Handbook of Clinical Trials in Ophthalmology Vinod Kumar, Neha Goel, Pooja Shah, AK Gupta
Page numbers followed by t refer to table.
Acetonide 111
ACG See Angle closure glaucoma
Acute spinal cord injury, treatment of 385
Acyclovir 3
prevention trial 3
Advanced glaucoma 37
intervention study 36
Aflibercept 118, 174, 175
group 174, 176
Age-related choroidal neovascularization 233
Age-related eye disease study 273, 276, 282
Age-related macular degeneration 109, 171, 186, 188, 194, 195, 202, 237, 249, 253, 257, 258, 273, 275
clinical trials in 186, 207, 245t, 253, 273, 281t
prevention trial, complication of 278, 282
subfoveal neovascular 220
treatment of 191
trials 230
Ahmed glaucoma valve 49
Albuminuria 81
Allergen 132
Allograft reaction episodes 12
Amblyopia 328, 337
clinical trials in 328
treatment 359
index 330
study 328, 331335, 338, 340, 342344, 346, 347, 349, 350, 352355, 357360, 363t
vision therapy for 349
Amblyopic eye 363t
Amikacin 296
Andhra Pradesh Eye Disease Study 59
Angioid streaks 188
Angle closure glaucoma 60, 64, 65t, 74
diagnosis of 58
Antiangiogenic drugs 133, 135
Antiglaucoma medications 14, 45
Antihypertensive drug therapy, moderate 85
Anti-retroviral therapy, active 402, 412
Anti-vascular endothelial growth factor 109, 210, 309
therapy 109, 120
treatment 147
Applanation tonometry 62
Aravind Comprehensive Eye Survey 61
Argon laser
trabeculoplasty 27
treatment 39
Argon study 186, 188
Aspergillus species 6
Aspirin 97
Atenolol 83
Atropine 331, 339, 347
eye drops 346
protocol 329
Autorefraction 127
Avastin 227, 228, 310
Bacterial endophthalmitis 295
management of 295
postoperative 295
Bacterial keratitis 8
Baseline vision 119
BCVA See Best corrected visual acuity
Benzoporphyrin 190
Best-corrected visual acuity 31, 53, 101, 110, 127, 132, 141, 151, 183, 201, 202, 219, 224, 255, 271, 389
score 194
Beta blocker betaxolol 27
Beta radiation epiretinal therapy 264
Bevacizumab 109, 118, 140, 146, 147, 174, 175, 227, 228, 230, 231, 237, 309
group 139
treatment 175
use of 140
Bilateral refractive amblyopia 343
treatment of 344
Biopsy 296
Blepharitis 4
glucose 86
control 83
group B 199
pressure 86
control 85, 88, 89
duration of 79
samples 12
tests 374
Brain, magnetic resonance imaging of 376
Branch retinal vein 165, 177
occlusion 153, 183
Branch vein occlusion study 153
Brolucizumab 148, 243
BRVO See Branch retinal vein occlusion
groups 44
results of 43
Captopril 83
Cardiovascular disease, risk of 97
Cataract 145, 198, 276, 405
extraction 42, 43, 84
formation 146
grading 59
progression 170
surgery 67, 105, 114, 115, 145, 325
Ceftazidime 296
Center for Disease Control and Prevention 403
Central corneal
measurement 31
scarring 10
thickness 53, 166
Central foveal thickness 127, 151, 183, 220
Central keratometry 16
Central macula 122
Central macular thickness 127, 140, 146, 256
Central nervous system 372
Central retinal
thickness 137, 151, 217, 219, 239
vein occlusion 54, 156, 167, 171, 173, 178, 183
Central subfield macular thickness 166
Central vein occlusion study 156
Central-involved diabetic macular edema 121
treatment for 120
Cerebrovascular accident 135, 136
CFT See Central foveal thickness
Chennai Glaucoma Study 63
Choriocapillaris 190
Choroidal melanoma 396, 398
Choroidal neovascularization 25, 202, 203t, 207, 210, 249, 253, 257, 258, 264, 279, 282
Chronic inflammation, cycle of 15
Clear lens extraction 45, 47
Clinically isolated syndrome 375
Clinically significant macular edema 88, 95, 101, 151
CMT See Central macular thickness
Collaborative initial glaucoma treatment study 29
Collaborative ocular melanoma study 396, 400t
Color vision 93
Confirmed microbiologic growth 297
Conjunctival hemorrhage 141, 172, 217
Conjunctival sac 52
Conjunctivitis 4
Contact lenses 16, 324
Contralateral eye involvement 406
Contrast sensitivity testing 303
Cornea 40
clinical trials in 1, 20t
donor study 13
Corneal allograft 12
Corneal astigmatism 16
Corneal endothelial cell density 13
Corneal scarring 10
Corneal tissue 1
Corneal transplantation 12
studies, collaborative 11
Corneal ulcers trial, steroid in 8
Corticosteroid 120, 131
treatment 2
Cotton-wool spots 91
Creatinine clearance 86
CRT See Central retinal thickness
CRVO See Central retinal vein occlusion
Cryotherapy 301, 303, 304
multicenter trial of 301
CSME See Clinically significant macular edema
Cycloplegic refraction 16
Cytomegalovirus 402, 403, 405407, 409, 410, 412
De novo glaucoma procedure 51
Deferred panretinal photocoagulation 116
Dense macular hemorrhage 162
Denver developmental screening test 306
Dexamethasone 132, 144, 145, 146148, 168, 175, 177179
dose of 169
group 178
implant 147
intravitreal implant 168
single-dose 177
complications of 80
type 2 85
control 88, 113
and complications trial 80
duration of 79
effect of 113
epidemiology of 88
interventions and complications, epidemiology of 82
macula in 132
related deaths 85
treatment of 80
Diabetes mellitus 134, 151
insulin-dependent 88
non-insulin-dependent 85
type 1 141, 142
type 2 79, 83, 96, 141, 142
Diabetic macular edema 101, 103, 127, 136, 137, 143, 144, 146, 147, 151
development of 107
focal photocoagulation for 111
management of 139, 198
mild 106
pharmacotherapy in 149t
study, center-involved 114
treatment for 108110, 115, 134
vision-impairing 118
Diabetic retinopathy 7880, 83, 86, 87t, 101, 103, 115, 127, 131, 153, 188
clinical research network 103
clinical trials in 78, 90, 103, 131
landmark trials in 101t
regression of 91
risk of 121
study 90, 101
vitrectomy study 98, 101
Diabetic vascular complications 85
Disc stereophotographs 39
Disease-modifying therapies 376
Diurnal intraocular pressure 69
DME See Diabetic macular edema
Docosahexaenoic acid 282
Donor cornea, characteristics of 14
Dorzolamide 34
DR See Diabetic retinopathy
DRS See Diabetic retinopathy study
DRVS See Diabetic retinopathy vitrectomy study
Dry eye 15
disease 15
symptoms 15
Early lens extraction 45, 47
Early manifest glaucoma trial 27, 73
Early proliferative retinopathy 96
Early treatment diabetic retinopathy 101
study 46, 93, 133, 159, 291, 300
chart 256, 263
vision test 328
Edema, ranibizumab for 132
Eicosapentaenoic acid 22, 276
EMGT See Early manifest glaucoma trial
Emotional stress 4
Endophthalmitis 106, 117, 122, 138, 254
vitrectomy study 295, 299, 300t
Endothelial damage 190
Endothelial function 16
Endothelial tight junction proteins 168
Epimacular brachytherapy 264
Epiretinal membrane 18, 405
Epithelial keratitis 4
ETDRS See Early treatment diabetic retinopathy study
European Glaucoma Prevention Study 32, 33
Expanded disability status scale 379, 382, 383
Extracapsular cataract extraction 299
Eye 30, 94, 99, 100, 120, 170, 188
affected 6
course of 35
indicated for 97
involvement, second 406
natural history for 160
nepafenac in 115
number of 117
pain 141, 172
photocoagulation for 92
progression of 108
refractory 147, 148
treatment-naive 176
untreated 188
