vogt - koyanagi - harada disease ( vkh ) is a granulomatous inflammatory disorder affecting the eyes , auditory system , meninges , and skin [ 1 , 2 ] .
it is one of the most common causes of uveitis in asia and accounts for approximately 16% of all uveitis cases in china .
clinically , vkh is divided into four stages : prodromal , acute , convalescent , and chronic recurrent .
exudative retinal detachment is a common cause of visual function impairment among vkh patients , but secondary alterations in retinal morphology and function also occur [ 5 , 6 ] . due to advancements in retinal imaging , such as fundus autofluorescence ( faf )
[ 7 , 8 ] and optical coherence tomography ( oct ) [ 9 , 10 ] , important clinical insight into the pathophysiology of the retina can be achieved noninvasively .
recent studies report a significant association of the inner segment ( is)/os junction and the cone outer segment tips ( cost ) line in various retinal diseases with visual function [ 1113 ] .
however , the majority of previous studies have used best corrected visual acuity ( bcva ) as a measure of visual function .
recently , microperimetry was found to provide a more comprehensive assessment of macular sensitivity and functional changes in the macula [ 14 , 15 ] .
we investigated the characteristics of late - stage vkh via oct , especially photoreceptor microstructure integrity and its potential correlation to visual function .
patients with late - stage vkh ( defined as 12 months from disease onset ) who visited the uveitis clinic at fudan university eye and ent hospital ( shanghai , china ) between april 2011 and march 2013 were enrolled in this cross - sectional study .
the diagnosis of vkh was made according to the revised diagnostic criteria proposed by the international nomenclature committee .
the inclusion criteria were treatment with high - dose corticosteroid therapy ( iv methylprednisolone at 1  g / d for 3  d ) followed by a slow tapering of the drug dose over a 6-month period , undergoing a thorough examination , including oct and microperimetry , and providing the required information at the 12-month follow - up , including sex , age at vkh onset , bcva at initial presentation , current bcva , interval from the onset of vkh symptoms to the initiation of high - dose corticosteroid treatment , and current ocular inflammatory status .
exclusion criteria were inadequate mydriasis ( < 7  mm ) , media opacities ( caused by cataract or other ) , and glaucoma ( defined as characteristic optic nerve damage or typical visual field defects accompanied by compatible optic nerve damage ) .
this study was conducted in accordance with the tenets of the declaration of helsinki and was approved by the local ethics committee of the fudan university eye and ent hospital .
1.5.12.0 , heidelberg engineering , heidelberg , germany ) using the volume scan mode ( 1024  25 ; 25 lines , 1024 a - scans per line , each line comprising 30 averaged scans obtained using eye tracking ) , which covered a 30  30 degree area centered on the fovea .
microperimetry covered the central 12 of the macula ; therefore , only nine scans at the central macula ( firstly the scan across the central fovea was found and then subsequent four scans in both the superior and inferior directions were picked ) , which covers about 12 of the central macula , were selected for further analysis .
changes in the is / os junction , the cost line , and the rpe layer were graded by an experienced ophthalmologist ( chunhui jiang ) , who was masked for the clinical and other findings of the patients .
grading was performed using a scale from 1 to 3 based on a standardized protocol ( table 1 ) .
also if one part of the outer nuclear layer ( onl ) was thinner than the other , or all onl was obviously much thinner than normal , then it was considered as thinning of onl .
based on a 42 staircase strategy on a set of 45 goldmann iii stimulating spots covering the central 12 of the fundus , all tests were performed using an automated pattern in which a 1 circle was the target .
the intensity of each stimulus was varied according to a 1-step ( 0.1log ) scale from 020 decibels ( db ) for an equivalent duration of 200  ms per step .
the software automatically calculated the mean sensitivity , which was defined as the average of all 45 scores .
all analyses were performed using a statistical software package ( spss for windows , ver .
differences in mp and bcva between groups of late - stage vkh eyes with different oct grading were examined using the mixed linear model test .
differences in each prognostic factor ( sex , age of onset , initial bcva , and interval from onset to treatment ) were analyzed using generalized estimation equations test .
the durations between patients who were still using systemic corticosteroids alone or in combination with an immunosuppressant or not at 12 months were analyzed using mann - whitney u test .
during the study period , 34 vkh patients with a follow - up of longer than 12 months visited our clinic .
twenty - nine patients ( 15 males and 14 females , 58 eyes ) who met the inclusion criteria were enrolled in the study . the mean follow - up time was 12.2 months ( range 1214 months ) .
the mean age at onset was 34.24  10.67 years ( range 1265 years ) ; mean bcva at onset was 0.96  0.56 ( logmar , range 2.000 ) ; mean bcva at 12 months was 0.07  0.16 ( logmar , range 0.40 to 0.08 logmar ) ; and mean retinal sensitivity was 17.05  2.35  db ( range 9.920  db ) . at 12 months , 16 of the 29 patients were still using systemic corticosteroids alone or in combination with an immunosuppressant . among them , 10 patients were tapering down and using low - dose prednisone .
