retinal changes associated with the development of age - related macular degeneration ( amd ) have become even more important than once described .
even prompt therapy of the wet form of amd with antivascular , endothelial , growth factor drugs has been shown to ameliorate vision loss .
if diagnosis is established earlier  during the dry form of amd , there is a better chance that visual acuity can be maintained .
rheohemapheresis ( formally known as rheopheresis ) has been investigated over the past decade as a possible method of positively affecting amd in its dry - form stage .
rheohemapheresis is a method of double plasma filtration performed in order to eliminate high - molecular - weight substances  especially proteins such as fibrinogen , 2-macroglobulin , immunoglobulin m ( igm ) , thrombomodulin , and low - density ( ldl ) cholesterol [ 36 ] .
this method leads to the improvement of rheological parameters ( reduction of plasma and whole blood viscosity ) , as well as the improvement of erythrocyte aggregation and their flexibility [ 6 , 7 ] .
it can also lead to a significant improvement of blood flow in the choroid , which is reduced in patients with amd .
when treating our patients suffering from the dry form of amd accompanied by reticular drusen or even drusenoid detachment of the retinal pigment epithelium , we noticed positive morphological changes of the retina after rheohemapheresis treatment , including the preservation of the photoreceptor inner / outer segment ( is / os ) junction , as well as stabilisation or even improvement of retinal function : best - corrected visual acuity ( bcva ) and electroretinography results . a description of the above changes and their correlation is the subject of this work .
at our department , we have seven years of experience in treating amd using rheohemapheresis .
so far , 61 patients with the dry form of amd , soft drusen , confluent soft drusen , and drusenoid pigment epithelium detachment ( dped ) have been treated .
we perform long - term monitoring of morphological and functional changes in the retina [ 12 , 13 ] .
the interrelationship of morphological changes in the photoreceptor inner and outer segment ( is / os ) junction retinal layer as well as changes in visual acuity and retinal function ( electroretinography ) was evaluated in the group of 24 patients ( 40 eyes ) who were long - term followed ( for 2.5 years or longer ) .
all patients had the dry form of amd with the presence of drusenoid pigment epithelium detachment .
twelve of these patients ( 22 eyes ) with an average age of 64.3 years ( range : 6483 years ) were treated with rhf .
twelve controls ( 18 eyes ) with an average age of 65.6 years ( range : 6483 years ) were randomized .
ophthalmologic inclusion criteria were high - risk , preangiogenic form of amd with soft drusen , reticular drusen , confluent soft drusen , and dped  in accordance with the eureye study and ability to complete the series of 8 rheohemapheresis procedures within 10 weeks .
exclusion criteria were any retinal or choroidal disorders other than amd , optic nerve disorders , glaucoma , conditions limiting the examination of the fundus , and acute bleeding in the studied eye .
general exclusion criteria for rheohemapheresis treatment were the usual exclusion criteria of extracorporeal circulation or therapeutic hemapheresis and the absence of peripheral veins suitable for establishing an extracorporeal circuit .
rheohemapheresis was performed in the treatment group , as described in detail in our previous work [ 3 , 13 ] .
after plasma separation ( blood - cell separator , cobe spectra or optia , terumo , lakewood , co , usa ) , the separated plasma was pumped through the rheofilter ( evaflux , kawasumi , tokyo , japan ) to remove high - molecular - weight factors . using this filter , we repeatedly ( 8 times over the period of 10 weeks ) removed a precisely defined spectrum of high - molecular - weight substances , such as fibrinogen , ldl cholesterol , and 2-macroglobulin , from the blood of the patient , thus reducing blood viscosity in an attempt to improve the perfusion of the retina and the choroid .
fundus photography and fluorescein angiography were performed using a digital fundus camera ( zeiss ff 450 , jena , germany ) .
the dped area was measured in mm by fundus photography using visupac software ( zeiss meditec ag , jena , germany ) , which is acceptable for measuring the area of retinal affections .
spectral domain- ( sd- ) oct ( cirrus hd - oct , zeiss meditec , jena , germany ) with an axial resolution of 6  m was used to evaluate central retinal thickness .
thickness in the central point of the 1  mm fixation zone was evaluated using 6 radial scans .
sd - oct enabled us to distinguish between dped and the vascular type of retinal pigment epithelium detachment . a detailed image of the photoreceptor is / os junction was obtained using a 5-line raster scan , which precisely shows the shape , coherence , and defects of the photoreceptor is / os junction as well as the detachment of this layer from the retinal pigment epithelium ( rpe )
multifocal erg ( mferg ; reti - port plus mferg system , roland consult gmbh , brandenburg , germany ) was performed according to the standards of the international society for clinical electroretinography and vision ( iscev ) [ 16 , 17 ] .
