Studies and Trials

To determine whether laser photocoagulation helps to prevent severe visual loss from proliferative diabetic retinopathy.
To determine whether a difference exists in the efficacy and safety of argon versus xenon photocoagulation for proliferative diabetic retinopathy

Study Pattern
Patient eligibility criteria was presence of proliferative diabetic retinopathy in at least one eye or severe non proliferative retinopathy in both eyes. One eye of each patient was assigned randomly to immediate photocoagulation (scatter panretinal treatment, direct local treatment to new vessels and focal treatment for macular edema). The other eye was assigned to follow up without photocoagulation. The eye chosen for treatment was then randomly assigned to either argon laser or xenon arc photocoagulation.

Results

Both argon and xenon photocoagulation reduced the risk of severe visual loss by 50 percent or more compared with no treatment (Severe vision loss was defined as visual acuity <5/200 at two consecutively completed 4 monthly follow up visits).
The study identified a stage of retinopathy, termed high-risk proliferative diabetic retinopathy, where the benefits of photocoagulation definitely outweighed the risks (5 year rate of SVL in such eyes was reduced from 50% without treatment to 20% with treatment).
There was modest risk of decrease in visual acuity (usually only one line) and visual field (risk greater with xenon than argon photocoagulation).

Conclusion

Early PRP is recommended for high-risk proliferative diabetic retinopathy.

Early Treatment Diabetic Retinopathy Study (ETDRS)

Purpose

To evaluate the effectiveness of both argon laser photocoagulation and aspirin therapy in delaying or preventing progression of early diabetic retinopathy to more severe stages of visual loss and blindness.
To help determine the best time to initiate photocoagulation treatment in diabetic retinopathy.
To monitor closely the effects of diabetes mellitus and of photocoagulation on visual function.
To produce natural history data that can be used to identify risk factors and test etiologic hypotheses in diabetic retinopathy.

Study Pattern

Patient eligibility criteria was presence of mild to very severe NPDR and/or non high risk PDR with or without macular oedema in both eyes. One eye of each patient was assigned randomly to immediate photocoagulation and the other eye to deferral of photocoagulation (careful follow up) until high-risk PDR developed. Eyes with diabetic macular edema were assigned to immediate or deferred focal photocoagulation (direct laser for focal leaks and grid laser for diffuse leaks). Patients were assigned randomly to aspirin or placebo. The term "clinically significant macular oedema" was coined to designate this level of severity.

Results

Focal photocoagulation reduced the risk of moderate vision loss (defined as doubling of visual angle) by 50% or more and increased the chance of a small improvement in visual acuity.
Both early scatter and deferral were followed by low rates of severe visual loss (5 year rates in deferral subgroups were 2-10%; in early photocoagulation groups these rates were 2-6%.groupsstatistically significant reduction in severe visual loss for those eyes with early treatment, especially for those patients with non-insulin-dependent diabetes mellitus (NIDDM). However, the reduction was small and the risk was low in the deferral group.
Aspirin use did not affect the progression of retinopathy to the high-risk proliferative stage but aspirin also did not increase the risk of vitreous hemorrhage, did not affect vision, and was associated with a decreased risk of cardiovascular disease.

Conclusion

Focal photocoagulation should be considered for eyes with CSME.
Scatter treatment is not indicated for eyes with mild to moderate non-proliferative diabetic retinopathy. As the retinopathy progresses to the severe non-proliferative or early proliferative stage, scatter treatment should be considered, especially for patients with Type 2 diabetes and it should be performed without delay for virtually all eyes with high-risk proliferative retinopathy.
Aspirin has no clinically important beneficial effect on the progression of retinopathy. However, since aspirin also has no clinically important harmful effects for diabetic patients with retinopathy therefore there is no ocular contraindications to aspirin use when required for cardiovascular disease or other medical indications.

Diabetic Retinopathy Vitrectomy Study (DRVS)

Purpose

To compare early vitrectomy versus conventional management for recent severe vitreous hemorrhage secondary to diabetic retinopathy. To compare early vitrectomy and conventional management in eyes that have good vision but a poor prognosis because they are threatened with hemorrhage or retinal detachment from very severe proliferative retinopathy.
To study the natural history of severe proliferative diabetic retinopathy.

Study pattern
Patient eligibility criteria were the presence of recent severe vitreous hemorrhage (within 5 months) or very severe proliferative retinopathy with extensive active fibrovascular proliferation and useful vision in patients with Type 1 and Type 2 diabetes mellitus. Early vitrectomy 1-6 months after the onset of hemorrhage. Conventional management includes vitrectomy if hemorrhage fails to clear during a waiting period of 12 months or if retinal detachment involving the center of the macula develops at any time.

Results

In the severe vitreous hemorrhage trial, 2-year results showed that recovery of good vision (10/20 or better) was more frequent in the early vitrectomy group (25 percent versus 15 percent in the conventional management group) and the advantage was more apparent in Type 1 diabetics who were younger and had more severe fibrovascular proliferation (36 percent with visual acuity of 10/20 or better in the early vitrectomy group versus 12 percent with conventional management). In Type 1 diabetics, the risk of loss of light perception was the same in two groups (28 percent and 26 percent, respectively) but in Type 2 diabetics, there was a trend toward more frequent loss of light perception in the early group (25 percent versus 19 percent).

Conclusion

For eyes with recent severe vitreous hemorrhage, early vitrectomy provided a greater chance of prompt recovery of visual acuity although greater early risk of visual acuity of no light perception must be kept in mind. The benefit is more pronounced for patients with Type 1 diabetes, particularly for those in whom severe vitreous hemorrhage occurred after a shorter duration of diabetes. This benefit remained at least as great after 4 years of followup as it was at 2 years.
The DRVS findings support early vitrectomy in eyes known or suspected to have very severe proliferative diabetic retinopathy as a means of increasing the chance of restoring or maintaining good vision.

Editors Note:At the present time, it should be noted that the results of DRVS were obtained before the development of modern vitrectomy instrumentation, techniques and endolaser photocoagulation. With these techniques, results are more favorable. Nowadays in general, the recommended timing of vitrectomy for severe diabetic vitreous hemorrhage is before 3 months for Type 1 diabetics and 6 months for Type 2 patients.