another six patients were receiving corticosteroids and cyclosporine prescribed at 3  mg / kg / d and were tapering , guided by the severity of ocular inflammation .
the oct findings in the late - stage vkh eyes were localized to the outer retina .
the findings included thickening of the rpe layer ( 28/58 eyes ) ; breakage or disappearance of the cost line ( 51/58 eyes ) and/or the inner segment / outer segment ( is / os ) junction ( 28/58 eyes ) ; and thinning of the outer nuclear layer ( onl ) ( 17/58 eyes ) .
the grading of the rpe , cost line , and is / os conjunction is listed in table 2 .
notably , all eyes displaying intact cost lines also displayed intact is / os junctions and normal rpe layers . however , 23 of the 30 eyes displaying intact is / os junctions displayed fragmented ( grade 1 , 3 eyes ; grade 2 , 20 eyes ) cost lines . in 18 of the 51 eyes displaying fragmented cost lines ( grade 1 or 2 ) and in 16 of the 28 eyes displaying fragmented is / os junctions ( grade 1 or 2 ) , the central fovea remained intact ( figures 1(a)1(c ) ) .
our analysis revealed a strong correlation between retinal sensitivity / bcva and the oct findings of the cost line , is / os junction , and rpe layer ( all p  0.01 , table 2 ) ( figure 2 ) .
for clarification , the patients were categorized according to the cost line and is / os junction characteristics , which were graded as intact ( + ) or not (  ) ( table 3 ) .
the three groups had similar gender / age distributions ( table 3 ) but different bcva and retinal sensitivities .
the is / os+/cost+ group displayed the best retinal sensitivity and bcva ; furthermore , only this group displayed relatively normal retinal sensitivity ( table 3 ) .
the oct findings for the cost line and is / os junction displayed clear correlations to the interval from symptom onset to the initiation of high - dose corticosteroid treatment and usage of systemic corticosteroids and/or immunosuppressant at 12 months after onset ( table 3 ) .
the is / os+/cost+ group exhibited the smallest interval from symptom onset to treatment and no usage of systemic corticosteroids and/or immunosuppressant .
in contrast , 11/23 and 21/28 patients in the is / os+/cost and is / os/cost groups were using systemic corticosteroids alone or in combination with an immunosuppressant .
patients who were using systemic corticosteroids alone or in combination with an immunosuppressant at 12 months had longer durations than those without ( using versus not using , median 30 versus 9 , p < 0.0001 by the mann - whitney u test ) .
changes of the outer retina and rpe in late - stage vkh patients , including thickening of the rpe layer , disruption or loss of the cost line and is / os junction , and thinning of the onl , were clearly demonstrated by sd - oct .
further analysis revealed a close correlation between these oct findings , which also correlated to the bcva , retinal sensitivity , and clinical characteristics .
better oct findings correlated to better vision , prompt treatment at disease onset , and less incidence of systemic corticosteroids and/or immunosuppressant at 12 months after onset . clinical findings of late vkh patients vary greatly . da silva et al .
recently reported that , in late - stage vkh eyes ( > 6 months past disease onset ) , grading by color fundus photos ( which was mainly based on diffuse fundus depigmentation or subretinal fibrosis ) correlated well with full - field electroretinogram ( erg ) results .
however , not all vkh patients had diffuse fundus depigmentation or subretinal fibrosis ; therefore , an objective method with higher resolution might be useful in the study of vkh patients with less fundus change .
oct is routinely used in the diagnosis and follow - up of many retinal diseases [ 913 ] .
reported defects in the is / os junction and multifocal thickening of the rpe in late - stage vkh patients .
however , the use of oct to identify retinal morphological changes in late - stage vkh patients has not been extensively studied [ 5 , 7 , 8 , 18 ] .
this study comprised a relatively large series of late - stage vkh patients , in whom oct clearly demonstrated retinal changes and rpe .
in addition to defects in the is / os junction and thickening of the rpe , thinning of onl and a high prevalence ( 51/58 ) of defects in the cost line were found , thereby indicating that oct is useful in the observation of late - stage vkh eyes .
all eyes displaying intact cost lines displayed normal is / os junctions or rpe layers , whereas those displaying intact is / os junctions or normal rpe layers displayed disrupted cost lines .
it has been reported in central serous chorioretinopathy   or macular hole   patients that the cost line is later to recover than are the is / os line and other characteristics .
notably , patients displaying cost line and is / os junction defects or loss at the perifovea exhibited intact structures at the central fovea .
