vision in these dogs has been restored and verified by ERG and behavioral testing wherein vision was assessed by the ability to avoid obstacles in dim light. Based on these studies, six different clinical phase I studies of RPE65-/- patients are in preparation or have already begun. Results of a total of 18 patients have been published and more than 30 patients are likely to be treated in these initial trials. Some of the patients reported striking results in terms of an increased light sensibility and the improvement to navigate an obstacle parcours.
Generally, retinal degenerative diseases originate in one of the following cell types, the retinal pigmented epithelium (RPE) and the photoreceptors. Therefore, one of the most important steps in developing retinal gene therapy strategies is to target the transgene expression efficiently to one of the two cell types. To date, 12 AAV serotypes and more than 100 isolates have been identified and all of them display tissue preference and specific cellular tropism following subretinal injection in the retina. It has been shown that AAV serotypes 2 and 5 efficiently transduce the RPE and the photoreceptors in all species tested, while AAV serotype 4 specifically transduces the RPE. Other serotypes are currently in examination for use in retinal gene transfer.
The choice of the ideal AAV serotype as well as the optimal composition of promoter, therapeutic gene and polyadenylation-signal within the expression cassette is crucial for an optimal expression profile of the transgene in the retina. With regard to the control of transgene expression, several different promoters have been used to drive transgene expression in the eye. Initially, powerful and ubiquitous viral promoters assured a strong expression profile of the transgenes within the retina. More recently however, tissue specific promoters, such as the promoter for the RPE65 gene or the VMD2 gene have been used to drive cell type specific expression of the transgenes in order to avoid unwanted side effects due to nonspecific expression in other tissues. The three already started phase I clinical studies employ different constructions, which are encapsidated in AAV serotype 2. The promoter driving the expression of the human RPE65 gene in both American clinical trials is the strong and nonspecific hybrid promoter construct CBA (chicken beta actin promoter fused to an early enhancer sequence of the CMV promoter). In contrast, the clinical trial in England uses the tissue specific promoter for the human RPE65 gene. The French clinical trial, which is still in preparation, will contain an expression cassette wherein transgene expression is driven by the RPE65 specific promoter and which is encapsidated in AAV serotype 4.
Using AAV vectors, several well characterized mouse models of retinal degenerative disorders due to mutations in at least 12 different genes (AIPL1, GUCY2D, ABCA4, Rho, Peripherin2, LRAT, RPE65, Rs1h, OA1, OCA1, RPGRIP1, GNAT2) have been successfully treated. However, since the differences between men and mice in retinal morphology, function as well as immunology and size are imminent, naturally occurring cat and dog models have to be used in the future in order to verify and modify initial treatment strategies developed in mice.
Successful and very promising gene therapy results in RPE65 deficiency and the rise of new animal models for retinal degenerative disorders will likely pave the way for more human clinical trials to come in the near future.


CLINICAL EXPERIENCES FROM RPE65 GENE THERAPY TRIALS
F. Simonelli

Dipartimento di Oftalmologia, Seconda Universit? degli Studi di Napoli, Napoli, Italy

Gene therapy has the potential to reverse the natural course of disease progression or arrest further visual degeneration in patients with incurable inherited retinal dystrophies. It has previously been demonstrated that adeno-associated virus (AAV)-mediated delivery of RPE65 via subretinal injection results in improved visual and retinal function in animal models of Leber congenital amaurosis caused by RPE65 mutations (also known as LCA2) although the extent of recovery results to be age-dependant. The preliminary results of our Phase 1 trial, testing gene therapy in humans with LCA-RPE65, were reported after the treatment of the first three young adults, all of whom showed improvement in subjective and objective measures of retinal and visual function. The inclusion of pediatric subjects in the trial allowed evaluating age-dependant effects and other factors on the extent of visual recovery after gene therapy.
Retinal and visual function has been evaluated in 12 subjects (from 8 to 44 years of age) with LCA-RPE65 up to 2 years after a single unilateral subretinal injection of AAV2-hRPE65v2.
AAV administration was well tolerated and all subjects showed sustained improvement in subjective and objective measures of vision. The greatest improvement was observed in children, all of whom gained ambulatory vision.
This study included the 4 youngest individuals in the world to have received gene transfer for a non-lethal disease. It also included the 2 oldest individuals to have received subretinal gene transfer to date. The safety, extent, and stability of visual recovery in all subjects treated support the use of AAV-mediated gene therapy for treatment of inherited retinal diseases although the earlier the intervention, the greater the potential gain.