Fasting plasma glucose 84
Fibrocellular tissue 200
Fibrovascular proliferations 99
Fibrovascular tissue 200
Filtering surgery 35
Financial stress 4
First trabeculectomy fail 36
Fleischer's ring 10
Fluocinolone acetonide 143
sustained-release 131
Fluorescein angiography 138, 159, 187, 188, 211, 225, 235
Fluorouracil filtering surgery study 40
Focal laser photocoagulation 190
Focal photocoagulation 106
Foscarnet-ganciclovir cytomegalovirus retinitis trial 409
Fovea 154, 158
avascular zone 186
Foveal study 186, 188
Fuchs’ dystrophy 13
Fundus fluorescein
angiograms 155
angiography 132, 159
Fundus photographs 103
Fungal corneal ulcers 5
Fusarium species 6
Ganciclovir 410
Glasgow coma scale score 388
Glasses 16
Glaucoma 14, 27, 42, 58, 62, 63, 169
clinical trials in 27
detection of 62
epidemiological studies of 57, 74t
filtering surgery 40
landmark trials in 72t
laser in 66
laser trial 39
follow-up study 38
medication 49, 51
number of 68
neovascular 54, 92, 99
prevalence of 57, 62, 63
research foundation 73
secondary 62
surgery 14, 46, 144
risk of future 66
uncontrolled 176
Glaucomatous optic nerve 62
Glial dysfunction 147
Glycated hemoglobin 79
Glycemic control 82
duration of 79
Goldmann perimetry 95, 303
Gonioscopy 62
Good vision, chances of 100
Good visual acuity 196
Graft rejection, risk of 14
Gram stain 297
Gram-negative organisms 298
Head injury trial 387
Health and vision, perception of 198
Hematology testing 132
Hemiretinal vein occlusion 162
Hemorrhage 200
preretinal 164
retinal 159, 164
suprachoroidal 42
Hereditary optic disease outpatient study, rescue of 390, 391
Herpes simplex virus
epithelial keratitis trial 3
eye disease 4
Herpes simplex virus
infection 3
iridocyclitis 2
management of 1
Herpes stromal keratitis 1, 2
Herpetic eye disease 1, 3
management of 3
Horizon study 67
Hyperglycemia 84
severe 81
Idiopathic neovascular membranes 202
Immune recovery uveitis 403
Implantable dexamethasone 168
Indocyanine green angiography 260
Infant aphakia treatment study 324, 325, 327t
Infectious endophthalmitis 163
Infectious keratitis 5
Inflammatory cells 168
Influence glaucoma 27
Insulin 83, 84
injections 81
therapy 83
Intensive blood glucose control 84
International Optic Nerve Trauma Study 387
International Retina Group 147
Interquartile range 140
Intraocular injections 134, 166, 168
Intraocular lens 295, 324, 327
implantation 47
Intraocular pressure 42, 45, 51, 64, 65, 73, 92, 104, 131, 158, 183
elevation of 67
Intraocular ranibizumab 217
Intraocular steroids 135
Intraocular surgery 176
Intraoperative optical coherence tomography 17
Intraretinal edema 256
Intravitreal administration 171
Intravitreal aflibercept 118, 267, 271
injection, safety of 175
Intravitreal bevacizumab 108, 131, 139, 146, 234, 312
monotherapy 312
Intravitreal corticosteroid injection 163
Intravitreal dexamethasone 146
Intravitreal injections 122, 131, 145, 162, 171, 309
safety of 167
Intravitreal lucentis, safety assessment of 221
Intravitreal ranibizumab 110, 111, 113, 116, 117, 127, 271
Intravitreal steroids 109
Intravitreal triamcinolone 144, 164
acetonide 127
Intravitreous bevacizumab 140
IOP See Intraocular pressure
Iridocyclitis 4
Iris neovascularization 183
Iritis 4
Ischemic central retinal vein occlusion, treatment of 54
Ischemic heart disease 79
Ischemic optic neuropathy decompression trial 388
IVR See Intravitreal ranibizumab
IVTA See Intravitreal triamcinolone acetonide
Jupiter study 69
Kaplan-Meier analysis 209
Keratitis 4
corneal scarring in 10
evaluation of 9
mild-to-moderate 10
Keratometry 326
Keratopathy 12
Kidney diseases 80
Krypton study 186, 188, 189
Landolt C chart 266
Laser 137
monotherapy 137
peripheral iridotomy 45
photocoagulation 127, 137, 154, 175, 186, 190, 202t
role of 93
therapy 139, 309
trabeculoplasty failure 38
treatment 39, 190
Laser-ranibizumab-triamcinolone study 109
Latanoprost 71
monotherapy 71
Later perfluoropropane 284
Leber's hereditary optic neuropathy 390
Lens 40, 324
neovascular 188
subgroup analyses of 196
type of 186
Less severe retinopathy 96
movement 168
recruitment 147
Lipid concentrations 86
Longitudinal optic neuritis study 373
Lower-extremity amputation 79
LP See Laser photocoagulation
Lucentis 134, 210
Lumbar puncture 374
Lymphocytotoxic antibodies 12
Macula 96
Macular edema 92, 95, 107, 118, 132, 134, 136, 153, 157, 161, 163, 165, 168, 179, 183, 255, 405
development of 116
duration of 169
photocoagulation on 96
treatment for 161, 165, 171
Macular grid laser photocoagulation 160
Macular laser 135
photocoagulation 141
procedures 136
Macular photocoagulation study 186
Macular program 58
Manifest refraction 10
Manual refraction 112
Mean binocular visual acuity 344
Menstrual periods 4
Mercury trial 71
Metamorphopsia score 291
Metformin 83, 84
Methylprednisolone 385, 386
Mild macular grid 127
Mitomycin C 42
MMG See Mild macular grid
Monoclonal antibody fragment 131
Monocular visual impairment 328
Monofocal episode 375
Multicenter cohort study 224
Multifocal episode 375
Multiple sclerosis 372, 374, 375, 381, 394
study, early treatment of 380
trial outcomes index, functional assessment of 383
Mycotic infections 7
Mycotic ulcer treatment trial 5, 7
Myocardial infarction 135
Myopia 63
high 188
pathologic 193, 194
Myopic choroidal neovascularization 194
Naloxone 385, 386
National Acute Spinal Cord Injury Study 385
National Eye Institute 5, 73, 90, 328
National Health Service 233
National Institute of Diabetes 80
National Institutes of Health 301
Neovascular age-related macular degeneration 207, 223, 225, 227, 243
treatment of 225, 242
Neovascular complications, treatment of 162
Neovascular proliferation, active 100
Neovascularization, development of 153, 154, 156
Nephropathy 80
Netarsudil 71
drop of 71
Neuronal cell death 147
Neuro-ophthalmology, clinical trials in 372, 393t
Neuropathy 80, 86
Neurosensory retina 190
Nocardia ulcers 9
Nonarteritic anterior ischemic optic neuropathy 388
Non-contact specular microscopy 326
Noncytomegalovirus ocular opportunistic infections 40
Nonfatal myocardial infarctions 136
Non-fusarium group 7
Noninfectious endophthalmitis 163
Non-nocardia ulcer 9
Nonocular safety 168
Nonproliferative diabetic retinopathy 90, 95, 127
Nonproliferative retinopathy, mild to moderate 81
Nonrandomized small tumor pilot study 398
Non-staphylococcus epidermidis 298
Normal tension glaucoma study, collaborative 34
NPDR See Nonproliferative diabetic retinopathy
OAG See Open-angle glaucoma
Occlusion therapy 328, 331
Ocular herpes simplex infection 4
Ocular histoplasmosis syndrome 198
Ocular hyperemia 141
Ocular hypertension 32, 69, 70, 73, 74, 169
study 66
treatment of 30, 52
Ocular hypotensive medication 32
Ocular inflammation 176
Ocular motility 326
Ocular neovascularization 208
Ocular treatment index 325
OHT See Ocular hypertension
Omega-3 long-chain polyunsaturated fatty acids 276
Open-angle glaucoma 27, 43, 52, 59, 63, 65, 70, 73, 74