Diabetes Control and Complications Trial (DCCT)

Purpose:

To assess the effect of tight glycemic control on complications of diabetes (nephropathy, neuropathy and diabetic retinopathy) for persons with Type 1 diabetes.

Study Pattern
Patients with IDDM with no retinopathy at base line (the primary-prevention cohort) and with mild retinopathy (the secondary-intervention cohort) were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections.

Results
In the primary-prevention cohort, intensive therapy (mean HbA1c 7.2%) reduced the risk for the development of retinopathy by 76 percent as compared with conventional therapy (mean HbA1c 9.0%). In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent. In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria (urinary albumin excretion of 40 mg per 24 hours) by 39 percent, that of albuminuria (urinary albumin excretion of 300 mg per 24 hours) by 54 percent and that of clinical neuropathy by 60 percent.
The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia. Because of this risk, DCCT researchers do not recommend intensive therapy for children under age 13, people with heart disease or advanced complications, older adults, and people with a history of frequent severe hypoglycemia. Persons in the intensive management group also gained a modest amount of weight, suggesting that intensive treatment may not be appropriate for people with diabetes who are overweight. DCCT researchers estimate that intensive management doubles the cost of managing diabetes because of increased visits to a health care professional and the need for more frequent blood testing at home. However, this cost is offset by the reduction in medical expenses related to long-term complications and by the improved quality of life of people with diabetes.

Conclusion
Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM.

Epidemiology of Diabetes Interventions and Complications (EDIC)

Purpose
To examine the long-term effects of conventional vs. intensive diabetes treatment received during the DCCT on the subsequent development and progression of microvascular, neuropathic and cardiovascular complications of type 1 diabetes. This involves studying the influence of genetic factors and other risk factors such as HbA1c, blood pressure, lipid levels, and treatment modalities on the development and progression of these complications.
To examine the impact of intensive control versus standard control on quality of life.
To look at the cost-effectiveness of intensive control.

Study Pattern
EDIC followed the DCCT patient cohort after all patients were converted to intensive insulin therapy.

Results
EDIC researchers reported that the risk of any heart disease was reduced by 42 percent in people who had been in the intensive treatment group. Volunteers in the intensive treatment group also cut their risk of nonfatal heart attack, stroke, or death from cardiovascular causes by 57 percent. Moreover, despite the fact that glycemic control as measured by HbA1c became virtually equivalent between groups, the benefits of early intensive control persisted long after the DCCT ended with continuing benefit of reduced rates of retinopathy progression observed in patients who formerly were in intensive therapy group. Similar risk reductions of othermicrovascular complications such as nephropathy and neuropathy were also observed. Researchers call the long-lasting benefit of tight control “metabolic memory.”

Conclusion
Early optimal control of blood glucose is critically important for long-term ocular and systemic outcome.

United Kingdom Prospective Diabetes Study (UKPDS)

Purpose

Can the risk of cardiovascular and microvascular complications in Type 2 diabetes be reduced by intensive blood glucose control?
In patients with high blood pressure, can the risk of complications be reduced by tight control of blood pressure?
Does any specific treatment for Type 2 diabetes like sulfonylurea drugs, the biguanide drug metformin, or insulin or for high blood pressure like ACE inhibitor (captopril) or β-blocker (atenolol) confer any particular benefit?

Study Pattern
After an initial treatment with diet alone for three months, people with a raised fasting blood glucose were randomly allocated to one of various treatment policies. Some people were allocated to a conventional policy, primarily with diet alone. Moderately high blood glucose levels were accepted into this group. Others were allocated to an intensive policy group aiming for near-normal glucose control, with two different sulphonylureas tablets or to insulin. Overweight people could also be randomised to a tablet called metformin, as an additional option. Each of these treatments has now been shown to be advantageous. People with raised blood pressure as well as diabetes were randomly allocated to a policy aiming for tight blood pressure control, using two treatments that might be thought to be particularly beneficial, an ACE inhibitor or beta-blocker or to a less tight blood pressure control. Both ACE inhibitors and beta-blockers have now been shown to be advantageous.

Results
Intensive blood glucose control reduces the risk of progression of diabetic retinopathy by 17%, need for laser photocoagulation surgery by 29%, development of vitreous hemorrhage by 23% and risk of legal blindness by 16% and early kidney disease by 33%. In addition, there was some evidence, albeit inconclusive, that it reduced the risk of heart attacks and it reduced the risk of requiring an operation for a cataract The therapies studied were each shown to be effective.
Better blood pressure control reduces the risk of death from long-term complications of diabetes by a third, strokes by more than a third and serious deterioration of vision by more than a third.In addition, improved blood pressure also decreased the progression of the small blood vessel disease of diabetes. ACE inhibitors and beta-blockers were each shown to be effective.

Conclusion
The complications of type 2 diabetes, previously often regarded as inevitable, could be reduced by improving blood glucose and/or blood pressure control.

Action to Control Cardiovascular Risk in Diabetes (ACCORD)

Purpose
To test three complementary medical treatment strategies for type 2 diabetes to enhance the options for reducing the still very high rate of major CVD morbidity and mortality in this disease.
To test the effects on major CVD events of intensive glycemia control, of fibrate treatment to increase HDL-cholesterol and lower triglycerides (in the context of good LDL-C and glycemia control), and of intensive blood pressure control (in the context of good glycemia control), each compared to an appropriate control in individuals with type 2 diabetes including those at especially high risk for cardiovascular disease (CVD) events Each treatment strategy will be accompanied by standard advice regarding lifestyle choices, including diet, physical activity, and smoking cessation, appropriate for individuals with diabetes.

Study Pattern
The three specific primary ACCORD hypotheses were as follow. In middle-aged or older people with type 2 diabetes who are at high risk for having a cardiovascular disease (CVD) event because of age, evidence of subclinical atherosclerosis, or existing clinical CVD.