REFRACTIVE SURGERY IN CHILDREN: YES
E. Paysse

Ophthalmology and Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA

Purpose: To debate the positive reasons to perform refractive surgery in children.
Methods: The background and reasoning involved in determining the proper patients that could be offered refractive surgery, including excimer laser procedures, refractive lensectomy and phakic intraocular lenses will be presented. A review of the visual, refractive, and behavioral outcomes will be presented.
Results: Refractive surgery is an effective treatment for high myopia and hyperopia in the subset of children with severe anisometropia or severe bilateral ametropia who do not respond to traditional therapy. The outcomes for astigmatism are less predictable and very little has been published on this issue. Excimer laser procedures are most effective for myopia up to approximately 10 diopters and hyperopia of up to 5 diopters with phakic intraocular lenses and refractive lensectomy probably being better for higher levels of myopia and hyperopia, though the number of children published in the literature with these intraocular surgeries thus far is small.
Conclusions: Pediatric refractive surgery is an effective treatment for severe anisometropia or severe bilateral ametropia in children who do not respond to standard therapy.


STATE OF THE ART: BEVACIZUAB (AVASTIN) FOR RETINOPATHY OF PREMATURITY (ROP)
H. Mintz-Hittner

USA

1. Introduction to the use of anti-VEGF therapy for ROP
2. Fear of toxicity—Primarily systemic
3. Fear of complications—Primarily local
4. Evidence of ocular safety
a. Histopathology
b. Electrophysiology
5. Published case series—Monotherapy or in combination with laser and/or vitrectomy
a. For ROP stages 4-5
b. For ROP stage 3
6. Advantages of Anti-VEGF therapy as monotherapy (without laser complications)
a. Specific benefit of Avastin: large molecular size injected into the premature viscous vitreous which (without laser) allows only 1:1000 to be detected in the blood or in the fellow eye. It is readily available and relatively inexpensive. No systemic complications to date.
b. Immediate response against VEGF (including that in the vitreous already)
c. Usually requires only one injection because of known pathogenesis of ROP in terms of post menstrual age (PMA).
d. Avoids all of the possible complications of laser therapy including anterior segment cataracts, iris synechiae, angle closure glaucoma, inflammatory phthisis, etc.
e. Vascularization proceeds into the retinal periphery (visual field is not lost and especially in zone I cases binocular field is not excessively destroyed inducing strabismus).
f. Myopia is generally less severe that following laser—with treatment at ETROP almost no myopia occurs.
7. Disadvantages of anti-VEGF therapy (with or without laser therapy).
Patients must be followed closely for a longer time following Avastin therapy than following laser therapy because of the possibility of delayed recurrence.
a. Vision threatening ROP usually occurs before 45 weeks (PMA).
b. Recurrence following laser therapy for ROP usually occurs before 55 weeks (PMA).
c. Recurrence following Avastin therapy for ROP may occur after 60 weeks (PMA).
8. Current status of the BEAT-ROP clinical trial.
9. Conclusions