results of 64t
Open-label randomized controlled trial 319
Ophthalmic diseases, management of 17
Ophthalmology, clinical trials aids in 412t
Ophthalmoscopy, indirect 99
Optic disc 31, 32
Optic nerve
evidence of 39
typical 44
Optic neuritis 372
treatment 373
trial 372
Optical biometry 326
Optical coherence tomography 17, 105, 211, 217, 227, 255
Oral acyclovir, efficacy of 1
Oral voriconazole 7
Ozurdex 132
PACG See Primary angle closure glaucoma
Panretinal photocoagulation 90, 106, 116, 127, 135, 183
treatment to 111
Parenting stress index 325
Pars plana vitrectomy 284, 290, 293, 296, 300
Patching protocol 329
PDR See Proliferative diabetic retinopathy
Pediatric eye disease 363t
investigator group 328, 349
Pegaptanib 209
sodium 208
Penetrating keratoplasty 3
Peribulbar triamcinolone acetonide 106
Peripheral diabetic retinopathy lesions 121
Peripheral retinal
ablation 309
vessels, development of 312
Peripheral vision, loss of 116
Phakic eyes 43
Pharmacotherapy 116
Photodynamic therapy 191, 202, 203t, 210, 253, 266, 271
application of 190
Photokeratoscopy 16
Pigmentary glaucoma 29, 44
Placebo 386
controlled clinical trial 376
Placental growth factor 171
Pneumatic retinopexy 290, 292
POAG See Primary open-angle glaucoma
Point-of-care glycated hemoglobin 113
Polymorphous dystrophy, posterior 13
Polypoidal choroidal vasculopathy 257, 261, 267, 271
treatment of 266
Port delivery system 225
Prednisolone phosphate 1
Presumed ocular histoplasmosis 186, 202
Primary angle closure glaucoma 46, 58, 65, 66, 74
treatment of 45, 47
Primary open-angle glaucoma 64, 74
Primary rhegmatogenous retinal detachment 290
management of 290
Proliferative diabetic retinopathy 79, 90, 116, 127, 133
development of high-risk 96
severe 99
Proliferative retinopathy 90
Proteinuria, gross 79
PRP See Panretinal photocoagulation
Pseudoexfoliation 44
glaucoma 29
Pseudophakia 405
Pseudophakic corneal edema 13
Pseudophakic eyes 147
Pulse oximetry 314
Radial keratotomy 16
prospective evaluation of 16
Radiation therapy 264
Randomized clinical trial 261, 342, 348, 376
Randot preschool stereoacuity test 336
Ranibizumab 109, 110, 117, 118, 131, 134, 136, 165, 166, 177179, 210, 212, 216, 225, 230, 253, 254, 260, 266, 271, 319, 320
efficacy and safety of 216, 261
efficacy of 136
extension trial of 223
injection 111, 134
monotherapy 137, 138, 258, 260
safety of 177, 178
study of 219
treatment 177
Refraction 57
Rehabilitative services 78
Renal disease, severe 99
Residual subretinal fluid 19
Restore lost vision 135
Retina 40
Retinal capillary perfusion 161
Retinal detachment 99, 106, 163, 198, 406
clinical trials in 284, 293t
management of 284
rates of 299
Retinal disorders 103
Retinal glial cell 147
Retinal hemorrhages, extensive 91
Retinal ophthalmology 113
Retinal photographs 84
Retinal pigment epithelium 190
Retinal thickening 106, 107, 114, 148
measurement of 114
Retinal vascular
disease 158
occlusions, clinical trials in 153, 180t
Retinal vein occlusion 153, 168, 175, 179
comparative treatments for 174
corticosteroid for 161
Retinitis 402, 403, 405407, 409, 410
previously diagnosed 403
progression 403, 406
Retinopathy 176
progression of 92
severe 96
stage of 92
Retinopathy of prematurity 301, 312, 319
clinical trials in 301, 321t
cryotherapyfor 301
effects of light reduction on 315
Retinopathy of prematurity study
early treatment for 304
high oxygen percentage in 314
photographic screening for 316
Retinotomy 286
Rhegmatogenous retinal detachment 200, 201, 287, 293
Rhopressa 70
Rocket trial 70
Scanning laser ophthalmoscopy 32
Scleral buckling 287
Scleral flap 42
Selective laser trabeculoplasty 51
Severe vision loss, development of 91
Sham treatment 191
Silicone oil
removal 286
study 284
Silicone study 286
classification system 286
long-term outcome in 286
biomicroscopy 62
photograph 159
Smoking, history of 14
Snellen equivalent 138
Spectral-domain ocular coherence tomography 225
aureus 297, 298
epidermidis 298
haemolyticus 298
lugdunensis 298
Stereoscopic fundus evaluation 59
inflammatory action of 8
related toxicities 163
treatment 2
Stromal keratitis, development of 4
Subclinical diabetic macular edema study 108
Subfoveal lesions 188
Subfoveal recurrent 189
Submacular surgery 198, 201
trials 198, 199, 204t
Subretinal fluid 254
Subretinal pigment epithelial fluid 256
Subtenon's injections 106
Sulfonylurea 83, 84
Sulfur hexafluoride 284
Sun exposure 4
Supplemental therapeutic oxygen 312
Systemic antibiotics 297
role of 295
Systemic bevacizumab therapy 227
Teller acuity card procedure 306
Therapeutic keratoplasty 6, 7
Titmustest 336
Tonometry 326
Topical antibiotics 122
Topical antiglaucoma agents 31
Topical corticosteroids 2
Topical natamycin 8
Topical prednisolone phosphate 8
Topical steroids, receiving 2
Topical therapy 45
Topical trifluridine 4
Torpedo trial 255
Total macular volume 122
Trabeculectomy 42, 43, 45, 145
group 43, 45
study 42
Transient photosensitivity reactions 192
Transient visual disturbances 197
Traumatic optic neuropathy 385
Triamcinolone 109, 110, 111
Trifluridine prophylaxis 2
Ultrasonic corneal thickness 16
Urinalysis 132
Urine albumin 84
VA See Visual acuity 183
Vancomycin 296
Vascular endothelial growth factor 131, 183, 207, 249, 253
inhibition study 208
trap-eye 238, 240
VEGF See Vascular endothelial growth factor
Vellore eye study 57
Verteporfin 190193, 196, 210
photodynamic therapy 190, 193, 261, 271
efficacy and safety of 260
plus ranibizumab 257, 258
therapy 193, 196, 197
favor of 196
use of 193
treatment 193, 197
group 195
Vision loss
cause of 168
from macular edema, risk for 154
mild 119
moderate 105, 195
rate of 135
severe 195
Vision related subscales 138
Vision specific quality 11
Visual activities 29
Visual acuity 29, 37, 41, 51, 57, 62, 84, 91, 99, 100, 103, 120, 127, 133, 142, 147, 159, 162, 164, 165, 188190, 192, 196, 199, 202, 208, 211, 215, 221, 234, 254, 291, 327, 330, 331, 333, 334, 339, 341, 346, 387
course of 99
improvement in 199, 350
loss 191, 407
risk of severe 201
masked assessment of 343
measurements 164
evaluation of 112
monitoring 171
reduced 172
risk of 100
spectacle-corrected 16
stabilization 193
Visual benefit 144
Visual field 31, 93, 97, 404
decrease of 38
defects 389
loss 27, 407
advanced 28
testing 303
Visual function 93
preservation of 42
Visual impairment 138, 405
Visual improvement 119, 143, 170
Visual loss 35, 79, 92
Visual prognosis 298
Vitrectomy 97, 290, 295, 297
early 98, 99
evaluation of 105
primary 287
Vitreomacular traction 105, 127
Vitreous hemorrhage 18, 99, 100, 113, 127, 158, 163, 164
development of 154, 155
experience 156
severe 98, 99
Vitreous tap 296
Vogt's striae 10
Voriconazole 5, 6
Voyager study 52
Xenon technique 91
Zidovudine 410
Chapter Notes

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Clinical Trials in CorneaCHAPTER 1

Archita Singh,
Noopur Gupta
  • 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.