mferg traces were recorded from the central 60 of the retina using a resolution of 61-scaled hexagons .
we evaluated the amplitudes of the positive peak component from the first - order kernel analysis of the central element , representing the foveal response ( 01.8 ) of the four rings centered on the fovea : 1st ring ( 1.87.0 ) , 2nd ring ( 513 ) , 3rd ring ( 1122 ) , and 4th ring ( 1730 ) .
all examinations were performed at baseline and at 2.5-year follow - up . for statistical analysis
, we used nonparametric tests ( the kruskal - wallis test , mann - whitney u test , and chi - square approximation ) .
the study protocol was approved by the institutional ethics committee and the reported investigations were in accordance with the principles of the current version of the helsinki declaration .
median best - corrected visual acuity ( bcva ) before rheohemapheresis in the treatment group was 74.0 letters ( 56.2 to 81.3 letters ; 95% ci ) and increased to 79.0 letters ( 57.3 to 83.4 letters ; 95% ci ) , ( p = 0.187 ) after 2.5 years . in the control group ,
mean bcva decreased from 74.0 letters ( 25.2 to 82.6 letters ; 95% ci ) at baseline to 72.5 letters ( 23.4 to 83.1 letters ) after 2.5 years ( p = 0.041 ) .
while the difference in bcva between the treatment groups was insignificant at baseline ( p = 0.457 ) , bcva was significantly higher in the treatment group after 2.5 years ( p = 0.021 ) . at baseline , mean dped was 3.68  4.45  mm in treated patients and 4.12  6.64  mm in controls , reaching the central fovea in all cases .
after 2.5 years , the mean dped area decreased significantly to 0.71  1.27  mm in the rheohemapheresis group ( p < 0.001 ) , whereas it increased significantly to 9.19  9.51  mm in the controls ( p < 0.01 ) .
the differences in size of the dped area were only insignificant at baseline ( p = 0.605 ) and significant after 2.5 years ( p < 0.001 ) .
reduction of the size of the dped area after rheohemapheresis was found in 19/22 rheohemapheresis - treated eyes ( 86.4% ) , as opposed to only 3/18 eyes ( 16.7% ) in the control group .
enlargement of the dped area occurred as part of the natural progress of amd over the same period of 2.5 years in 15/18 ( 83.3% ) eyes in the control group , compared to only 3/22 eyes ( 13.6% ) of treated patients .
the study and control groups were comparable.in the group of treated patients , the photoreceptor is / os junction was attached to the dped in 6/22 ( 27.3% ) eyes .
( dped was accompanied by a detachment of the photoreceptor is / os junction in the remaining 16/22 eyes , i.e. , 72.7% , without defect in 15/22 eyes and with defect in 1 eye).in the control group , the photoreceptor is / os junction was attached to the dped in 6/18 ( 33.3% ) ( dped was accompanied by a detachment of the photoreceptor is / os junction in the remaining 12/18 eyes ( 66.6% ) , without defect in 4 eyes and with defect in 8 eyes ) . in the group of treated patients , the photoreceptor is / os junction was attached to the dped in 6/22 ( 27.3% ) eyes .
( dped was accompanied by a detachment of the photoreceptor is / os junction in the remaining 16/22 eyes , i.e. , 72.7% , without defect in 15/22 eyes and with defect in 1 eye ) . in the control group ,
the photoreceptor is / os junction was attached to the dped in 6/18 ( 33.3% ) ( dped was accompanied by a detachment of the photoreceptor is / os junction in the remaining 12/18 eyes ( 66.6% ) , without defect in 4 eyes and with defect in 8 eyes ) . 

( 1 ) the group of patients . in the group of treated patients , where the photoreceptor is / os junction was intact in 6/22 ( 27.3% ) eyes , it remained without defect even after 2.5 years .
however , in 7 cases of the attached is / os junction , there was a certain residual defect .
in one additional eye with the is / os junction at baseline , the defect of this layer significantly improved after attachment . 

