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   Table of Contents      
ORIGINAL ARTICLE
Year : 2016  |  Volume : 64  |  Issue : 11  |  Page : 829-834

Pearl necklace sign in diabetic macular edema: Evaluation and significance


1 Department of Ophthalmology, M. S. Ramaiah Medical College, Bengaluru, Karnataka, India; Department of Ophthalmology, Wolverhampton Eye Infirmary, New Cross Hospital, Wolverhampton, England, UK
2 Department of Ophthalmology, Wolverhampton Eye Infirmary, New Cross Hospital, Wolverhampton, England, UK

Date of Submission07-Jul-2016
Date of Acceptance09-Oct-2016
Date of Web Publication13-Dec-2016

Correspondence Address:
Kshirasagar Ajay
18th Main Road, 6th Block, Koramangala, Bengaluru - 560 095, Karnataka, India

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0301-4738.195597

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  Abstract 

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.

Keywords: Diabetic macular edema, hard exudates precursor, pearl necklace sign


How to cite this article:
Ajay K, Mason F, Gonglore B, Bhatnagar A. Pearl necklace sign in diabetic macular edema: Evaluation and significance. Indian J Ophthalmol 2016;64:829-34

How to cite this URL:
Ajay K, Mason F, Gonglore B, Bhatnagar A. Pearl necklace sign in diabetic macular edema: Evaluation and significance. Indian J Ophthalmol [serial online] 2016 [cited 2017 Jul 26];64:829-34. Available from: http://www.ijo.in/text.asp?2016/64/11/829/195597

Hyperreflective dots on macular optical coherence tomography (OCT) scan of eyes with diabetic macular edema (DMO) have been observed across all retinal layers and within the walls of intraretinal microaneurysms.[1],[2] In existing literature, there has been a debate about the nature and origin of these dots. Some authors have attributed these dots to subthreshold hard exudates.[2],[3],[4]

Gelman et al.[5] reported a series of 21 eyes with chronic exudative maculopathy where these hyperreflective dots were arranged as a contiguous ring along the inner wall of cystoid spaces in the retina (pearl necklace sign). They speculated that this sign indicated the presence of lipoproteins or lipid-laden macrophages in patients with exudative maculopathy and chronic cystoid macular edema.[5]

We conducted this study to estimate the prevalence of this "pearl necklace" sign seen on spectral domain OCT (SDOCT) in eyes with DMO and study the evolution of this sign following intravitreal therapy with ranibizumab. This would help confirm or refute the speculation of these dots being subthreshold hard exudates and could throw light on the visual prognosis in such eyes.


  Materials and Methods Top


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. All patients received intravitreal treatment in a "one-stop" setting as per the treatment protocol.

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 μ, as per NICE guidelines,[6],[7] 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" sign); the location of these cystoid spaces was noted for each case. 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, same sections were performed to allow matching sections for evaluation. 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.


  Results Top


Totally, 267 patients (age 24-91 years, 64 ± 14.8 years) were seen and initiated on intravitreal ranibizumab therapy in the DMO clinic between April 2013 and March 2015. All eyes were treatment naïve. 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 [Figure 1] and lining the inner wall of a neurosensory detachment in 5 eyes [Figure 2]. The follow-up period ranged between 10 and 24 months (16 ± 4 months).
Figure 1: Pearl necklace sign in outer plexiform layer

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Figure 2: The sign in subretinal space

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Table 1: Details of patients displaying pearl necklace sign


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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 μ at baseline and 365 ± 62.3 μ 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 [Figure 3]a, which were also visible clinically [Figure 3]b. The location of these hard exudate clumps was closely associated with the location of the intraretinal/subretinal cysts seen on OCT [Figure 4]a-c and correlated with the color fundus photograph [Figure 5]a-c. In seven eyes, as the edema resolved, the pearl necklace sign disappeared completely, without leaving visible hard exudates. Macular edema and the pearl necklace sign persisted, despite treatment in seven eyes.
Figure 3: (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

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Figure 4: (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++

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Figure 5: (a) Pearl necklace sign before treatment. (b) Optical coherence tomography scan at month 3 posttreatment showing HE. (c) Color fundus photograph of the eye in Fig. 5b showing new clump of HE in the location of pearl necklace

