neovascular glaucoma ( nvg ) is a severe consequence of a number of ocular and systemic conditions , such as proliferative diabetic retinopathy ( pdr ) , retinal vein occlusion ( rvo ) , ocular ischemic syndrome ( ois ) , tumors , trauma , or uveitis . it is indisputable that increased awareness of risk factors and the early detection of retinal ischemia can minimize poor prognosis of nvg ; however , many nvg patients suffer loss of vision as a result of irreversible high intraocular pressure ( iop ) despite the use of preexisting treatments , such as panretinal laser photocoagulation ( prp ) , pars plana vitrectomy ( ppv ) , and trabeculectomy with mitomycin c ( lec ) . the main causative factor of nvg is retinal hypoxia that initiates the subsequent release of angiogenesis factors , and nvg is characterized by changes in the appearance of the iris , angle closure glaucoma , and formation of new vessels . gartner and henkind showed that the main mechanism of intraocular pressure elevation was angle closure , with peripheral anterior synechia . however , nvg occurs when new fibrovascular tissue proliferates onto the iris and chamber angle structures , including the trabecular meshwork , typically in response to ischemia of various etiologies [ 2 , 4 , 5 ] . previous studies have demonstrated increased production of several proangiogenic factors , including vascular endothelial growth factor ( vegf ) . in addition to the ischemic retina , nonpigmented ciliary epithelium and iris contribute to vegf synthesis in nvg patients . the created fibrovascular neovascularizational membrane promoted by these proangiogenic factors inhibits the aqueous flow and leads to an increase in iop . recent studies on intravitreal injection of anti - vegf agents as stand - alone or as combination treatment with other nvg treatments have reported excellent results [ 812 ] ; however , responses to treatment with a single injection are considered temporary [ 13 , 14 ] . we performed a retrospective study of 142 nvg patients ( 181 eyes ) with ocular ischemic diseases who had visited the oita university hospital between september 2006 and may 2014 ( follow - up duration : mean  std , 23.8  18.8 months ; range : 4.081.1 months ) . nvg was staged according to the degree of neovascularization , angle closure , and intraocular pressure ( iop ) . anterior segment fluorescein angiography ( fa ) and indocyanine green angiography ( ia ) for iris and angle neovascularization were used to confirm the presence of newly formed vessels . nvg staging criteria in this study were as follows : rubeosis group , angle and/or iris neovascularization only without peripheral anterior synechia ( pas ) and normal iop ; open - angle nvg group , open angle and high iop ( > 21  mmhg ) due to neovascularization ; and angle closure nvg group , closed angle and high iop ( > 21  mmhg ) with pas . adequate prp was defined as more than 3000 laser burns sufficient for disappearance of nonperfusion area ( npa ) . for patients with clear optic media and corneal edema , we performed adequate prp after anti - vegf ( bevacizumab [ 11 , 1418 ] or ranibizumab [ 8 , 9 , 19 ] ) intravitreal injections ( 0.5  mg/0.05  ml ) . for patients with severe ischemic retinopathy , anti - vegf patients administered bevacizumab were informed regarding the off - label use of these drugs in the majority of cases at the time of injection and the approval of their use by the institutional review board of oita university . patients with optic media opacity were first treated with cataract surgery or ppv before adequate prp . combination therapy was defined as single anti - vegf intravitreal injection within 2 weeks of other treatments . a proportion of patients were treated with stand - alone anti - vegf intravitreal injections according to patient preference when iop elevation or neovascularization exacerbation was observed ( figure 1 ) . concurrent administration of medications , such as systemic acetazolamide and combination eye drops , with all other treatments was performed as required . observation items were age , gender , initial logmar va ( visual acuity ) , initial iop , the extent of newly formed vessels in iris and/or angle , previous treatments , preexisting complications , treatments , final logmar va , final iop , concurrent medications , and follow - up duration . nvg cause - specific final iop , logmar va , and patient backgrounds were evaluated in the present study . iop and the number of concurrent medications at 4 months after each treatment , including stand - alone anti - vegf , additional prp , ppv , and lec , were also analyzed . further , long - term iop prognosis associated with anti - vegf and intravitreal injection combination therapy within 2 weeks of other treatments was also evaluated . finally , we conducted multivariate statistical analyses to identify iop prognostic factors of nvg . comparisons between cause - specific nvg patient groups and treatment groups were assessed by one - way repeated measures analysis of variance ( anova ) and the steel - dwass test . iop after each treatment was analyzed using the kaplan - meier test ( end point ; iop > 21  mmhg ) . after - treatment iop with or without anti - vegf combination therapy was analyzed using the paired - t test for pre - treatment iop . long - term prognosis was compared between the presence and absence of anti - vegf combination therapy using the mann - whitney u test and kaplan - meier methods ( end point ; iop > 21  mmhg ) . log - rank test and cox proportional - hazards models were created to identify prognostic factors of nvg using final iop > 21  mmhg as the study end point . causative disease ( pdr , rvo , and ois ) , angle closure , previous treatments ( prp , ppv ) , preexisting complications ( hyphema , vitreous hemorrhage ) , and treatments ( additional prp , ppv , lec , and anti - vegf agents ) were included as covariates . iop , age , logmar va , and follow - up durations were presented as means  sd . all statistical analyses were performed using spss statistics 23 ( ibm , new york ) and jmp11 ( sas institute inc . we enrolled 142 patients ( 181 eyes ) with nvg due to ocular ischemic disease . underlying retinal diseases included pdr in 134 eyes , rvo in 29 , and ois in 18 . the mean follow - up duration was 23.8  18.8 months ( range , 4.081.1 months ) . all patients at initial visits had nonperfusion areas ( npa ) on fa . at the final follow - up visit , all patients were confirmed to have no evidence of npa on fa following treatment , with iop  21  mmhg observed in 125 ( 72.3% ) eyes . the mean follow - up duration was 26.2  22.1 months ( range , 4.081.1 months ) in pdr patients , 17.6  18.8 months ( range , 4.070.1 months ) in rvo patients , and 16.5  13.0 months ( range , 4.040.0 months ) in ois patients . nvg patients with pdr were younger and had a higher prp ratio ( 81/134 , 60.4% ) than the rvo ( 8/29 , 27.6% ) and ois groups ( 5/18 , 27.8% ) . nvg patients with rvo had a greater closed - angle ratio ( angle closure nvg group , 17/29 , 58.6% ) and higher iop ( 42.4  13.8  mmhg ) than the pdr ( 45/134 , 33.6% , 36.4  13.8  mmhg ) and ois groups ( 7/18 , 38.9% , 35.0  11.9  mmhg ) . patients in the nvg with ois group had a higher incidence of hyphema ( 6/18 , 33.3% ) than other groups ( table 1 ) . in the analysis of nvg cause - specific final iop , nvg patients with pdr had lower iop ( 20.7  14.2  mmhg ) than the nvg with rvo ( 27.3  14.2  mmhg ) and ois ( 26.0  15.3  mmhg ) groups ( figure 2 ) . the majority of nvg patients had substantially lower final logmar va values ( 1.71  1.55 ) ; however , the nvg with pdr group had better logmar va values ( 1.39  1.45 ) compared with the those of the rvo ( 2.69  1.43 ) and ois ( 2.39  1.68 ) groups ( figure 3 ) . severe vision loss cases ( final logmar va , 1.0 ) were 49.2% ( 66/134 ) in pdr , 86.2% ( 25/29 ) in rvo , and 66.7% ( 12/18 ) in ois ; all of them had optic atrophy . the causes for the modest vision loss ( final logmar va , 0.3 to 1.0 ) were macular edema or corneal edema . the mean follow - up durations pre- and post - treatment are shown in table 2 . prp was administered to all patients who received stand - alone anti - vegf therapy . approximately half ( 7/17 , 41.2% ) of these patients had previously received anti - vegf injections ( mean number of injections , 11.1  10.4 , range , 331 ; mean duration , 2.0  1.1 months , range 0.73.9 months ) . forty - nine patients ( 55.1% ) in the additional prp group , 15 ( 53.6% ) in the ppv group , and 3 ( 9.4% ) in the lec group received anti - vegf combination therapy . we performed lec at a median time of 7.2  11.5 months after initial visits . twenty - three patients ( 71.9% ) in the lec group had angle closure glaucoma . patients in the lec group had previously received anti - vegf therapy ( 23/32 , 71.9% ) , ppv ( 7/32 , 21.9% ) , and adequate additional prp ( 32/32 , 100.0% ) . only 1 patient ( 3.1% ) in the lec group underwent repeat surgery ( table 2 ) . we compared iop and the number of concurrent medications at 4 months after each treatment . lec had the strongest hypotensive effect among all the treatments , resulting in persistent declines in iop in 93.8% ( 30/32 ) of patients ( mean 24.5  22.6 months ; range , 4.360.7 months ) ( figure 4 ) . iop progression and bleb survival rate after lec had comparable kaplan - meier curves ( data not shown ) . stand - alone anti - vegf therapy , additional prp , and ppv also resulted in decreased iop ; however , iop often increased several months after these treatments ( figure 4 ) . all treatments with or without anti - vegf combination therapy had a significant effect on iop . no significant differences in the post - treatment iop were observed between patients treated with or without anti - vegf combination therapy ( figure 6 ) . when we examined long - term iop prognosis after additional prp and lec using univariate analysis , no differences were observed between patients treated with or without anti - vegf combination therapy ( figure 7 ) . finally , we evaluated factors influencing final iop using multivariate statistics . angle closure was found to have the greatest effect on final iop ( hazard ratio 3.059 ; 95% confidence interval 1.8984.916 ) , followed by pdr ( 0.759 ; 0.3910.930 ) . nvg with pdr had a better prognosis in terms of iop and logmar va at the final visit . many pdr patients could escape optic atrophy because of higher prp ratio and comparatively restricted ischemic retinal areas at the initial visit than others . patients with nvg as a result of rvo with broad ischemia had a greater angle closure ratio , higher iop , and worse va prognosis . regarding treatment - specific prognosis , lec had the strongest hypotensive effect compared to other treatments , with long - term decreases in iop maintained in 93.8% of patients . during this study duration , we were unable to evaluate superior anti - vegf compounds that have since become available , such as aflibercept , and devices , such as the tube surgical treatment option . our superior lec - iop outcomes compared with those of previous studies   may be due to the high bleb survival rate as a result of lack of active neovascularization despite angle closure . full prp followed by lec is known to have efficacy in reducing