PEDIATRIC OPHTHALMOLOGY: AVASTIN IN RETINOPATHY OF PREMATURITY
K.K. Nischal

UK

Advances in surgical techniques and developments in the evolution of surgical instruments have brought many strides in the treatment of adult ocular diseases and conditions. The safe translation of such techniques to the developing child’s eye is of utmost importance. In this section we discuss three important areas; Refractive surgery and cataract surgery as pertains to the child’s eye and the role of anti-vegf in paediatric ophthalmology. It is important to remember that the child’s eye is unique not only because it is smaller than that of an adult but also because its tissues are more elastic, there is the effect on emmetropisation of any intervention to consider, the growth of the eye itself and the longer lifespan by decades compared to adults.
The question is ‘Just because we can, should we apply adult technologies and techniques to children?’
Refractive surgery has become an important field of ophthalmology and so it is incumbent upon paediatric ophthalmologists to ensure that prior prejudices do not hinder the translation of this technology for helping children. It is worth remembering that many developmentally delayed children will not wear glasses for significant refractive errors; an already compromised child thus becomes more compromised due to ametropic amblyopia. However the effects of LASIK, PRK on the structural integrity of the cornea as the child’s eye grows cannot be dismissed. In this section the merits and possible disadvantages of Refractive surgery are discussed in point-counter-point fashion.
Anti-Vegf e.g. Avastin has become one of the fastest growing industries within ophthalmology. More and more case reports are surfacing of the use of such agents in Retinopathy of prematurity. Controlled studies in this area are scarce. The controversy here is that VEGF is a factor necessary for neural development; if we inject anti-VEGF into the vitreous of a premature infant how much is absorbed systemically and how much of this will effect neural development? These questions cannot go unanswered and yet the miraculous response (in some cases) of aggressive ROP to anti-VEGF injection cannot be denied. How do we as paediatric ophthalmologists rationalise these two attitudes? In a question and answer session we aim to answer these crucial questions.
Paediatric cataract surgery has advanced dramatically in the past ten years. Primary implantation even in infants has become increasingly popular. There are still some issues that we have not answered fully. What is the best postoperative refraction for infants? Why are there greater myopic shifts then we had anticipated even in the absence of glaucoma? What effect is there on the infant eye of primary implantation in terms of glaucoma risk and late complication risk i.e. ten or fifteen years post implantation? Is it safe to do a vitrectomy on children for paediatric cataract surgery? Should we implant in cases of JIA? Using expert panel different cases highlighting these issues will be discussed.


DELAYED LENS REMOVAL AND IOL IMPLANTATION
F. Kuhn

USA

Traumatic cataract occurs in up to half of eyes with severe injury. While its consequences are not disastrous themselves, the presence of lens damage signals an injury that is more severe than that without. In addition, the lens opacity prevents direct visualization of the retina, and may possibly delay treatment that would have been urgent.
The correct answer as to whether the lens should be removed promptly or during a delayed or secondary procedure is not always easy to determine. The benefits or delayed removal include reduced inflammation, the availability of proper technology and planning as well as personnel.
Regarding the timing of IOL implantation, this is a much less controversial issue. The only benefits of primary IOL implantation are the instant potential of fighting against amblyopia and convenience (i.e., avoiding a second surgery). However, many arguments can be listed in favor of delayed IOL implantation: Reduced inflammation, better planning, reduced interference with subsequent vitreoretinal surgery, and a more ideal condition regarding the selection of the type of IOL.


ORBITAL AND EYELID TRAUMA
N. Rosen

Israel

Orbital foreign bodies after trauma are sometimes serious surgical challenges.
Diagnosis of this type of trauma is often delayed and infections accompany many cases. Occasionally inert orbital foreign bodies can be safely observed without surgery and the decision whether to remove a foreign body or not depends on the composition of the foreign body, its shape and size its location and the chances for the development of infection
Surgical techniques for the removal of orbital foreign bodies vary and sometime require the partnership and assistance of neurosurgeons or ENT specialists.
An array of cases will be described and discussed. A short surgical movie will be shown.


CHEMICAL INJURY AND ADVANCES IN OCULAR SURFACE RECONSTRUCTION: LIMBAL STEM CELL TRANSPLANTATION, AMNIOTIC MEMBRANE TRANSPLANTATION, LAMELLAR KERATOPLASTY, PERMANENT KERATOPROSTHESIS
N. Schrage