Does a therapeutic strategy that targets a HbA1c of < 6.0% reduce the rate of CVD events more than a strategy that targets a HbA1c of 7.0% to 7.9% (with the expectation of achieving a median level of 7.5%) ?
In the context of good glycemic control, does a therapeutic strategy that uses a fibrate to raise HDL-C/lower triglyceride levels and uses a statin for treatment of LDL-C reduce the rate of CVD events compared to a strategy that only uses a statin for treatment of LDL-C?
In the context of good glycemic control, does a therapeutic strategy that targets a systolic blood pressure (SBP) of < 120 mm Hg reduce the rate of CVD events compared to a strategy that targets a SBP of < 140 mm Hg?

The primary outcome measure for the trial was the first occurrence of a major cardiovascular disease event, specifically nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death.

Secondary hypotheses included treatment differences in other cardiovascular outcomes, total mortality, microvascular outcomes, health-related quality of life, and cost-effectiveness.

Result
The glycemia trial was terminated early in Feb 2008 due to higher mortality in the intensive compared with the standard glycemia treatment strategies. The results were published in June 2008 (N Eng J Med2008;358:2545-59). Study-delivered treatment for all ACCORD participants was stopped on June 30, 2009, and the participants were assisted as needed in transferring their care to a personal physician. The lipid and blood pressure results (as well as updated glycemia results) will be published in early 2010. All participants are continuing to be followed in a non-treatment observational study.

Sorbinil Retinopathy Trial (SRT)

Purpose:

To evaluate the safety and efficacy of the investigational drug sorbinil, an aldose reductase inhibitor, in preventing the development of diabetic retinopathy and neuropathy in persons with insulin-dependent diabetes.

Study Pattern
Initially, patients were using a dosage schedule of one 250-mg tablet daily. Because of several serious hypersensitivity reactions among patients taking sorbinil in clinical trials, dosage schedule was titrated to 25 mg daily for 2 weeks, followed by 75 mg daily for 2 weeks, then 250 mg daily for the duration.

Result
Retinopathy
The course of DR was not significantly different between the sorbinil group and the placebo group. The number of microaneurysms increased at a slightly slower rate in the sorbinil group than in the placebo group. But about 7 percent of the patients assigned sorbinil developed hypersensitivity reactions including toxic epidermal necrolysis, erythema multiforme and stevens Johnson syndrome in the first 3 months.
Neuropathy
Overall, no evidence was found that the early clinical signs and symptoms of diabetic neuropathy were altered by sorbinil.

Conclusion

It is unlikely that sorbinil will achieve prophylactic usage because of the hypersensitivity reactions and outcome similarities between the group treated with sorbinil and the control group.has a clinically important effect on the course of retinopathy in adults with insulin-dependent diabetes of moderate duration. These data are consistent, however, with a slightly slower progression rate in the microaneurysm count among patients assigned to take sorbinil, a finding of uncertain clinical importance.

The Silicone Study

Purpose

To compare the postoperative tamponade effectiveness of intraocular silicone oil with that of an intraocular long-acting gas (initially sulfur hexafluoride [SF6], later perfluoropropane [C3F8]) for the management of retinal detachment complicated by proliferative vitreoretinopathy (PVR), using vitrectomy and associated techniques.
To evaluate the ocular complications that result from the use of silicone oil and gas.

Study pattern
All study patients underwent vitrectomy and were randomized intraoperatively either to silicone oil or to gas. Two groups of eyes were entered into the study: eyes that had not had a prior vitrectomy (Group 1) and those that had undergone previous vitrectomy outside the study (Group 2). End points of the study were visual acuity of 5/200 or greater and macular reattachment for 6 months following the final surgical procedure.

Results
Chronically elevated IOP was more prevalent in silicone oil eyes than in C3F8 gas eyes. Chronic hypotony was more prevalent in C3F8 gas eyes than in silicone oil eyes. The presence of diffuse contraction of the retina anterior to the equator should alert the vitrectomy surgeon that the eye is likely to be hypotonous postoperatively.
In patients undergoing retinotomy, silicone oil and C3F8 gas appeared to be equally effective tamponade modalities. In eyes undergoing retinotomy that have not been previously vitrectomized, silicone oil may initially increase the likelihood of visual success and may decrease the likelihood of hypotony at 6 months; however, long-term observations at 24 months suggested a trend toward worsening in silicone oil-filled eyes and improvement in gas-filled eyes.
The postoperative incidence rates of corneal abnormalities are equivalent between oil and gas.
As part of the study, a Silicone Study classification system for PVR was developed based on the characteristic patterns of retinal distortion produced by the contraction of proliferative membranes on the retina or within the vitreous base.
Eyes with anterior PVR and clinically significant posterior PVR changes had a better visual prognosis if silicone oil rather than C3F8 gas was used.

Conclusion
Overall, silicone oil was superior to sulfur hexafluoride gas and roughly equivalent to perfluoropropane (C3F8) gas in the management of retinal detachment with severe PVR. Despite their overall equivalence, however, certain subgroups of eyes appeared to do better with silicone oil like severe anterior PVR and certain with C3F8 like presence of silicone IOL with open posterior capsule.

Endophthalmitis Vitrectomy Study (EVS)

Purpose

To determine the role of initial pars plana vitrectomy in the management of postoperative bacterial endophthalmitis.
To determine the role of intravenous antibiotics in the management of bacterial endophthalmitis.
To determine which factors, other than treatment, predict outcome in postoperative bacterial endophthalmitis.

Study Pattern
Patient eligibility criteria was presence of bacterial endophthalmitis in an eye that had cataract surgery or lens implantation within 6 weeks of onset of infection and a visual acuity of 20/50 or worse and light perception or better.Patients were randomized to one of two standard treatment strategies for the management of bacterial endophthalmitis. Eyes received either (1) initial pars plana vitrectomy with intravitreal antibiotics, followed by retap and reinjection at 36-60 hours for eyes that did poorly as defined in the study or (2) initial anterior chamber and vitreous tap/biopsy with injection of intravitreal antibiotics, followed by vitrectomy and reinjection at 36-60 hours in eyes doing poorly. In addition, all eyes were randomized to either treatment or no treatment with intravenous antibiotics.