elevated iop associated with nvg . in addition , lec contributes to the quality of life of nvg patients by requiring the lowest combination eye drops compared to other treatments . although other treatments may decrease iop in the short - term , iop often increases several months after treatment . while additional prp with anti - vegf therapy and additional prp combined with surgery are accepted as important treatments , angle closure nvg group is thought to require lec . approximately half of patients in the stand - alone anti - vegf therapy group required repeated injections in the present study . anti - vegf intravitreal injections are reported to have efficacy in inducing the regression of new vessels , although this effect appears to be temporary [ 15 , 22 ] . intravitreal injection of anti - vegf agents in patients with nvg reportedly causes reduced vascular permeability , decreased inflammatory reaction , loss of vascular function , and endothelial cell degeneration [ 14 , 16 ] . on iris - angle angiography , dye leakage on fluorescein angiography is decreased after intravitreal injection of anti - vegf agents . vascular structures in the iris and angle can be observed with indocyanine angiography ; however , intravitreal injection of anti - vegf agents has no effect on these structures despite reports indicating the disappearance of newly formed vessels examined using a slit lamp . histopathological changes in the trabecular meshwork in nvg following intravitreal injection of anti - vegf agents revealed that vascular endothelial cells were still present in the trabecular meshwork and fenestrations disappeared . therefore , repeated stand - alone anti - vegf injections are necessary to control iop in nvg eyes with residual retinal ischemia . in the present study , the repeated stand - alone anti - vegf group consisted of a small number of who refused adequate prp and lec due to poor general condition or for psychological reasons . anti - vegf combination therapy was found to have no effect on the prognosis of nvg prognosis in terms of iop control in the present study . the iop prognosis of ppv with anti - vegf combination therapy was worse than that without anti - vegf combination therapy according to the results of univariate analysis . this finding may be attributable to the use of anti - vegf combination therapy in severe cases of retinal neovascularization in the present study . a previous study reported ivb increased surgical success rates by decreasing risk of perioperative bleeding ; however , other studies have that ivb does not improve long - term prognosis [ 15 , 18 ] . the efficacy of anti - vegf combination therapy in improving surgical iop outcomes remains controversial ; however , it remains an accepted therapy for reducing perioperative surgical complications . furthermore , we can not try other now available superior anti - vegf compounds   such as aflibercept   and devises like the tube surgical option of treatment [ 2426 ] due to disapproval at that time . in addition , as lec was performed after various treatments , including adequate prp ( 100% ) , anti - vegf stand - alone therapy ( 71.9% ) , and ppv ( 21.9% ) , it should be noted that extensive preparation is necessary for the success of lec . our follow - up duration after the last lec treatment ( mean 24.5  22.6 months ) may have been inadequate for accurate assessment of long - term prognosis . therefore , lec with survival blebs after other adequate treatments , including anti - vegf treatments , appears to be the effective treatment for nvg . anti - vegf combination therapy had no effect on long - term nvg - iop prognosis but is recommended prior to angle closure . in patients where the target iop is not obtained following adequate prp with / without the use of anti - vegf agents , early lec may improve the prognosis of nvg - iop this time , and a high index of suspicion based on patient history and early recognition of high risk eyes are crucial for favorable long - term outcomes . moreover the randomized prospective study including newest iop - lowering devises and drugs may be necessary for next prospective study in the future .
purpose . to perform multivariate analysis for identifying independent predictors of elevated intraocular pressure ( iop ) with neovascular glaucoma ( nvg ) , including antivascular endothelial growth factor ( vegf ) intravitreal injections 
 . methods . 
 we retrospectively reviewed 142 nvg patients ( 181 eyes ) with ischemic retinal diseases [ proliferative diabetic retinopathy ( pdr ) in 134 eyes , retinal vein occlusion ( rvo ) in 29 , and ocular ischemic syndrome in 18 ] . 
 we analyzed age , gender , initial / final logmar va , initial / final iop , extent of iris and/or angle neovascularization , treatments , preexisting complications , concurrent medications , and follow - up duration . 
 results . 
 the mean follow - up duration was 23.8  18.8 months . at the final follow - up , 125 ( 72.3% ) eyes 
 had iop  21  mmhg . 
 nvg patients with rvo had a higher degree of angle closure and higher iop . 
 nvg with pdr had better iop and logmar va . 
 angle closure had the greatest impact on final iop . 
 greater than 90% of patients treated with trabeculectomy with mitomycin c ( lec ) had persistent declines in iop ( 21  mmhg ) . 
 stand - alone and combination anti - vegf therapies were not associated with improved long - term prognosis of iop . conclusions . angle closure was found to have the greatest effect on nvg - iop prognosis . when target iop values are not obtained after adequate prp with or without anti - vegf 
 , early lec may improve the prognosis of iop .