the mechanism underlying this finding is not fully understood , but the high density of photoreceptors at the fovea may play an important role . alternatively , the cones at the fovea display a different configuration and arrangement than cones at other regions of the fundus , which might also explain these findings . whether these structures were preserved or were first to regenerate , studying
the mechanism behind this characteristic might improve our understanding of vkh and of the neuroprotection or neuroregeneration of the retina .
our study also demonstrated a strong correlation between the cost line and/or is / os junction integrity and visual function in late - stage vkh patients .
a former paper reported a similar correlation in patients with macular holes [ 12 , 20 ] .
however , bcva was employed as the measure of visual function in previous studies . this time , microperimetry , which provides a quantitative measurement of retinal sensitivity at the macula ,
, we found that only the is / os+/cost+ eyes exhibited normal results ( is / os+/cost+ group : 19.56  0.36  db ; normal group : 19.1  0.9  db ) .
these results suggest that the presence or reappearance of an intact cost line might serve as a more sensitive indicator of photoreceptor functional status than that of the is / os junction . in accordance with yokota 's report of a higher cone density in eyes displaying intact cost lines than in eyes displaying disrupted cost lines , our finding supported fujita and itoh 's theory that the recovery of the cost line , but not the is / os junction , suggests enhanced restoration of the photoreceptors [ 11 , 12 ] . on the other hand , it might also suggest that retinal sensitivity measured by microperimeter appeared to be able to provide a comprehensive and accurate evaluation of macular function in late - stage vkh patients and might do the same in patients with other retinal diseases .
the oct findings were also related to the mean interval from symptom onset to the initiation of systemic steroid therapy and using of systemic corticosteroids and/or immunosuppressant at 12 months after onset ( table 3 ) .
therefore , the interval from symptom onset to the initiation of systemic steroid therapy is an important prognostic factor for patients with late - stage vkh .
chee reported that early treatment ( < 2 weeks ) of high - dose corticosteroids was associated with better visual results in vkh patients .
our is / os+/cost group displayed a relatively normal bcva and an average treatment interval of 20.22  13.12 days .
in contrast , only the cost+/is / os+ group exhibited normal retinal sensitivity , normal bcva , and treatment interval of 6.71  0.76 days .
this result suggests that more prompt treatment might be required to achieve complete restoration of macular structure and function .
the importance of prompt treatment was also suggested by the correlation with less incidence of systemic corticosteroids and/or immunosuppressant at 12 months after onset .
the strengths of our study include its well - defined population who underwent standard long - term follow - up .
a relatively large sample size was achieved by using sophisticated statistics like  mixed linear model  and others .
these methods correct the dependence of both eyes from the same patients , so both eyes of the patients could be included . the primary outcome measures used in this study (
oct findings , microperimetry , retinal sensitivity , and bcva ) are largely objective measures that are easily quantifiable .
the study 's retrospective design is a limitation , as is the fact that longitudinal assessment of disease activity and visual function could not be assessed due to the use of a cross - sectional study design .
the mechanisms underlying particular findings , such as the preservation of the retinal structure at the fovea , are not fully understood .
further follow - up study might be able to tell us more about how these vkh patients recovered from their acute episode and how the functional and anatomic recovery were correlated . in summary ,
our study demonstrated a significant correlation between the oct findings and visual function in late - stage vkh patients , as determined via bcva and microperimetry .
the integrity of the cost line was more sensitive than that of the is / os junction .
moreover , prompt initiation of high - dose corticosteroid treatment was associated with improved prognosis for visual function , retinal structure , and less incidence of systemic corticosteroids and/or immunosuppressant at 12 months .
 
 purpose . to characterize the optical coherence tomography ( oct ) findings in late - stage vogt - koyanagi - harada ( vkh ) disease and its correlation with visual function 
 . methods . 
 the records of patients with late - stage vkh disease ( defined as 12 months from disease onset ) were retrospectively reviewed . 
 the analysis focused on the oct findings and microperimetry , in addition to the possible correlation between morphology and functional findings . 
 results . 
 twenty - nine patients ( 58 eyes ) were included . 
 mean age at onset was 34.24  10.67 years . 
 the oct revealed that the outer retina and retinal pigment epithelium ( rpe ) were mainly affected . 
 these effects included rpe thickening and breakage or disappearance of the cone outer segment tip ( cost ) line and/or inner segment / outer segment ( is / os ) junction . 
 the cost line and is / os results were related to macular function and the interval between symptom onset and initiation of high - dose corticosteroid treatment ( all p < 0.01 ) . 
 eyes with intact cost lines demonstrated intact is / os and normal rpe layers as well as better visual function and normal retinal sensitivity . conclusions . 
 the oct findings are strongly correlated with macular function , as well as other clinical findings in late - stage vkh . with respect to the cost line and retinal sensitivity 
 especially , the oct and microperimetry findings may be useful for evaluating later - stage vkh . 
1. Introduction
2. Methods
3. Results
4. Discussion