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In three eyes, the pearl necklace sign was seen in cystoid spaces located subfoveally [Figure 6]a. With intravitreal therapy, although there was resolution of macular edema, large clumps of hard exudates appeared subfoveally [Figure 6]b. This was associated with a drop in the vision of 20 letters or more in these three eyes.
Figure 6: (a) Subfoveal pearl necklace sign. (b) Three injections later HE++ subfoveally

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  Discussion Top


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.[8],[9] 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.[10]

The presence of similar HF on SDOCT, across all retinal layers, has also been reported in DMO.[1],[2],[4] Gelman et al.[5] 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. Five of these eyes had DMO.

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. This confirms the previously held belief that intraretinal HF represent precursors of hard exudates. 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 μ are comparable to those achieved in RESTORE and DRCRnet studies.[11],[12]

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.


  Conclusions Top


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.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Framme C, Schweizer P, Imesch M, Wolf S, Wolf-Schnurrbusch U. Behavior of SD-OCT-detected hyperreflective foci in the retina of anti-VEGF-treated patients with diabetic macular edema. Invest Ophthalmol Vis Sci 2012;53:5814-8.  Back to cited text no. 1
    
2.
Bolz M, Schmidt-Erfurth U, Deak G, Mylonas G, Kriechbaum K, Scholda C; Diabetic Retinopathy Research Group Vienna. Optical coherence tomographic hyperreflective foci: A morphologic sign of lipid extravasation in diabetic macular edema. Ophthalmology 2009;116:914-20.  Back to cited text no. 2
    
3.
Ota M, Nishijima K, Sakamoto A, Murakami T, Takayama K, Horii T, et al. Optical coherence tomographic evaluation of foveal hard exudates in patients with diabetic maculopathy accompanying macular detachment. Ophthalmology 2010;117:1996-2002.  Back to cited text no. 3
    
4.
Uji A, Murakami T, Nishijima K, Akagi T, Horii T, Arakawa N, et al. Association between hyperreflective foci in the outer retina, status of photoreceptor layer, and visual acuity in diabetic macular edema. Am J Ophthalmol 2012;153:710-7.  Back to cited text no. 4
    
5.
Gelman SK, Freund KB, Shah VP, Sarraf D. The pearl necklace sign: A novel spectral domain optical coherence tomography finding in exudative macular disease. Retina 2014;34:2088-95.  Back to cited text no. 5
    
6.
NICE Guidance. Ranibizumab for Treating Diabetic Macular Oedema. Available from: https://www.nice.org.uk/guidance/ta274. [Last accessed on 2016 Sep 30].  Back to cited text no. 6
    
7.
NICE Guidance. Fluocinolone Acetonide Intravitreal Implant for Treating Chronic Diabetic Macular Oedema after an Inadequate Response to Prior Therapy. Available from: http://www.nice.org.uk/guidance/ta301. [Last accessed on 2016 Sep 30].  Back to cited text no. 7
    
8.
Coscas G, De Benedetto U, Coscas F, Li Calzi CI, Vismara S, Roudot-Thoraval F, et al. Hyperreflective dots: A new spectral-domain optical coherence tomography entity for follow-up and prognosis in exudative age-related macular degeneration. Ophthalmologica 2013;229:32-7.  Back to cited text no. 8
    
9.
Ogino K, Murakami T, Tsujikawa A, Miyamoto K, Sakamoto A, Ota M, et al. Characteristics of optical coherence tomographic hyperreflective foci in retinal vein occlusion. Retina 2012;32:77-85.  Back to cited text no. 9
    
10.
Framme C, Wolf S, Wolf-Schnurrbusch U. Small dense particles in the retina observable by spectral-domain optical coherence tomography in age-related macular degeneration. Invest Ophthalmol Vis Sci 2010;51:5965-9.  Back to cited text no. 10
    
11.
Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, Massin P, Schlingemann RO, et al. The RESTORE study: Ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology 2011;118:615-25.  Back to cited text no. 11
    
12.
Diabetic Retinopathy Clinical Research Network (DRCR.net), Beck RW, Edwards AR, Aiello LP, Bressler NM, Ferris F, et al. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol 2009;127:245-51.  Back to cited text no. 12
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
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