Department of Ophthalmology, Town hospital of Cologne, Cologne, Germany

Since first publications of eye burns in beginning of 20-th century the type and the incidence of severe eye burns changed from fire burns and lime burns to alkali and chemical exposures of unknown classes and mixtures. The initial treatment is yet based on expert opinions and validated only on level II EBM studies. Experimental work in early phase and late phase treatment has undergone considerable improvement within the last 20 years. Historically there were starting with surgical milestones like tenonplasty (Kuckelkorn, Reim et al.), limbal grafts (Tseng Tsubota et al), and amniotic membrane grafts (de Roethe, Tsubota). We recognized that initial treatment with water or buffers has never been evaluated to be the best treatment. Thus our group evaluated systematically the effect of initial treatment. We started with living rabbits and could show that corneal calcification due to initial and continued phosphate buffer rinsing is of 100% incidence in severe eye burns. Our main instrument in evaluation of ocular exposures was developed within the last 10 years with the ex vivo eye irritation test (EVEIT) that allows to keep alive isolated rabbit corneas for more than 20 days in culture and expose them towards any type of biological, chemical or physical stress. In combination with pH measurements, high resolution and video optical coherence tomography we are now able to observe the action of corrosives on the eye dynamically. Thus we targeted to evaluate the action of alkali, acid and other corrosives on the eye. Further we evaluated rinsing with buffers, water, amphoters and saline solution in decontamination of the ocular surface. We identified that buffer solutions showed good action in acid and low action in alkali or vice versa. We proved that the concept of amphoteric and hyperosmolar rinsing alkali, acid and hydrofluoric acid burns showed good results in decontamination but inhibited epithelial regrowth in a distinct extend in ex vivo eye irritation test (EVEIT). Very small exposures could be treated with any type of rinsing fluid and healed. The stronger the burn the less substances treated well in initial rinsing. Our concept targets to rinsing all eyes that have been burned with amphoteric hyperosmolar rinsing therapy followed by the concept of Reim et al. with unpreserved steroidal, antibiotic and ascorbic acid eye drops each hour for at least 48 hours. If delayed epithelial healing occurs we start with necrotectomy and combined amniotic grafts on the cornea and conjunctiva in early phase treatment. Lid reconstruction starts before any conjunctival or corneal reconstructive surgery is done. Best success in visual repair is achieved if severe inflammation can be cooled clinically and corneal melting is prevented. Tenonplasty combined with amniotic grafts in our hands prevented in all cases corneal melting in the early phase, which we observed often in the past. On the long run corneal grafts combined with limbal ring grafts from the same donor and amniotic membrane in overlay technique below the conjunctival tissue gave good rehabilitation in several severe hopeless cases since 5 years now. Immunosuppression with steroids and mycofenolate and additional VEGF inhibition is crucial to maintain a good result. The ACTO-TexKPRO was implanted some disaster cases and gave visual rehabilitation for at least 6 months.
Overall the therapy of eye burns is still experimental with a good foundation of experimental basic research. Systematic interventional randomized studies are missing due to the difficult inclusion and the low incidence in western countries. Thus we are dependent on improved primary prevention and optimized experimental secured secondary prevention.


POST-TRAUMATIC ENDOPHTHALMITIS AND SYMPATHETIC OPHTHALMIA
W. Mieler

Chicago, Illinois, USA

Every open-globe injury has the potential to develop endophthalmitis, along with a small risk of developing sympathetic ophthalmia. Patients that sustain intraocular foreign bodies (IOFBs) have an approximate 7 to 13% risk of infection, and this is even higher in the setting of organic matter contamination, where the risk rises up to almost 30%. Open-globe injuries, including lacerations or those induced by blunt trauma, have a risk of infection ranging between 3 and 7%. Numerous factors play a role in the potential for development of infection, and several important factors include the setting and mechanism of the injury, the pathogens encountered the treatment which is applied to the injury, and the timing of the treatment itself. Traumatic settings often harbor especially virulent pathogens, including a very common predilection for Bacillus species. The treating physician has to always be suspicious for the possibility of infection, and in many cases, needs to deal with these issues in an urgent manner.
Sympathetic ophthalmia occurs in approximately 0.2% of open-globe injury cases, and presents as a bilateral, diffuse, granulomatous uveitis. Precisely what triggers the condition remains debatable, though exposure of uveal tissue outside of the eye seems to be a common denominator. The mechanism is most likely an autoimmune delayed-type hypersensitivity reaction to an infectious antigen or to the intraocular tissue itself (uveal, retinal, and/or RPE). The role of “s” antigen or uveal melanin remains unknown. The majority of cases occur between two weeks and three months following an injury, with 90% occurring within one year. Not only can the traumatized eye be involved, though the fellow non-traumatized eye can be severely impacted as well.
This presentation will review the common features of post-traumatic endophthalmitis, and sympathetic ophthalmia. Preventive measures will be discussed, along with treatment options. The numerous controversial issues in dealing with these difficult issues will be thoroughly reviewed and discussed. For post-traumatic endophthalmitis, these issues will include the timing of intervention, employment of a single or staged surgical approach, the role of prophylactic antibiotics, which antibiotics to employ in the setting of proven infection, route and duration of antibiotic administration, use of corticosteroids, etc. Regarding sympathetic ophthalmia, issues to be discussed include timing of surgical repair of open-globe injuries, management options in dealing with exposed uveal/retinal tissue when repairing an injury, the role and timing of enucleation when an eye cannot be surgically stabilized, the role of enucleation of the exciting eye when sympathetic ophthalmic has developed, and the type and duration of treatment once SO has developed (corticosteroids and immunosuppressives).


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