Results
There was no difference in final visual acuity or media clarity with or without systemic antibiotics. If patients presented with hand motions or better acuity, there was no difference in visual outcome with or without an immediate 3 port pars plana vitrectomy. However, vitrectomy tripled (33 percent compared with 11 percent) the frequency of achieving 20/40 or better acuity; approximately doubled (56 percent compared with 30 percent) the chance of achieving 20/100 or better acuity; and decreased by more than one-half (20 percent compared with 47 percent) the frequency of severe visual loss in the subgroup of patients who presented with visual acuity of light perception only. These differences were statistically significant.

Conclusion
Initial management for patients who meet EVS entry criteria should include 3 port pars plana vitrectomy if patients present with vision worse than hand motions, but that an initial vitreous tap/biopsy should generally be sufficient if presenting vision is hand motions or better. Systemic antibiotics were not of benefit in this study, although all patients should receive intravitreal antibiotics.

Optic Neuritis Treatment Trial (ONTT)

Purpose

To assess the beneficial and adverse effects of corticosteroid treatment for optic neuritis.
To determine the natural history of vision in patients who suffer optic neuritis.
To identify risk factors for the development of multiple sclerosis in patients with optic neuritis.

Study pattern
Patient eligibility criteria included acute unilateral optic neuritis with visual symptoms for 8 days or less.The treatment phase of the study was called the Optic Neuritis Treatment Trial (ONTT), whereas the current long-term followup phase is called the Longitudinal Optic Neuritis Study (LONS). Patients were randomized to one of the three following treatment groups, each regimen followed by a short oral taper.

Oral prednisone (1 mg/kg/day) for 14 days
Intravenous methylprednisolone (250 mg every 6 hours) for 3 days, followed by oral prednisone (1 mg/kg/day) for 11 days
Oral placebo for 14 days

Results

Brain MRI is a powerful predictor of the early risk of multiple sclerosis after optic neuritis.
Visual recovery begins rapidly (within 2 weeks) in most optic neuritis patients without any treatment, and then improvement continues for up to 1 year. Although most patients recover to 20/20 or near 20/20 acuity, many still have symptomatic deficits in vision.
Treatment with high-dose, intravenous corticosteroids followed by oral corticosteroids accelerated visual recovery but provided no long-term benefit to vision. It provided a short-term reduction in the rate of development of multiple sclerosis, particularly in patients with brain MRI changes consistent with demyelination. However, by 3 years of followup, this treatment effect had subsided.
Treatment with standard-dose oral prednisone alone did not improve the visual outcome and was associated with an increased rate of new attacks of optic neuritis.

Conclusion
Treatment with oral prednisone in standard doses should be avoided, but treatment with intravenous methylprednisolone should be considered, particularly if brain MRI demonstrates multiple signal abnormalities consistent with multiple sclerosis or if a patient needs to recover vision rapidly. However, as with the decision on whether to perform a brain MRI, the decision as to whether to prescribe this treatment must be made on an individual patient basis. Prescribing no treatment for acute optic neuritis also is a viable option.

Ischemic Optic Neuropathy Decompression Trial (IONDT)

Purpose:

To assess the safety and efficacy of optic nerve sheath decompression surgery for non-arteritic ischemic optic neuropathy (NAION).

Study Pattern

Patient eligibility criteria was age 50 years or older, with acute NAION and visual symptoms for 14 days or less since the onset of symptoms, and visual acuity worse than or equal to 20/64.
Patients were assigned to receive surgery with optic nerve sheath decompression or careful followup and the improvements in visual acuity at 6 month were compared. A cohort of patients, with a baseline visual acuity of better than 20/64 are also being followed to better understand the natural history of the disease, including second eye involvement.

Results

Patients assigned to surgery did no better when compared with patients assigned to careful followup. Patients receiving surgery had a significantly greater risk of losing three or more lines of vision at 6 months

Conclusion

Optic nerve decompression surgery for NAION is not effective, may be harmful, and should be abandoned.

All randomized and natural history patients are being followed for the purpose of learning more about the natural history of NAION and the incidence of NAION in the second eye.

The International Optic Nerve Trauma Study (IONTS)

Purpose

To compare visual outcomes for patients with TON treated with observation, systemic steroids, or optic canal decompression.

Study pattern

Patients with a history of traumatic head injury, subnormal visual function, and an afferent pupillary defect.were assigned to no treatment (observation) versus corticosteroids or surgical decompression within 7days of traumatic event.

Results

Visual acuity increased by more than 3 lines in 32% of the surgery group, 52% of the corticosteroid group, and 57% of the observation group. However, the study was nonrandomized and uncontrolled, and the small numbers.

Conclusion

The study found no difference in the final visual acuity and commented that the decision to treat or not treat should be made on an individual patient basis

Treatment is based on visual acuity and response to intravenous corticosteroid therapy. Patients are initially started on systemic methylprednisolone therapy. Optic canal decompression is indicated (1) if visual acuity does not improve to 20/400 or better despite 24-48 hours of steroid therapy or (2) if visual acuity is 20/200 or better but deteriorates during or after completion of steroid therapy.

Collaborative Ocular Melanoma Study (COMS)

Purpose:

To determine which of two standard treatments, enucleation or brachytherapy, is more likely to prolong survival of patients with medium-sized choroidal melanoma.
To determine whether preoperative radiation prolongs life for patients whose eyes with large choroidal melanoma are enucleated.
To assess the natural history of small choroidal melanomas.

Study design:

COMS is a 3-arm study that includes two multicenter randomized clinical trials for medium and large melanomas and one non randomized observational study of small choroidal melanomas since patient group with small choroidal melanoma was not large enough to be eligible for the COMS clinical trials.
Small choroidal melanomas were 1.5 – 2.4 mm in apical thickness and 5 -16 mm in diameter.Medium choroidal tumors were 2.5 – 10 mm in thickness and no more than 16 mm in longest base diameter. Large tumors were greater than 10 mm in height or greater than 16 mm in basal diameter.
Patients with small choroidal melanomas were enrolled in a registry and followed clinically. Patients with medium sized choroidal melanomas are randomized with equal probability to either enucleation or brachytherapy using iodine-125. Patients with large tumors are randomized with equal probability to either enucleation or a 5 day course of external beam radiation therapy (20 Gy) followed by enucleation. Time to death is the primary outcome; patients will be followed for at least 10 years or until death. Secondary outcomes included metastasis-free survival, cancer-free survival, and years of useful vision..