overall , is / os junction defects were demonstrated in 8/22 eyes ( 31.8% ) .
defects reached the central foveola in 4 eyes ( 8.8% ) , thus negatively affecting photoreceptor function and vision .
integrity of the is / os junction layer was preserved in only 3/18 eyes ( 16.7% ) after 2.5 years and is / os junction defects were diagnosed in 15/18 eyes ( 83.3% ) , 12 of which reached the foveolar region and adversely affected vision .
it is important to note that none of the treated patients progressed into the wet form during the 2.5-year follow - up . in the control group ,
6 eyes with detachment of the is / os junction at baseline developed choroidal neovascularization ( cnv ) ( confirmed by fluorescein angiography ) .
the amplitudes of foveal responses and responses in the most peripheral areas of the retina , as shown on the multifocal erg , changed only slightly during the entire follow - up period in both groups of patients . in the parafoveal and paramacular regions of eccentricity between 1.8 and 13
the differences were statistically nonsignificant between groups of patients in both periods of examination , except for the activity in the region of eccentricity between 1.8 and 7 , which was significantly higher in treated patients ( p = 0.04 ) at 2.5-year follow - up .
the implicit times of the majority of responses increased after 2.5 years in all patients . at baseline , they were significantly longer in the controls ( p values ranging from < 0.05 to < 0.01 ) , with the exception of the foveal response . at 2.5 years , the foveal response was significantly longer in the control group ( p = 0.035 ) .
in general , retinal activity remained stable or even improved in treated patients with early decrease or complete disappearance of dped and detachment of the photoreceptor is / os junction , along with preservation of its integrity or development of only small defects in the parafoveal region ( figures 2(a ) , 2(b ) , 2(c ) , 3(b ) , and 3(c ) ) .
in contrast , in patients with long - lasting or persistent dped with detachment of the is / os junction and development of its defects or even development of cnv , retinal activity was even reduced .
the photoreceptor is / os junction layer is currently receiving attention from many researchers [ 10 , 1822 ] . according to baba et al .
, the state of this thin hyper - reflective layer , which lies above the rpe layer , directly correlates with bcva after successful macular hole repair .
bcva deterioration has proved to be an early indicator of transformation to the wet form of amd .
we have verified the direct correlation of the state of the is / os photoreceptor junction and bcva on patients with stargardt disease .
disruption of the is / os junction is associated with poor vision in uveitic macular edema and retinitis pigmentosa [ 22 , 23 ] . as a result of our findings
, we can add the is / os junction as another indicator of the risk of transformation to the wet form of amd .
the detachment of the photoreceptor is / os junction ( figure 1 ) is usually located at the top of the area affected by drusenoid retinal pigment epithelium detachment ( dped ) .
sikorski et al . found that rupture of is / os photoreceptor junction detachment is directly associated with the emergence of submacular neovascularization .
schuman et al . reported thinning of the is / os photoreceptor layer and the progress of its changes over drusen and dped . in the present study
, we found reattachment of the photoreceptor is / os junction layer in the study group .
after the 2.5-year follow - up , 8 eyes were reattached without is / os junction defect after rhf ; the is / os junction defect was partially reattached in another 8 of the treated eyes . however , in only 4 of these eyes ( 18.1  % of the entire sample ) , the defect reached the central fovea . the fact that , after rheohemapheresis , patients only rarely developed the photoreceptor is / os junction defect affecting the central foveola and that mean visual acuity
actually slightly improved in the majority of these patients is considered an obvious interdependence . in control patients , we did not observe full restoration ( reattachment ) of a photoreceptor is / os junction layer when detached at the baseline .
drusenoid retinal pigment epithelium detachment usually progresses ( which was observed in 7 eyes ) ; otherwise , rupture occurs  caused by submacular neovascularization development , as has also been observed by other authors [ 24 , 25 ] .
the photoreceptor is / os junction layer rupture is usually apparent in patients with neovascularization .
the remaining fluid as well as the fluid under the detached drusenoid retinal pigment epithelium then spreads into the inner retinal layers and can cause macular edema . in the control group , we observed 6 cases ( 33.3% ) of submacular choroidal neovascularization .
the following is one possible mechanism of its development : the existing dped was later accompanied by a detached layer adjoined to it from above ( i.e. , by detachment of the photoreceptor is / os junction ) .
dped and is / os layer detachment gradually grew in size and eventually ruptured due to the development of submacular choroidal neovascularization .
as evidence of progression to the wet form of amd , fluid inside and underneath the inner retinal layer appeared on sd - oct .
these findings are supported by the findings of occult submacular choroidal neovascularization using fluorescein angiography .
patients with preservation of photoreceptor is / os junction integrity or development of only small , paracentral defects by early decrease or complete disappearance of the dped area also exhibited slightly increased retinal activity , which led to significantly higher parafoveal activity in treated patients using mferg ( see section 3.4 ) .
we found a significantly higher amplitude of parafoveal responses in eccentricity between 1.8 and 7 in treated patients 2.5 years after initiation of the treatment ( p = 0.04 ) .