Despite the availability of antiviral agents that are effective in treating herpes simplex epithelial keratitis, inflammation in the corneal tissue and iris can lead to corneal scarring and visual impairment in many patients. Prior to the HEDS-I trials, the role of topical corticosteroids in the management of herpes simplex virus (HSV) stromal keratitis was uncertain. The value of adding an oral antiviral agent to topical corticosteroids and topical antiviral agents was also unknown.
Herpetic Eye Disease Study-I consisted of three randomized, placebo-controlled trials (1992–1996). All patients received the topical antiviral trifluridine as prophylaxis against recurrences of HSV epithelial ulceration. Patients were evaluated weekly for 10 weeks, every other week through week 16, and again at 6 months.
Herpes Stromal Keratitis, Not on Steroid Trial (HEDS-SKN): Patients with active HSV stromal keratitis who had not used a topical corticosteroid in the preceding 10 days were randomized to treatment with topical 1% prednisolone phosphate drops (8 times a day for 7 days, progressively 2decreased over 10 weeks to once a day) or topical placebo drops (same schedule was followed).
Herpes Stromal Keratitis, on Steroid Treatment (HEDS-SKS): Patients with active HSV stromal keratitis who already were being treated with a topical corticosteroid were randomized either to oral treatment with acyclovir (400 mg five times daily) for 10 weeks or to the identical dose of placebo capsules. Patients also received topical prednisolone phosphate in the dosage schedule described above for the SKN trial.
Herpes Simplex Virus Iridocyclitis, Receiving Topical Steroids (HEDS-IRT): Patients with active HSV iridocyclitis were randomized either to oral treatment with acyclovir (400 mg five times daily) for 10 weeks or to the identical dose of placebo capsules. Patients also received topical prednisolone phosphate in the dosage schedule described above for the SKN trial.
Inclusion Criteria
Patients ≥12 years, no active HSV epithelial keratitis, no prior keratoplasty of the involved eye, and not pregnant.
Study Measures
The primary outcome was the time to development of preset criteria for treatment failure during the 16-week period of examination.
HEDS-SKN: 106 patients were enrolled. 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. However, delaying the initiation of corticosteroid treatment did not affect the eventual outcome of the disease.
HEDS-SKS: 104 patients were enrolled. Over the 16-week follow-up period, there was no difference in the rate of treatment failure between the two groups. Thus there was no apparent benefit in the addition of oral acyclovir to the treatment regimen of a topical corticosteroid and a topical antiviral.
HEDS-IRT: 50 patients were enrolled during a 4-year recruitment period. Although the number of patients enrolled in this trial was too small to achieve statistically conclusive results, the trend in the results suggested a benefit in adding oral acyclovir to the treatment of HSV iridocyclitis in patients receiving topical corticosteroids and trifluridine prophylaxis.3
  • To determine whether early treatment (with oral acyclovir) of HSV ulcerations of the corneal epithelium prevents progression to the blinding complications of stromal keratitis and iridocyclitis.
  • To determine the efficacy of low-dose oral acyclovir in preventing recurrent HSV eye infection in patients with previous episodes of herpetic eye disease.
  • To determine the role of external factors (such as ultraviolet light or corneal trauma) and behavioral factors (such as life stress) on the induction of ocular recurrences of HSV eye infections and disease.
Ocular HSV infection can lead to corneal scarring and neovascularization, permanent endothelial dysfunction and corneal edema, secondary glaucoma, and cataract. Despite the availability of topical antiviral agents that are highly active against HSV keratitis, there is still no known effective method for reducing the frequency of recurrence or severity of stromal keratitis and iridocyclitis. In addition, the prognosis is poor for recovery of good vision following penetrating keratoplasty (PK) for actively inflamed or highly vascularized herpetic corneas.
Herpetic Eye Disease Study-II consisted of two randomized, placebo-controlled trials that assessed the role of oral acyclovir in the management of herpetic eye disease (1992–1996) and one epidemiologic study that investigated risk factors, including stress, for the development of ocular recurrences of the disease.
Herpes Simplex Virus Epithelial Keratitis Trial (HEDS-EKT): Evaluated the benefit of oral acyclovir (400 mg five times a day for 21 days) given during treatment of an acute HSV keratitis (dendritic or geographic keratitis) in preventing the occurrence of later blinding complications.
Study Measures
The primary outcome was the time to the first occurrence of stromal keratitis or iridocyclitis in the study eye (eye with epithelial keratitis at time of study entry).
Acyclovir Prevention Trial (HEDS-APT): Evaluated the benefit of long-term acyclovir treatment (400 mg twice a day for 1 year) in patients with a recent history of HSV eye disease but no current active disease. Episodes of recurrent 4HSV eye disease during the trial were treated with topical corticosteroids and antivirals as indicated, but patients continued to receive the oral acyclovir or placebo for the entire 365-day period.
Inclusion Criteria
To be eligible, a patient must have experienced any kind of ocular herpes simplex infection (blepharitis, conjunctivitis, keratitis, or iridocyclitis) in the preceding year. The infection must have been inactive and untreated for at least the previous 30 days.
Study Measures
The primary outcome was the time to the first recurrence of any type of HSV eye disease in either eye.
Ocular HSV Recurrence Factor Study (HEDS-RFS): Evaluated the effect of psychological, environmental, and biological factors on recurrence episodes of herpetic eye disease. Patients recruited into the HEDS-APT trial were eligible to participate in HEDS-RFS if they are 18 years or older. At entry, all subjects filled out a questionnaire to estimate the negative affectivity trait measure. Subjects also filled out a short questionnaire every week for 52 weeks to track acute and chronic stressors (e.g., illnesses, injuries, menstrual periods, sun exposure, and emotional and financial stress). The investigators ensured patient privacy by the patients’ mailing of the weekly logs directly to the HEDS National Coordinating Center.
HEDS-EKT: Patient recruitment was stopped after enrolment of 287 of the originally planned 502 patients because of a lack of any suggested efficacy of the treatment protocol. In the treatment of acute HSV epithelial keratitis, there was no benefit on addition of oral acyclovir to treatment with topical trifluridine in preventing the development of stromal keratitis or iritis. Importantly, the study found that the risk of stromal keratitis or iridocyclitis was quite low (much lower than the published risk in the literature) in the year following an episode of epithelial keratitis treated with topical trifluridine alone.
HEDS-APT: Of the 703 patients enrolled, 357 were randomly assigned to the acyclovir group, and 346 to the placebo group. Only 4% of patients in the acyclovir group and 5% in the placebo group stopped treatment because of side effects. One-half of these side effects were due to gastrointestinal upset; some patients may have had intolerance to the lactose contained in the study capsules (treatment medication that does not contain lactose is 5now available). The study concluded that prophylactic oral acyclovir reduced the probability of recurrence of any form of ocular HSV by 41%. Importantly, researchers noted a 50% reduction in the rate of return of the more severe form of the disease—stromal keratitis—among patients who had this infection during the past year.