Results:
Of small choroidal melanomas initially managed by observation, 21% demonstrated growth by 2 years and 31% by 5 years.
Patients with medium sized choroidal melanomas have similar survival rates for two alternative treatments for primary eye cancer--radiation therapy and enucleation.
Patients with large eye melanomas had similar five-year survival rates regardless of whether they were treated with radiation prior to removal of the eye or had their eye removed without prior radiation therapy.

Conclusion:
The findings of small sized melanoma study underscores the need to follow patients with small melanomas closely after diagnosis.
Enucleation has no advantage over brachytherapy for medium sized choroidal melanomas.
There is no advantage of giving external radiation prior to enucleation for patients with large choroidal melanomas.

Cryotherapy for Retinopathy of Prematurity Study (CRYO-ROP)

Purpose:

To determine the safety and efficacy of trans-scleral cryotherapy of the peripheral retina in certain low birth-weight infants with retinopathy of prematurity (ROP) for reducing blindness from ROP.
To determine the long-term outcome for eyes that had severe (threshold) ROP, both with and without cryotherapy.

Study design
Infants eligible were those with birth weights less than 1,251 grams and presence of threshold disease which was defined as stage 3+ of the International Classification of Retinopathy of Prematurity occupying five or more contiguous or eight cumulative 30° sectors [clock hours] of stage 3 ROP in zone I or II in the presence of plus disease. One eye of eligible infants was randomly selected for treatment with contiguous non-overlapping spots of transscleral cryotherapy to the entire anterior cuff of avascular retina. The average number of individual freezes used was 50.

Results
The CRYO-ROP study reports at 3 months and 1, 3.5, 5.5, 10 and 15 years showed that unfavourable structural outcomes (defined by categorising ROP residua in the posterior retina and which include retinal detachment) were less in the treated group than in the untreated group at all time points. Cryotherapy reduced by approximately one-half the risk of unfavorable retinal outcome from threshold ROP. Although the surgery was stressful, no major complications occurred during or following treatment.

Conclusion
Cryotherapy reduces the risk of unfavorable retinal and functional outcome from threshold ROP.

Current status
Laser photocoagulation was not studied in cryo ROP study, since no practical laser delivery instrument had been developed at the time of this study. Afer its introduction, laser therapy gained acceptance as an alternative to cryotherapy. When LIO systems became available around 1990, the only laser offered was an argon photocoagulator. Now diode laser photocoagulator (810 nm) has become more popular than argon because of its portability and a lower incidence of postoperative cataract formation.
The indication of ablative treatment have now been revised according to the Early Treatment for Retinopathy of Prematurity Randomized Trial study. The finding of threshold ROP, as defined in the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity, is no longer the preferred time of intervention.

Early Treatment for Retinopathy of Prematurity Study (ETROP)

Purpose:

To determine whether earlier treatment in carefully selected cases will result in an overall better visual outcome and retinal structural outcomes than treatment at the conventional CRYO-ROP threshold point in the disease.

Study design
Earlier treatment is defined as retinal ablation administered to the avascular retina when an eye reaches high risk prethreshold retinopathy of prematurity (ROP).

Term	Definition
Prethreshold	Zone I, any stage ROP less than threshold Zone II, Stage 2 with plus disease Zone II, Stage 3 without plus disease Zone II, Stage 3 with plus disease, but less than the criteria for threshold disease.

The level of risk was determined by a risk analysis programme (RM-ROP2)122 which used, among other factors, degree of ROP (stage, zone and presence of plus), rate of ROP progression, birthweight, gestational age and ethnicity to classify eyes as at either ‘high-risk’ (i.e. ³15% chance) or ‘low-risk‘ (<15% chance) of an unfavourable outcome without treatment. Infants with bilateral high-risk prethreshold ROP had one eye randomized to early treatment with the fellow eye managed conventionally (control eye). In asymmetric cases, the eye with high-risk prethreshold ROP was randomized to early treatment or conventional management.

Type I Prethreshold ROP (High Risk)	Zone I, any Stage ROP with plus disease Zone I, Stage 3 with or without plus Zone II, Stage 2 or 3 ROP with plus disease
Type II Prethreshold ROP (Low risk)	Zone I, Stage 1 or 2 ROP without plus disease Zone II, Stage 3 ROP without plus disease

Results
Compared with conventional management, early treatment was associated with decreased risk at nine months of poor grating visual acuity (19.5% vs. 14.5%) and of structural damage to the eye (15.6% vs. 9.1%).
Conclusion
The results showed an overall significant benefit for the early treatment of eyes with high-risk prethreshold disease.

Supplemental Therapeutic Oxygen for Prethreshold Retinopathy Of Prematurity (STOP-ROP Trial)

Purpose:

To determine the efficacy and safety of supplemental therapeutic oxygen for infants with prethreshold retinopathy of prematurity (ROP) to reduce the probability of progression to threshold ROP and the need for peripheral retinal ablation.

Study design
Premature infants with prethreshold ROP were randomized to a conventional oxygen arm with pulse oximetry targeted at 89% to 94% saturation or a supplemental arm with pulse oximetry targeted at 96% to 99% saturation, for at least 2 weeks, and until both eyes were at study endpoints. An adverse ophthalmic endpoint for an infant was defined as reaching threshold criteria for laser or cryotherapy in at least 1 study eye. A favorable ophthalmic endpoint was regression of the ROP into zone III for at least 2 consecutive weekly examinations or full retinal vascularization.

Results
The rate of progression to threshold in at least 1 eye was 48% in the conventional arm and 41% in the supplemental arm. Rates of severe sequelae were similar in both treatment arms. A subgroup analysis suggested that infants without plus disease may be more responsive to supplemental therapy than infants with plus disease. Pneumonia and/or exacerbations of chronic lung disease occurred in more infants in the supplemental arm (8.5% conventional vs 13.2% supplemental). Also, fewer conventional than supplemental infants remained hospitalized, on oxygen and on diuretics. Growth and developmental milestones did not differ between the 2 arms.