in contrast , in patients with development of is / os junction defects or even progression of the disease to its wet form , central retinal activity and visual acuity were even reduced .
development of photoreceptor is / os junction defects in the control group probably contributed to the slight decrease of electrical retinal activity in the parafoveal and paramacular regions of eccentricity between 1.8 and 13 using mferg .
this may be due to the long - term accumulation of fluid between the rpe and is / os junctions , which causes  stretching  of photoreceptor outer segments , thus leading to their malfunction even without the development of associated rpe atrophy .
the question of treating the dry form of amd by rheohemapheresis has not yet been fully answered .
case series , two controlled trials and five completed randomized controlled trials , have reported the efficacy of rheohemapheresis in treating dry amd .
these studies ( inclusive of our two [ 3 , 26 ] ) have shown an improvement in the number of lines that can be read on etdrs charts , improvement in the pepper visual skills for reading tests , a decrease in viscosity parameters , shortening of arteriovenous passage times , and improvement in electroretinograms .
the studies have shown improvements shortly after completion of treatment , lasting up to four years [ 6 , 18 ] .
considerable confusion has been aroused by the preliminary results from the mira 1 study  an extensive , sham - controlled , randomized , multicenter trial conducted in the usa .
its encouraging first results were later challenged and a clear positive effect was not proved [ 27 , 28 ] .
however , analysis revealed that 37% of treated patients and 29% of control patients were protocol violators who did not fulfill the trial 's inclusion criteria of amd leading to bias in the study 's final outcome . excluding those subjects who had vision loss due to other causes
, this trial demonstrated significant improvement with treatment but the trial was underpowered by us fda licensure .
two hundred and seventy - nine patients with dry amd were treated and compared to 55 untreated controls . in the treated group , visual acuity gain greater than or equal to one etdrs line
vision loss greater than or equal to one etdrs line was seen in 17% of the treated patients versus 40% of controls .
the asfa ( american society for apheresis ) issues directives ( guidelines ) for individual procedures in various diseases ; according to the latest criteria from 2013 , rheohemapheresis is newly classified as a category ib treatment ( first line therapy ) .
the second limitation of this study is obviously the small number of patients , despite the relatively long follow - up .
the clinical impression of the importance of the is / os layer was established at the beginning of our research 7 years ago , but only patients with follow - up times longer than 2.5 years , that is , in the case of 40 eyes ( 22 eyes in the study group and 18 control eyes ) , were randomized for assessment of morphological and functional changes to the is / os layer .
our results will need to be confirmed on a larger number of patients in the future .
with the use of rheohemapheresis , preservation of photoreceptor is / os junction layer coherence in the fovea of patients with high - risk dry amd can be achieved , even when drusenoid retinal pigment epithelium detachment is already present .
after rheohemapheresis , there was a significant morphological improvement of the damaged is / os layer , as evidenced by reduction of the scope of the defect or reattachment of the detached is / os layer either with or even without the defect of this layer . after 2.5 years of follow - up , better visual acuity , reduced dped size , and improvement of some functional parameters ( electroretinography findings ) were observed in the study group .
 
 aim . to evaluate the long - term effect of rheohemapheresis ( rhf ) treatment of age - related macular degeneration ( amd ) on photoreceptor is / os junction status 
 . methods . in our study 
 , we followed 24 patients with dry amd and drusenoid retinal pigment epithelium detachment ( dped ) for a period of more than 2.5 years . 
 twelve patients ( 22 eyes ) were treated by rhf and 12 controls ( 18 eyes ) were randomized . 
 the treated group underwent 8 rhf standardized procedures . 
 we evaluated best - corrected visual acuity , is / os junction status ( sd oct ) , and macular function ( multifocal electroretinography ) at baseline and at 2.5-year follow - up . results . 
 rhf caused a decrease of whole - blood viscosity / plasma viscosity at about 15/12% . 
 bcva of treated patients increased insignificantly ( p = 0.187 ) from median 74.0 letters ( 56.2 to 81.3 letters ) to median 79.0 letters ( 57.3 to 83.4 letters ) , but it decreased significantly from 74.0 letters ( 25.2 to 82.6 letters ) to 72.5 letters ( 23.4 to 83.1 letters ) in the control group ( p = 0.041 ) . 
 the mferg responses in the region of eccentricity between 1.8 and 7 were significantly higher in treated patients ( p = 0.04 ) . 
 conclusions . 
 rhf contributed to sparing of photoreceptor is / os junction integrity in the fovea , which is assumed to be a predictive factor for preservation of visual acuity . 