In addition to the main findings, it was also noted that during the 12 months of treatment:
  • Oral acyclovir reduced the incidence of epithelial keratitis from 11% to 9%, and the incidence of stromal keratitis from 13% to 8%.
  • 4% of patients in the acyclovir group and 9% in the placebo group had more than one recurrence.
HEDS-RFS: Psychological stress does not appear to be a trigger of recurrences of ocular HSV disease. If not accounted for, recall bias can substantially overestimate the importance of factors that do not have a causal association with HSV infection.
To evaluate outcomes of topical natamycin vs. voriconazole in cases of fungal corneal ulcers.
Infectious keratitis is a leading cause of monocular vision loss worldwide. Fungal keratitis is endemic in tropical regions, accounting for as many as half of all corneal ulcers. Mycotic ulcer tends to have guarded visual prognosis contributing significantly to ocular morbidity. Fungal corneal ulcers can be more difficult to treat than bacterial corneal ulcers, with worse outcomes. Prior to the onset of this study natamycin was the only FDA approved topical antifungal agent in ophthalmology; though the use of topical voriconazole had been documented in few reports. The role of topical voriconazole in treatment of mycotic corneal ulcer and its comparison with topical natamycin was not studied in a randomized controlled trial.
Mycotic Ulcer Treatment Trial I (2013) was a National Eye Institute-supported, randomized, double-masked, active comparator-controlled 6multicentric interventional trial. The enrolled participants were randomized into two groups based upon the therapy they received into topical natamycin 5% and topical voriconazole 1%. The patients were advised to use the topical medication one drop every hour while awake for the first week followed by every 2 hourly till 3 weeks.
Inclusion Criteria
Patients above 16 years of age that presented with smear positive filamentous fungal keratitis (KOH wet mount, Giemsa or Gram stain) with a visual acuity in between 20/40 and 20/400 in the affected eye were included. Patients presenting with an impending perforation, bilateral corneal ulcers, visual acuity worse than 20/200 in nonaffected eye or those with mixed infections such as viral, bacterial, or acanthamoeba keratitis were excluded.
Study Measures
  • The primary outcome measure was the best spectacle corrected visual acuity (BSCVA) at 3 months in terms of log MAR.
  • The secondary outcome measures were BSCVA at 3 weeks, time to re-epithelialization, size of infiltrate or the scar at 3 weeks and 3 months, microbiological cure at 6 days, corneal perforation and/or the need full-thickness therapeutic keratoplasty.
The trial suspended recruitment after 323 patients as per recommendations of Data Safety and Monitoring Committee based on higher perforations/therapeutic keratoplasty occurring in voriconazole group (n = 34) compared to natamycin group (n = 18) (p = 0.02).
  • The most commonly identified organism was the Fusarium species (40% cases) followed by Aspergillus species (17% cases).
  • The median duration of follow-up was 31 days in natamycin group and 39 days in voriconazole group.
  • At 3 months visual acuity was worse by 1.8 lines in voriconazole group as compared to natamycin group. The mean BSCVA for Fusarium species was 4.1 lines better in natamycin prescribed group as compared to the voriconazole group.
  • The mean BSCVA was 0.49 log MAR in natamycin treated group and 0.60 log MAR in voriconazole treated group at 3 weeks follow-up.
  • 48% patients in the voriconazole group had culture positive at 6 days in contrast to 15% in natamycin treatment arm. Subgroup analysis revealed higher percentage in the Fusarium group.
  • Re-epithelialization was faster in Fusarium group when treated with natamycin. Otherwise no significant difference was seen in overall epithelialization rate.7
  • The scars were smaller in Fusarium only group in the natamycin treated arm at 3 months follow-up, but no such difference was noted in the non-Fusarium group.
  • Perforation of ulcer with or without therapeutic keratoplasty was seen in 34 patients in voriconazole group and only 18 in natamycin treatment group.
To assess the role of oral voriconazole therapy as compared to placebo as an adjunct to topical antifungal agents in filamentous fungal keratitis.
Mycotic Ulcer Treatment Trial I demonstrated better response of filamentous mycotic ulcers to topical natamycin 5% than topical voriconazole 1%. This result was attributed to subtherapeutic drug levels achieved in the tissue after intermittent topical drug use by the authors. Oral voriconazole has good ocular penetration and may provide consistent tissue drug levels especially in deep mycotic infections. Thus MUTT II investigated the role of adjuvant oral voriconazole therapy.
Mycotic Ulcer Treatment Trial II (2016) was a National Eye Institute-funded, placebo-controlled, double-masked, randomized clinical trial where in effect of oral voriconazole vs. placebo was studied in severe fungal corneal ulcer. The enrolled participants initially received topical 1% voriconazole, but after the results of MUTT I topical natamycin 5% was added in both arms. One group received oral voriconazole and second group received placebo drug.
Inclusion Criteria
Smear positive filamentous fungal keratitis patients with a vision of 20/400 or worse were enrolled for the study. Patients excluded were those with bilateral ulcers, coinfection, vision <20/200 in fellow eye, impending perforation, pregnancy, weight <40 kg or younger than 16 years.
Study Measures
The primary outcome was to measure the rate of ulcer perforation and/or therapeutic keratoplasty within 3 months of inclusion. Secondary outcomes were measure of BSCVA at 3 weeks and 3 months, infiltrates and/or scarring at 3 weeks and 3 months, time to re-epithelialize, microbiological cure at 6 days and complications.8
  • A total of 240 patients from India and Nepal were enrolled, out of which follow-up (3 months) data for only 207 patients was available.
  • Of the 119 patients (49.6%) in the oral voriconazole treatment group, 65 were male (54.6%), and the median age was 54 years (interquartile range, 42–62 years).
  • 46.2% perforations occurred in the placebo arm and 53.8% in the oral voriconazole group. There was no statistically significant difference in both groups in the rate of perforation and need for therapeutic PK [hazard ratio: 0.82; 95% confidence interval (CI): 0.57–1.18; p = 0.29].
  • The mean BSCVA and size of infiltrate and/or scar was comparable at 3 weeks and 3 months.
  • No significant difference was noted in microbiological cure (culture positivity at 6 day) amongst both groups.
  • The adverse events were more in oral voriconazole group (48.7%) vs. placebo group (23.1%).
  • There was a significant increase in the voriconazole-associated adverse effects such as elevated liver enzymes and visual hallucinations.
To determine the effect of topical corticosteroids as adjunctive therapy in bacterial keratitis to improve long-term clinical outcomes.
The use of topical steroids in cases of bacterial keratitis is potentially controversial with different studies suggesting variable outcomes. While anti-inflammatory action of steroids may decrease scarring and improve visual outcomes of bacterial keratitis there exist a potential risk of exacerbation of the pre-existing infection and secondary complications. There is lack of substantial evidence to support their use in cases of bacterial keratitis for long-term clinical improvements.
Steroid in Corneal Ulcers Trial (2012) is a National Eye Institute-funded, double-masked, placebo controlled, randomized multicentric clinical trial comparing placebo vs. topical corticosteroids in patients receiving treatment for bacterial keratitis. A total of 500 culture positive patients of bacterial keratitis after receiving 48 hours of topical moxifloxacin 0.5% were randomized to receive either topical prednisolone phosphate 1% or placebo. 9The steroids were administered as 1 drop 4 times per day for 1 week, then twice a day for 1 week, and then once per day for 1 week.