Conclusion
Use of supplemental oxygen did not cause additional progression of prethreshold ROP but also did not significantly reduce the number of infants requiring peripheral ablative surgery. However, it increased the risk of adverse pulmonary events. The finding that suggested a benefit of supplemental oxygen in prethreshold ROP without plus disease requires additional study. Although the relative risk/benefit of supplemental oxygen for each infant must be individually considered, clinicians need no longer be concerned that supplemental oxygen will exacerbate active prethreshold ROP.

The Effects of Light Reduction on Retinopathy of Prematurity (LIGHT-ROP)

Purpose:

To evaluate the effect of ambient light reduction on the incidence of retinopathy of prematurity (ROP).

Study design
Infants weighing less than 1,251 grams at birth were prospectively randomized within 24 hours of birth to wear goggles or not to wear goggles. Goggles contain 97 percent near neutral density filters and were worn until the infant reached either 31 weeks gestational age or 4 weeks postnatal age, whichever was longer. The goggled and nongoggled infants were exposed to the same ambient light conditions within any given Study Center.

Results
ROP was diagnosed in 54 percent in the goggles group and 58 percent in the control group.

Conclusion
A reduction in the ambient-light exposure does not alter the incidence of ROP.

Branch Vein Occlusion Study (BVOS)

Purpose:

To determine whether scatter argon laser photocoagulation can prevent the development of neovascularization.
To determine whether peripheral scatter argon laser photocoagulation can prevent vitreous hemorrhage.
To determine whether macular argon laser photocoagulation can improve visual acuity in eyes with macular oedema reducing vision to 20/40 or worse.

Study design
Patient eligibility criteria were onset of signs and/or symptoms of BRVO less than 18 months before the initial visit, vision of 5/200 or better, and sufficient clarity of the ocular media to permit confirmation of the condition with fundus photography. One-half of the patients were randomly assigned to treatment with argon laser photocoagulation; the other one-half remained untreated as controls.

Results
Argon laser treatment improved visual acuity significantly in patients with macular oedema and vision 20/40 or worse,with a gain of at least two lines of visual acuity in more laser-treated eyes compared to untreated eyes..
In addition, peripheral scatter argon laser photocoagulation reduced the likelihood of vitreous hemorrhage compared to untreated eyes. Scatter treatment before the development of neovascularization was shown not to be beneficial.

Conclusion
Argon laser treatment is recommended in patients with macular oedema and vision 20/40 or worse. Scatter treatment is recommended after development of neovascularization.

Central Vein Occlusion Study (CVOS)

Purpose:

To determine whether photocoagulation therapy can help prevent iris neovascularization in eyes with central vein occlusion (CRVO) and evidence of ischemic retina.
To assess whether grid-pattern photocoagulation therapy will reduce loss of central visual acuity due to macular oedema secondary to CRVO.
To develop new data describing the course and prognosis for eyes with CRVO.

Study design
Eligibility criteria were age 21 or older and patients willing to return for followup visits for 3 years following assignment into the appropriate group and randomization. Patients with retinal vascular disease other than that specified in the criteria, such as diabetic retinopathy, were ineligible. Patients with macular disease other than that due to CRVO were ineligible for that portion of the study.

Results
Macular grid photocoagulation was effective in reducing angiographic evidence of macular oedema but did not improve visual acuity in eyes with reduced vision due to macular oedema from CRVO.

Conclusion
Argon laser treatment does not improve visual acuity in patients with macular oedema. Panretinal photocoagulation treatment is recommended after development of neovascularization.

Herpetic Eye Disease Study (HEDS)

Purpose:

To evaluate the efficacy of topical corticosteroids in treating herpes simplex stromal keratitis in conjunction with topical trifluridine.
To evaluate the efficacy of oral acyclovir in treating herpes simplex stromal keratitis in patients receiving concomitant topical corticosteroids and trifluridine.
To evaluate the efficacy of oral acyclovir in treating herpes simplex iridocyclitis in conjunction with treatment with topical corticosteroids and trifluridine.
To determine the efficacy of low-dose oral acyclovir in preventing recurrent HSV eye infection in patients with previous episodes of herpetic eye disease.

Study Design:

HEDS consisted of three randomized, placebo-controlled trials. Patients with active HSV stromal keratitis who had not used a topical corticosteroid in the preceding 10 days were randomized to treatment with topical prednisolone phosphate drops or topical placebo drops. Patients with active HSV stromal keratitis who already were being treated with a topical corticosteroid were randomized either to oral treatment with 200 mg acyclovir capsules (400 mg five times daily) for 10 weeks or to the identical dose of placebo capsules. Patients with active HSV iridocyclitis were randomized either to oral treatment with 200 mg acyclovir capsules (400 mg five times daily) for 10 weeks or to the identical dose of placebo capsules. Results: Compared with the patients in the placebo group, the patients who received prednisolone phosphate drops had faster resolution of the stromal keratitis and fewer treatment failures. There was no apparent benefit in the addition of oral acyclovir to the treatment regimen of a topical corticosteroid and a topical antiviral for stromal keratitis. Treatment failures occurred at a higher rate in the placebo group than in the acyclovir group in HSV iridocyclitis.

During the 12 months of treatment, oral acyclovir reduced the incidence of epithelial keratitis from 11 percent to nine percent, and the incidence of stromal keratitis from 13 percent to eight percent; four percent of patients in the acyclovir group and nine percent in the placebo group had more than one recurrence.

Conclusion:

There was no benefit in the addition of oral acyclovir for stromal keratitis. There is benefit in adding oral acyclovir to the treatment of HSV iridocyclitis in patients receiving topical corticosteroids.Oral Acyclovir reduce the probability of recurrence of herpes in patients who had the infection in the previous year.

Age-Related Eye Disease Study (AREDS)

Purpose

To assess the clinical course, prognosis, and risk factors of age-related macular degeneration (AMD) and cataract.
To evaluate the effects of pharmacologic doses of antioxidants and zinc on the progression of AMD and of antioxidants on the development and progression of lens opacities.

