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this study was conducted at a tertiary eye care center , catering to a population of approximately a million .
all patients on the diabetes mellitus register held at general practices in the catchment population were screened by a national diabetic eye screening program , and all patients with referable diabetic retinopathy ( dr ) were seen in dedicated dr clinics . in these clinics ,
all patients underwent a comprehensive ophthalmic examination , including visual acuity evaluation , slit - lamp examination , and dilated fundus examination , along with sdoct imaging and infrared fundus photography , and those patients who met the nice guidelines for intravitreal treatment with ranibizumab were referred to a dedicated dmo clinic .
we retrospectively reviewed sdoct images of all eyes that were initiated on intravitreal ranibizumab treatment for dmo with central subfield thickness ( cst ) more than 400  , as per nice guidelines , between april 2013 and march 2015 .
each oct was carefully observed for the presence of hyperreflective dots in a contiguous ring around the inner wall of cystoid spaces (  pearl necklace 
images of patients displaying this sign were singled out and these were sequentially followed up for a minimum of 10 months to track the course of this sign .
sdoct images were acquired at every clinic visit as part of the established standard of care using the macula protocol for heidelberg sdoct ( spectralis hra + oct ; heidelberg engineering , heidelberg , germany ) .
octs were performed with volume scans with at least 19 single sections . on each follow - up
the oct images of patients included for the study were matched with the infrared fundus photograph of the corresponding location .
clinical charts were retrospectively reviewed and patient characteristics of age , gender , electronic early treatment for diabetic retinopathy study visual acuity and response to treatment , were recorded and correlated with sdoct imaging findings .
totally , 267 patients ( age 2491 years , 64  14.8 years ) were seen and initiated on intravitreal ranibizumab therapy in the dmo clinic between april 2013 and march 2015 .
35 eyes of 35 patients ( 23 males , 12 females ) were found to display the pearl necklace sign , giving a prevalence of 13.1% in our cohort of patients [ table 1 ] .
this sign was seen in cystoid spaces located in the outer nuclear / outer plexiform layer of the retina in 30 eyes [ fig . 1 ] and lining the inner wall of a neurosensory detachment in 5 eyes [ fig . 2 ] .
the follow - up period ranged between 10 and 24 months ( 16  4 months ) .
details of patients displaying pearl necklace sign pearl necklace sign in outer plexiform layer the sign in subretinal space in the 35 eyes showing the pearl necklace sign , the mean best - corrected visual acuity ( bcva ) letter score at the start of treatment was 46.7  12.9 letters ; at the final follow - up , the mean bcva was 53.5  14.1 letters . of the 35 eyes , 15 ( 42.8% ) improved by 10 letters or more ; 3 eyes lost 10 or more letters over the follow - up period .
the mean cst was 524  82  at baseline and 365  62.3  at final follow - up .
qualitative assessment of the pearl necklace sign over the follow - up period showed that of the 35 eyes , 28 showed a significant reduction in macular edema , and in 21 eyes the hyperreflective dots forming the pearl necklace coalesced to form a clump .
this appeared as a visible clump of hard exudates in infrared fundus photographs [ fig .
the location of these hard exudate clumps was closely associated with the location of the intraretinal / subretinal cysts seen on oct [ fig .
as the edema resolved , the pearl necklace sign disappeared completely , without leaving visible hard exudates .
( a ) optical coherence tomography of the eye in fig . 1 at month 3 ; fluid resolved and hard exudate clump at exactly the same spot .
( b ) color fundus photograph of the eye in fig . 3a ; clinically visible hard exudate in the area of pearl necklace ( a ) intraretinal pearl necklace extrafoveally .
( b ) four injections later showing partial resolution of edema and he in the same location as a pearl necklace .
( c ) 12 months and 10 injections later ; he++ ( a ) pearl necklace sign before treatment .