Inclusion Criteria
Culture-proven patients of bacterial keratitis were recruited. All eyes with perforated corneal ulcer, impending perforation, evidence of fungal, and viral or acanthamoeba keratitis were excluded. Patients with previous PK, use of steroids during the course of present ulcer, or fellow eye vision lower than 6/60 were not included in the study.
Study Measures
The primary outcome was BSCVA at 3 months. Other measures were the size of the scar at 12 months.
  • At 12 months follow-up a total of 399 patients were assessed.
  • There was no significant difference in clinical outcomes in steroid vs. placebo group at 3 months.
  • No significant difference was seen in BSCVA at 3–12 months.
  • Further analysis in non-Nocardia ulcer group demonstrated one-line difference (improvement) in BSCVA in steroid group vs. placebo arm at 12 months. No such difference was seen in Nocardia ulcers.
  • Steroids were also associated with a larger scar size in Nocardia ulcer group.
  • There was no significant difference in the rate of healing between treatment arms among patients whose re-epithelialization occurred within 21 days from enrolment. However, among patients with an epithelial defect at 21 days or later from enrolment, a higher proportion had received corticosteroids.
  • To describe the clinical course of keratoconus and to describe its visual and physiological manifestations, including high- and low-contrast visual acuity, corneal curvature, slit lamp biomicroscopic findings, corneal scarring, and quality of life.
  • To identify risk factors and protective factors that influence the severity and progression of keratoconus.10
Previous large-scale studies of keratoconus focused on incidence and prevalence, etiology, or clinical management of keratoconus. Few studies have characterized the course of the disease and risk factors for its progression in large number of keratoconus patients. The incidence of vision-threatening corneal scarring in keratoconus is unknown.
Prospective, multicenteric, natural history cohort study of 1,209 patients with mild-to-moderate keratoconus followed up for 8 years (1995–2004).
Inclusion Criteria
Patients with keratoconus ≥12 years; Vogt's striae, Fleischer's ring, or corneal scarring characteristic of keratoconus in at least one eye.
Study Measures
Patients were examined annually for visual acuity, patient-reported quality of life, manifest refraction, keratometry, photo documentation of cornea (to identify central corneal scarring), photo documentation of the flattest contact lens that just clears the cornea, slit lamp biomicroscopy, and corneal topography. In rigid contact lens wearers, the fluorescein pattern of the patient's habitual contact lens was documented.
  • Keratoconus patients are generally rigid gas permeable contact lens wearers with moderately steep corneas.
  • Advanced keratoconus (steeper average keratometric reading) was associated with a greater likelihood of Vogt's striae, Fleischer's ring, and/or corneal scarring.
  • The study group had asymmetric keratoconus. More the severity of disease, more the asymmetric disease status. Patient-reported unilateral eye rubbing, unilateral eye trauma was associated with steeper cornea. Asymmetric refractive spherical equivalent predisposes them to functional difficulties owing to reduced stereopsis.
  • Central corneal scarring is associated with decreased vision, and increased glare. Contact lens wear increased the risk of incident scarring in keratoconus more than twofold. It is implied that corneal scarring might be reduced by modifying the contact lens fit.
  • Over 8 years of follow-up, CLEK subjects exhibited a slow but clear increase in corneal curvature. Younger age and poorer high-contrast manifest refraction visual acuity at baseline predicted the rate of change in corneal curvature.11
  • Over 7 years of follow-up, CLEK subjects exhibited a slow but clear decrease in their best-corrected visual acuity (vision under low-contrast conditions decreasing more rapidly than vision under high-contrast viewing conditions). Better best-corrected visual acuity, steeper corneal curvature, and fundus abnormalities were predictive of greater acuity loss with time.
  • Progression of disease as measured by changes in visual acuity and corneal curvature resulted in continued decline in vision-related quality of life albeit this effect on vision-specific quality of life is worse than expected based on the condition's relatively low prevalence and clinical severity.
  • There was no difference in self-reported contact lens comfort between patients fitted with apical touch vs. apical clearance. No association was found between disease severity and contact lens discomfort.
  • After controlling for disease severity in the form of corneal curvature, a keratoconic eye fitted with a rigid contact lens resulting in an apical touch fluorescein pattern did not have an increased risk of being scarred centrally at baseline. This “natural history” sample cannot determine causal proof that one method of fitting lenses is safer than another. To achieve this, a randomized clinical trial is needed.
  • Increased likelihood of PK was associated with corneal scarring, steeper keratometry values, poorer visual acuity, and poorer contact lens comfort. CLEK study for the first time reported an increased risk of PK associated with younger age, worse vision-related quality of life, and flatter contact lens fits.
To determine the effect of histocompatibility matching and crossmatching of corneal transplant donors and recipients on the survival of corneal graft in high-risk patients.
Histocompatibility antigen matching and/or cross matching may have offered these patients an improved chance for successful outcome.12
Two multicenter double-masked, controlled, clinical trials (1986-1989) consisting of 400 patients each with a follow-up of 3 years.
  1. The Cross Match Study was a randomized study assessing the effectiveness of cross matching in preventing graft rejection among high-risk patients with lymphocytotoxic antibodies.
  2. The Antigen Matching Study was a prospective, observational study to assess the effectiveness of human leukocyte antigen (HLA)-A, B, and donor-recipient (D-R) matching in high-risk patients who had no lymphocytotoxic antibodies.
Blood samples from each enrolled patient were sent to the local CCTS tissue typing laboratory for HLA typing, and serum samples were sent to the Central Laboratory to be screened for preformed lymphocytotoxic antibodies. Depending on the results of the testing, patients were entered into the Crossmatch Study or the Antigen Matching Study. Patients in the Crossmatch Study received a cornea from either a positively cross matched donor or a negatively cross matched donor. Patients in the Antigen Matching Study received a cornea with 0 to 6 matched antigens.
Transplant patients were followed intensively during the first month after surgery. The number of clinic visits was tapered to 2 during the third and final year of follow-up, resulting in a total of 17 postoperative visits. Standard postoperative treatment regime, recognition and treatment of immunologic allograft reactions were developed and used.
Inclusion Criteria
Males and females aged 10 years or older with two to four quadrants of corneal stromal vascularization or a history of allograft rejection in the eye considered for surgery were eligible for both studies in the CCTS. Patients with conditions that would increase the risk of nonrejection graft failure, such as xerophthalmia or severe exposure keratopathy and patients with systemic diseases or with medication usage that might alter their immune response were excluded.
Study Measures
Irreversible failure of the corneal allograft due to all causes was the primary outcome variable in both studies. Allograft reaction episodes, irreversible failure due to rejection, and visual acuity were secondary outcome variables.
  • Donor-recipient tissue typing had no significant long-term effect on the success of corneal transplantation.
  • Data from the CCTS indicate that matching patient and donor blood types combined with treating patients with high-dose topical steroids after 13surgery may be potentially more effective in improving high-risk corneal transplantation. These two inexpensive strategies are considerably more economical than the more expensive donor-recipient tissue typing.
  • To determine long-term graft failure rate following keratoplasty when utilizing corneas from donors over 65 years of age in comparison to younger donors.
  • To assess the relation between donor/recipient ABO compatibility and graft rejection.
  • To assess if the corneal endothelial cell density (ECD) is an indicator of corneal health [in an optional Specular Microscopy Ancillary Study (SMAS)].
Whether donor age should be used to determine suitability of a cornea for transplantation has been controversial. Before the onset of this study there existed a surgeon bias toward preference for younger tissues for keratoplasties in view of better outcomes. This study was designed to assess the role of donor age in long-term corneal graft survival. The SMAS was developed to evaluate the effect of donor age on endothelial cell loss (ECL) during the 5 years after PK in the Cornea Donor Study (CDS) population.