Study DesignMen and women between the ages of 55 and 80 years whose macular status ranges from no evidence of AMD in either eye to relatively severe disease with vision loss in one eye but good vision in the fellow eye (20/30 or better) were eligible for the study. Eligible patients were randomized to treatment with placebo, antioxidants, zinc, or antioxidants plus zinc, and were followed for a minimum of 5 years.

ResultsPeople at high risk of developing advanced stages of AMD lowered their risk by about 25 percent when treated with a high-dose combination of vitamin C, vitamin E, beta-carotene, and zinc. In the same high risk group -- which includes people with intermediate AMD, or advanced AMD in one eye but not the other eye -- the nutrients reduced the risk of vision loss caused by advanced AMD by about 19 percent. For those study participants who had either no AMD or early AMD, the supplements did not provide an apparent benefit.
In the cataract portion of the study, researchers discovered that the same nutrients had no significant effect on the development or progression of age-related cataract.

ConclusionPeople at high risk of developing advanced stages of AMD are benefitted by treatment with a high-dose combination of vitamin C, vitamin E, beta-carotene, and zinc.

Macular Photocoagulation Study(MPS)

PurposeThe Macular Photocoagulation Study (MPS) consisted of three sets of randomized, controlled clinical trials.
Argon Study:To determine whether argon blue-green laser photocoagulation of leaking abnormal blood vessels in choroidal neovascular membranes outside the fovea (200 to 2,500 microns from the center of the foveal avascular zone [FAZ]) is of benefit in preventing or delaying loss of central vision in patients with age-related (senile) macular degeneration (AMD), presumed ocular histoplasmosis (POH), and idiopathic neovascular membranes (INVM)
Krypton Study:To determine whether krypton red laser photocoagulation of choroidal neovascular lesions with the posterior border 1 to 199 microns from the center of the FAZ is of benefit in preventing or delaying large losses of visual acuity in patients with AMD, POH, and INVM.
Foveal Study:To determine whether laser photocoagulation is of benefit in preventing or delaying further visual acuity loss in patients with new (never treated) or recurrent (previously treated with laser photocoagulation) choroidal neovascularization under the center of the FAZ.

Study DesignAMD patients were 50 years of age or older and had drusen visible in the macula of at least one eye. POH patients were at least 18 years old and had at least one characteristic histo spot in one or both eyes. INVM patients were at least 18 years old and had no evidence of AMD, POH, angioid streaks, high myopia, diabetic retinopathy, or any other condition that could be the cause of the neovascularization. In particular, INVM patients had neither drusen greater than MPS Standard Photograph No. 1.1 nor histo spots in either eye.

In each randomized trial conducted by the MPS Group, focal laser photocoagulation was compared to observation without treatment. Patients were assigned to laser treatment or to observation with equal probability. The first set of MPS randomized trials, the Argon Study, focused on the effectiveness of photocoagulation with argon blue-green laser in eyes with discrete extrafoveal choroidal neovascularization.
After the initiation of the Argon Study, a new krypton red laser became available. The Krypton Study design was analogous to the Argon Study, with the investigation of three underlying conditions, except that CNV was closer to the FAZ center.
The third set of MPS clinical trials, the Foveal Study, was designed to determine whether laser photocoagulation was effective for delaying or preventing further visual acuity loss in AMD patients who have subfoveal CNV. Among patients assigned to laser treatment in the Foveal Study, argon laser treatment was compared with krypton red laser treatment of these lesions.

ResultsArgon Study: Argon laser treatment, as applied in the study, dramatically reduced severe visual acuity loss in these conditions.
Krypton Study: There was a beneficial effect of krypton red laser treatment in eyes with AMD. The benefit was most pronounced in normotensive patients and was not apparent among hypertensive patients.
Foveal Study: Patients treated with laser had larger losses of visual acuity from baseline than untreated eyes. Laser treatment was particularly effective for subfoveal recurrent CNVM. Overall, eyes receiving direct laser treatment to the fovea for new CNV immediately lost more visual acuity than observed eyes. However, the amount of visual acuity loss in observed eyes increased to the level of loss in treated eyes at 12 months and exceeded the level thereafter.

ConclusionFor patients with any of the three above conditions, eyes with well-demarcated areas of classic choroidal neovascularization, as defined by fluorescein angiography, had a better visual prognosis when treated with laser photocoagulation, performed according to MPS guidelines, than when managed by observation. These outcome data apply to all three conditions when the position of the neovascularization is extrafoveal or juxtafoveal, that is, when the CNV does not involve the center of the fovea.
Eyes with age-related macular degeneration and subfoveal choroidal neovascularization benefited more from laser treatment than from observation when MPS eligibility guidelines and treatment protocol were observed. Eyes with smaller lesions and worse initial visual acuity had greater and earlier benefits of laser treatment. Eyes with large subfoveal neovascular lesions and good initial visual acuity are not good candidates for focal laser photocoagulation.

Ocular Hypertension Treatment Study (OHTS)

Purpose

To determine whether medical reduction of intraocular pressure prevents or delays the onset of glaucomatous visual field loss and/or optic disc damage in ocular hypertensive subjects judged to be at moderate risk for developing open-angle glaucoma.
To produce natural history data to assist in identifying patients at most risk for developing open-angle glaucoma and those most likely to benefit from early medical treatment.
To quantify risk factors for developing open-angle glaucoma among ocular hypertensive subjects.

Study Design

Men and nonpregnant women between the ages of 40 and 80 with IOP greater than or equal to 24 mm Hg but less than or equal to 32 mm Hg in at least one eye and IOP greater than or equal to 21 but less than or equal to 32 mm Hg in the fellow eye, as well as normal visual fields and optic discs were eligible for the trial. Patients presenting with best-corrected visual acuity worse than 20/40 in either eye, previous intraocular surgery, a life-threatening or debilitating disease, secondary causes of elevated IOP, angle-closure glaucoma or anatomically narrow angles, other diseases that can cause visual field loss, background diabetic retinopathy, optic disc abnormalities that can produce visual field loss or obscure the interpretation of the optic disc, or unwillingness to undergo random assignment were excluded from the trial.