5b showing new clump of he in the location of pearl necklace in three eyes , the pearl necklace sign was seen in cystoid spaces located subfoveally [ fig .
with intravitreal therapy , although there was resolution of macular edema , large clumps of hard exudates appeared subfoveally [ fig .
this was associated with a drop in the vision of 20 letters or more in these three eyes .
multiple studies published previously have described  hyperreflective foci  ( hf ) , detectable by sdoct techniques , in various retinal pathologies , including exudative age - related macular degeneration and retinal vein occlusion . in age - related macular degeneration , it has been reported that after a loading dose of three intravitreal ranibizumab injections , the number of hfs reduced ; the number of such hf at baseline was suggested as a predictive factor for the outcome of treatment . the presence of similar hf on sdoct , across all retinal layers , has also been reported in dmo .
gelman et al . described a novel  pearl necklace sign  of the contiguous ring of hyperreflective dots along the inner wall of cystoid spaces in the retina in 21 eyes with exudative macular diseases .
we found that this sign is not uncommon in dmo and was seen in 13.1% eyes in our series of patients .
75% of eyes where the dmo resolved with treatment developed clinically visible hard exudates in exactly the same location as the pearl necklace sign .
the characteristic arrangement along the wall of the cystoid spaces may indicate a relatively large amount of lipoproteins / lipid - laden macrophages that tend to precipitate and leave behind clinically observable hard exudates once the edema resolves following intravitreal therapy .
we did not find that the presence of this either predicts or adversely affects the outcome of treatment .
our results of a mean letter gain of 6.8 letters with 42.8% eyes improving by 10 letters or more and mean reduction in cst of 159  are comparable to those achieved in restore and drcrnet studies .
however , of note is the fact that three eyes that had a dramatic loss of vision ( 20 letters or more ) had subfoveal  pearl necklace sign  and a large clump of hard exudates appeared subfoveally as the edema resolved in these three eyes .
we infer that the presence of this sign in a subfoveal location may result in accumulation of this particulate entity subfoveally ( clinically visible hard exudates ) , causing irreversible damage to photoreceptors in that area , thereby limiting the long - term visual outcome .
hyperreflective dots arranged as a contiguous ring along the inner wall of cystoid spaces on the macular oct scan , termed as the pearl necklace sign , are commonly seen in dmo patients who require intravitreal treatment . with a resolution of edema ,
hard exudates frequently appear in the same location on the retina , implying that the pearl necklace sign is a precursor to hard exudates , in the majority of cases .
the presence of this sign does not affect visual prognosis or the response to intravitreal treatment , except where this sign is located subfoveally .
purpose:(1 ) the purpose of this study was to describe significance and prevalence of the newly reported pearl necklace spectral domain optical coherence tomography ( sdoct ) sign , in diabetic macular edema ( dmo ) , ( 2 ) to track the course of this sign over a period of at least 10 months.materials and methods : the pearl necklace sdoct sign refers to hyperreflective dots in a contiguous ring around the inner wall of cystoid spaces in the retina , recently described for the first time in 21 eyes with chronic exudative maculopathy . 
 a retrospective analysis was performed of sdoct images of all patients presenting to the dmo referral clinic of a tertiary eye care center , over a period of 24 months . 
 images of patients displaying this sign were sequentially analyzed for at least 10 months to track the course of the sign.results:thirty-five eyes of 267 patients ( 13.1% ) were found to display the pearl necklace sign . 
 twenty - eight eyes responded to intravitreal ranibizumab treatment with resolution of edema . in 21 eyes , 
 the dots coalesced to form a clump , visible in the infrared fundus photograph as hard exudates ; in seven eyes , dots disappeared without leaving visible exudates . in three eyes , the sign was seen in subfoveal cystoid spaces , with subsequent development of hard exudates , and drop in visual acuity of 20 letters or more.conclusion:pearl necklace sdoct sign is not infrequent in dmo . 
 this sign is a precursor to hard exudates in the majority of cases . 
 if this sign is seen subfoveally , drop in visual acuity can be expected , despite treatment .