It was a prospective, multicentric, intervention cohort study with triple masking (participant, investigator, assessor of outcomes). The study enrolled 1,101 patients (11 excluded due to ineligible diagnosis) between 2000 and 2002 and included 105 surgeons at 80 sites. 43 participating eye banks provided corneas with donor age range of 12–65 years and 65–75 years of age with endothelial cell densities of 2,300 to 3,300 cells/mm2. The results were assessed at 5-year and 10-year follow-up.
Inclusion Criteria
Any patient in the age group of 40–80 years with significant corneal disease (endothelial dysfunction, such as pseudophakic corneal edema, Fuchs’ dystrophy, posterior polymorphous dystrophy, endothelial failure from another cause, interstitial keratitis—nonherpetic type, or perforating corneal injury).14
Study Measures
  • Primary outcome was incidence of graft failure.
  • Secondary outcome measure was to measure ECD.
5-year Results
  • Graft failure was not affected by type of retrieval, tissue processing, time between death and retrieval or between retrieval and utilization, donor characteristics (including age), and characteristics of donor cornea.
  • Graft failure was higher (fourfold) in eyes undergoing keratoplasty for postcataract surgery decompensation/bullous keratoplasty (irrespective of lens status) and previous history of glaucoma surgery.
  • Preoperative ECD did not affect graft failure occurring secondary to endothelial decompensation. Lower 6-month ECD correlated with graft failure. Irrespective of donor age, ECL was substantial over the first 5 years even after successful transplant.
  • Higher ECD at 5 years was seen in those cases with larger grafts, female donors, and younger donor age.
  • ABO blood group incompatibility was not associated with risk of graft failure.
  • Donor age did not affect the graft survival. The 5-year survival rate for corneas 12–65 years and >65 years was comparable (86%).
  • Dual-grading and adjudication procedures produce reliable and reproducible assessments of ECD.
10-year Results
  • Graft failure rates were 12% ± 4% among eyes with no rejection in the first 5 years, 17% ± 12% in eyes with at least one probable rejection episode, and 22% ± 20% in eyes with at least one confirmed rejection episode.
  • Preoperative history of glaucoma, particularly previous glaucoma surgery and use of antiglaucoma medications at the time of transplant were associated with risk of graft rejection.
  • 10-year graft failure was higher in eyes with pseudophakic/aphakic decompensation, previous history of glaucoma or glaucoma surgery, older recipient age, history of smoking, and African American race.
  • Rate of ECL at 10 years was slightly higher with age of graft as compared to lower age donors.
To evaluate the role of oral omega-3-fatty acid supplements in patients with dry eye disease (DED).
Dry eye disease is a multifactorial disease of the tear film and ocular surface characterized by alteration of the tear film homeostasis. The omega-3-fatty acids are believed to have potential anti-inflammatory action which help break the cycle of chronic inflammation. This trial was designed for evaluating the efficacy and safety of long-term oral omega-3-fatty acids supplementation in DED.
It was a prospective, multicentric, randomized, double-masked “real world” clinical trial (2018). A total of 535 subjects were randomized in a ratio of 2:1 to omega 3 or placebo arm of the trial. A year long course of treatment was given. Participants were instructed to take five capsules per day. Each active capsule contained 400 mg EPA (eicosapentaenoic acid) and 200 mg DHA (docosahexaenoic acid), providing a daily dose of 3,000 mg omega 3 (2,000 mg EPA + 1000 mg DHA) while placebo arm received 5,000 mg olive oil. The patients were examined at 3, 6, and 12 months.
Inclusion Criteria
Patients ≥18 years of age with dry eye for at least 6 months and Ocular Surface Disease Index (OSDI) ≥25 were recruited.
Study Measures
Primary outcome was change in the dry eye symptoms based upon the OSDI score.
  • The mean OSDI scores were not significantly different between the omega 3 and placebo group.
  • There was no significant change in cornea staining, conjunctival staining, and Schirmer's score between the two groups.
  • No significant difference in clinical outcomes were noted in both groups.
  • To determine whether radial keratotomy (RK) is effective in reducing myopia.
  • To detect complications of the surgery.
  • To discover patient characteristics and surgical factors affecting the results.
  • To determine the long-term safety and efficacy of the procedure.
The study, involving 435 patients recruited 1981–1983, was a clinical trial designed to evaluate the short- and long-term safety and efficacy of one technique of RK. The surgical technique was standardized, consisting of eight centrifugal radial incisions made manually with a diamond micrometer knife. The diameter of the central, uncut, clear zone was determined by the preoperative spherical equivalent cycloplegic refraction (−2.00 to −3.12 D = 4.0 mm; −3.25 to −4.3 D = 3.5 mm; −4.50 to −8.00 D = 3.0 mm). The blade length, which determined the depth of the incision, was set at 100% of the thinnest of four intraoperative ultrasonic corneal thickness readings taken paracentrally at the 3−, 6−, 9−, and 12-o'clock meridians just outside the mark delineating the clear zone. The incisions were made from the edge of the trephine mark to the limbal vascular arcade and were spaced equidistantly around the cornea.
Patients were examined preoperatively and after surgery at 2 weeks, 3 months, 6 months, annually for 5 years, and at 10 years. Examinations in the morning and evening of the same day were done at 3 months, 1 year, 3 years, and 11 years in a subset of the patients to test for diurnal fluctuation of vision and refraction.
Inclusion Criteria
All participants were ≥21 years, had 2–8 diopters (D) of simple myopia correctable to 20/20 or better with glasses or contact lenses and stability of their myopia documented by previous records. Each patient agreed to have surgery on one eye and to wait 1 year for surgery on the other eye. Patients with systemic diseases that might affect corneal wound healing and patients with high corneal astigmatism were excluded from the study.
Study Measures
The primary outcome variables measured at each visit was the uncorrected and spectacle-corrected visual acuity and the refractive error with the pupil dilated and undilated. The corneal shape was measured with central keratometry and photokeratoscopy. Endothelial function was evaluated using specular microscopy. A slit-lamp microscope examination was made 17to check for complications from the incisions. Contrast sensitivity was tested in a subset of patients. Patient motivation and satisfaction were studied with psychometric questionnaires at baseline, 1 year, 5–6 years, and 10 years.
  • The 10-year follow-up PERK study results confirmed that RK reduced myopia but that the effectiveness of the outcome varied among patients.
  • These 10-year examinations indicated that the refractive error had not been stable in these eyes during the postoperative interval. There was a mean change in a hyperopic direction of +0.87 D between 6 months and 10 years after surgery. The average rate of change was 0.21 D per year between 6 months and 2 years, and +0.06 D per year between 2 and 10 years after surgery. Between 6 months and 10 years, the refractive error of 43% eyes changed in the hyperopic direction by 1.00 D or more. The hyperopic shift was statistically associated with incision length, with smaller clear zone diameters, and larger overall cornea diameters being associated with a greater change in refraction.
  • Few patients lost spectacle-corrected visual acuity, indicating RK is reasonably safe; and that patients’ acceptance is extremely high, with the majority stating they would have the surgery again.
  • The study demonstrated that for patients to be free of distance optical correction, a refraction within 0.50 D of emmetropia or a visual acuity of 20/20 in at least one eye was necessary.
To assess feasibility, safety, and utility of intraoperative optical coherence tomography (iOCT) in patients undergoing ophthalmic surgeries.
Optical coherence tomography allows high-resolution imaging of ocular tissues in 2 and 3 dimensions providing valuable cross-sectional anatomic information which has revolutionized clinical management of ophthalmic diseases. Integration of OCT in surgical environment can have profound implications in surgical management of ophthalmic diseases.18
This was a prospective, single-center, multisurgeon, consecutive, case series (2014). Intraoperative OCT was done using Bioptigen SDOIS portable spectral domain OCT (probe stabilized with microscope mount system or with handheld scanning). Procedure-specific imaging protocol was used for anterior and posterior segment surgeries. Surgeon feedback form was recorded immediately after surgery to assess utility of iOCT. 531 eyes were enrolled (275 anterior segment cases and 256 posterior segment surgical cases) over 24 months.