Ocular hypertensive subjects judged to be at moderate risk of developing primary open-angle glaucoma were randomly assigned to either close observation only or a stepped medical regimen. Medical treatment consists of all commercially available topical antiglaucoma agents.

ResultsIn univariate analyses, baseline factors that predicted the development of primary open-angle glaucoma (POAG) included older age, race (African American), sex (male), larger vertical cup-disc ratio, larger hoizontal cup-disc ratio, higher intraocular pressure, greater Humphrey visual field pattern standard deviation, heart disease, and thinner central corneal measurement. In multivariate analyses, baseline factors that predicted POAG included older age, larger vertical or hotrizontal cup-disc ratio, higher intraocular pressure, greater pattern standard deviation, and thinner central corneal meaturement.

ConclusionTopical ocular hypotensive medication was effective in delaying or preventing onset of POAG in individuals with elevated IOP. Although this does not imply that all patients with borderline or elevated IOP should receive medication, clinicians should consider initiating treatment for individuals with ocular hypertension who are at moderate or high risk for developing POAG.

Early Manifest Glaucoma Trial (EMGT)

Purpose

The primary purpose is to compare the effect of immediate therapy to lower the intraocular pressure (IOP) versus late or no treatment on the progression of newly detected open-angle glaucoma, as measured by increasing visual field loss and/or optic disc changes.
The secondary purposes are to determine the extent of IOP reduction attained by treatment, to explore factors that may influence glaucoma progression, and to describe the natural history of newly detected glaucoma.

Study Design
Patient eligibility criteria were newly detected and untreated chronic open-angle glaucoma with repeatable visual field defects by Humphrey perimetry. Patients were randomized to treatment with the beta blocker Betaxolol and argon laser trabeculoplasty (treated group) or to no initial treatment (control group) with close followup of both groups. The study outcome was glaucoma progression, which was based on specific criteria derived from analyses of Humphrey visual fields and masked evaluations of disc photographs.

Results

Results showed considerable beneficial effects of treatment that significantly delayed progression. Whereas progression varied across patient categories, treatment effects were present in both older and younger patients, high- and normal-tension glaucoma, and eyes with less and greater visual field loss.

Conclusion
There is beneficial effect of immediate therapy to lower the intraocular pressure (IOP) versus late or no treatment on the progression of newly detected open-angle glaucoma.

Advanced Glaucoma Intervention Study (AGIS)

Purpose

To assess the outcomes of trabeculectomy and argon laser trabeculoplasty in eyes that have failed initial medical treatment for glaucoma.

Study Design

Men and women between the ages of 35 and 80 with open-angle glaucoma that was not successfully controlled by medication were eligible for enrollment. Eligible eyes are randomly assigned to one of two intervention sequences: (1) trabeculectomy, followed by argon laser trabeculoplasty (ALT) should trabeculectomy fail, followed by a second trabeculectomy should ALT fail; or (2) ALT, followed by trabeculectomy should ALT fail, followed by another trabeculectomy should the first trabeculectomy fail. Antifibrotic agents may be used as an adjunct to trabeculectomy, but only in eyes with a previous history of invasive surgery.

Results

Blacks and whites differed in the way they benefited from the two treatment programs. The vision in eyes of black patients with advanced glaucoma tended to be better preserved in the program that started with the laser surgery. From initial treatment through seven years of follow-up, the average percent of eyes in black patients with decrease of vision was 28 percent in the program starting with laser surgery, as compared with 37 percent in the program starting with a trabeculectomy.
Through the first four years, the vision in eyes of white patients with advanced glaucoma tended to be better preserved in the program starting with laser surgery. Thereafter, however, the reverse was true; seven years after the initial treatment, the average percent of eyes in white patients with decrease of vision was 31 percent in the program starting with a trabeculectomy, as compared with 35 percent in the program starting with laser surgery.

Conclusion
It is recommended that black patients with advanced glaucoma begin a treatment program that starts with laser surgery, which is consistent with current medical practice. In contrast, white patients with advanced glaucoma who have no life-threatening health problems should begin a treatment program that starts with trabeculectomy. This recommendation is inconsistent with current medical practice."

Collaborative Initial Glaucoma Treatment Study (CIGTS)

Purpose
To compare the long-term effect of treating newly diagnosed open-angle glaucoma with standard medical treatment versus filtration surgery.

Study Design
Patients ranged in age from 25 to 75 with an intraocular pressure of 20 mm Hg or greater and evidence of optic nerve damage and/or visual field loss in one or both eyes. The ocular findings must exclude causes of glaucoma other than primary open-angle glaucoma, pigmentary glaucoma, or pseudoexfoliation glaucoma.

Eligible patients were randomized to receive either a stepped medication treatment regimen or filtration surgery to control their OAG. Patients randomized to the medication treatment arm are receiving a stepped regimen of topical medications, beginning with a single agent (typically a beta blocker), with additional medications added upon documented lack of intraocular pressure control or evidence of progressive visual field loss.

Results
Both treatment groups had substantial and sustained reduction in IOP from baseline with the surgical group running IOPs about 2-3 points lower than the medical group. The surgical group had more visual field loss and more visual acuity loss in the first 3 years of the Study, but these differences largely disappeared in years 4 and 5 of follow-up. The surgery group had more cataract extractions than the medical group. Quality of life results indicated that both groups were satisfied with their treatment. While the surgery group reported more local eye symptoms such as feeling something in the eye, most such symptoms were not sustained beyond the first 2-3 years of follow-up.

Conclusion
Based on these interim follow-up data, the investigators do not recommend changes to current approaches to managing newly diagnosed open-angle glaucoma patients. Longer follow-up is needed before specific treatment recommendations can be made in a chronic disease like glaucoma.

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Dr. Aditi Gupta, Dr. Parthopratim Dutta Majumder

Sankara Nethralaya, Chennai

Compiled by: Dr. Aditi Gupta, Dr.Parthopratim Dutta Majumder

Studies and Trials

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