Inclusion Criteria
Patients over 18 years requiring ophthalmic surgery. Exclusion criteria included any media opacity that precluded OCT scanning of the area of interest and inability to provide written informed consent.
Study Measures
Impact of iOCT on surgical decision-making, time implications of iOCT, and adverse events specifically related to iOCT were recorded.
  • Successful imaging was obtained in 98% at some point during the surgical procedure with variable image quality.
  • In the anterior segment group, 275 eyes were enrolled, and common surgical procedures performed were DSAEK, phacoemulsification, femtosecond-assisted phacoemulsification, and DALK.
  • Role of iOCT in anterior segment surgical decision-making:
    • DSAEK:
      • Graft apposition monitoring until optimal fluid removal was achieved.
      • Graft dislocation rate on postoperative day 1 was 3%.
    • DALK: Provided depth-related information regarding extent of trephination and residual bed information
    • Phacoemulsification: Allowed assessment of location of intraocular lens and wound architecture
    • INTACS: Assessment of location of implant
  • 256 eyes were included in posterior segment group, with nearly all eyes requiring vitrectomy and 15 eyes requiring scleral buckling with vitrectomy.
  • Common surgical procedures were epiretinal membrane (ERM) removal, full thickness macular hole (FTMH), rhegmatogenous retinal detachment (RRD), proliferative diabetic retinopathy, and vitreous hemorrhage.
  • Role of iOCT in posterior segment surgical decision-making:
    • ERM removal: To assess completeness of membrane removal, alterations in the outer retinal architecture were noted with 19observation of the expansion between the ellipsoid zone and the retinal pigment epithelium (RPE) after peeling.
    • FTMH: To identify changes in hole architecture, residual ILM, expansion between the ellipsoid zone and RPE after peeling.
    • RRD: To identify residual subretinal fluid.
    • Surgery to relieve vitreomacular traction—confirmation of release of traction and identification of newly formed FTMH.
  • Overall, the median number of scan sessions per case was 2 (range: 1–5 sessions) with 6 median total scans (range: 1–24 scans). The overall median time to obtain the first image after pausing surgery was 1.7 minutes (range: 0.3–12.4).
  • Overall median time surgery was paused to perform intraoperative OCT imaging was 4.9 minutes (range: 0.4–26.7) with a median duration surgery paused per scanning session of 2.8 minutes.
  • No adverse events were reported.
Table 1   Summary of clinical trials in cornea.
No of patients
Inclusion criteria
HEDS-1 SKN 1992-96
Efficacy of topical steroids in herpes simplex stromal keratitis
Patients ≥ 12 years, no active HSV epithelial keratitis, active HSV stromal keratitis
16 weeks
Prednisolone drops lead to faster resolution and fewer treatment failures
Efficacy of oral acyclovir in herpes simplex stromal keratitis
Patients ≥ 12 years, no active HSV epithelial keratitis, active HSV stromal keratitis, already on topical corticosteroid
16 weeks
No apparent benefit of the addition of oral acyclovir
Efficacy of oral acyclovir in treating herpes simplex iridocyclitis
Patients ≥ 12 years, no active HSV epithelial keratitis, with active HSV iridocyclitis
16 weeks
Benefit in adding oral acyclovir to the treatment of HSV iridocyclitis
Does oral acyclovir in HSV epithelium ulcerations prevent progression
Eyes with herpes simplex epithelial keratitis within one week of onset
One year
There was no benefit from the addition of oral acyclovir to treatment
Long-term acyclovir in patients with a recent history of HSV eye disease but no current active disease
Any kind of ocular herpes simplex infection in the preceding year. The infection must have been inactive for at least the previous 30 days
One year
Oral acyclovir reduced the probability that any form of herpes of the eye would return in patients21
Effect of psychological, environmental, and biological factors on recurrences of herpetic eye disease
Same as HEDS – EKT provided the patients were more than 18 years old
One year
Psychological stress does not appear to be a trigger of recurrences of ocular HSV disease
MUTT I 2010-2011
To evaluate outcomes of topical natamycin versus voriconazole in cases of fungal corneal ulcers in terms of visual acuity
Patients > 15 years of age that presented with a corneal ulcer which smear positive for fungal filaments, with a visual acuity between 20/40 and 20/400 in affected eye
3 months
Natamycin group was better at 3 months in terms of BSCVA as compared to voriconazole group. The benefits were more pronounced in Fusarium species in terms of faster epithelialization, less scarring and more chances of being culture negative at 6 days
MUTT II 2010-2015
To evaluate clinical outcomes of oral voriconazole as an adjunct to topical antifungals in severe fungal keratitis
Smear positive filamentous, with vision worse than 20/400 were enrolled
3 months
Voriconazole did not have any additional benefits as an adjunct to topical anti-fungal agents22
SCUT 2006-2010
To determine the effect of topical corticosteroids as adjunctive therapy in bacterial keratitis to improve long-term clinical outcomes
500 (399)
Culture proven bacterial keratitis which received 48 hours of topical antibiotic treatment
12 months
Steroids show some benefit in cases of non-nocardia bacterial keratitis. Clinicians should always be cautious while using steroids depending on the case of keratitis
CLEK 1995-2004
  • To describe the clinical course of keratoconus and to describe the relationships among its visual and physiological manifestations, including high- and low-contrast visual acuity, corneal curvature, slit lamp biomicroscopic findings, corneal scarring and quality of life
  • To identify risk factors and protective factors those influence the severity and progression of keratoconus
Diagnosed Keratoconus, Age > 12 yrs, irregular cornea in at least one eye; Vogt's striae, Fleischer's ring or corneal scarring characteristic of keratoconus in at least one eye
3 years
CCTS 1986-1989
To determine whether histocompatibility matching of corneal transplant donors and recipients can reduce the incidence of graft rejection in high-risk patients
Males/Female ≥ 10 yrs, with 204 quadrants of deep stromal vessels or a history of graft rejection
3 years
Donor-recipient tissue typing had no significant long-term effect on the success of corneal transplantation
To assess the effect of donor age on graft survival
Patients with endothelial dysfunction requiring penetrating keratoplasty
10 years
  • Graft failure was not affected by donor factors
  • Higher endothelial cell density was seen in younger grafts at both 5 and 10 years postoperative
  • ABO incompatibility was not affected by risk of graft failure
DREAM study
To assess the role of oral omega supplements in dry eye
≥ 18 years, with dry eye disease (OSDI ≥ 25)
1 year
No significant clinical improvement was seen with long-term supplementation in patients with dry eye disease24
To assess feasibility of iOCT in clinical practice
18 (in anterior segment arm)
>18 years, willing for ophthalmic surgery when indicated
Observational (Intraoperative) study
iOCT is a useful intraoperative tool for eyes undergoing anterior lamellar surgeries
PERK 1981-83
Determine efficacy, complications and factors affecting the results of RK in myopia Determine the long-term safety and efficacy of the procedure
435 + 99
Patients with age ≥ 21 years with 2 to 8 diopters of simple myopia correctable to 20/20 or better Stable refraction
10 years
  • RK reduced myopia but that the outcome varied
  • In 43% of patients there is hyperopic shift of 1 D by 10 years
  • RK is reasonably safe and patient acceptance is high. Residual myopia of −0.50 to −1.00 D is an advantage after RK
  1. Wilhelmus KR, Gee L, Hauck WW; Herpetic Eye Disease Study. A controlled trial of topical corticosteroids for herpes simplex stromal keratitis. Ophthalmology. 1994;101:1883–96.
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