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. 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.
Gelman et al. 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.
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
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, 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.
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 [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).
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 [Fig. 3a], which were also visible clinically [Fig. 3b]. The location of these hard exudate clumps was closely associated with the location of the intraretinal/subretinal cysts seen on OCT [Fig. 4a–c] and correlated with the color fundus photograph [Fig. 5a–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.
In three eyes, the pearl necklace sign was seen in cystoid spaces located subfoveally [Fig. 6a]. With intravitreal therapy, although there was resolution of macular edema, large clumps of hard exudates appeared subfoveally [Fig. 6b]. 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. 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.
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.
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Conflicts of interest
There are no conflicts of interest.
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
2. Bolz M, Schmidt-Erfurth U, Deak G, Mylonas G, Kriechbaum K, Scholda CDiabetic Retinopathy Research Group Vienna. . Optical coherence tomographic hyperreflective foci: A morphologic sign of lipid extravasation in diabetic macular edema Ophthalmology. 2009;116:914–20
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
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
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
6. NICE Guidance. Ranibizumab for Treating Diabetic Macular Oedema.Last accessed on 2016 Sep 30 Available from: https://www.nice.org.uk/guidance/ta274
7. NICE Guidance. Fluocinolone Acetonide Intravitreal Implant for Treating Chronic Diabetic Macular Oedema after an Inadequate Response to Prior Therapy.Last accessed on 2016 Sep 30 Available from: http://www.nice.org.uk/guidance/ta301
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
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
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
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
12. Beck RW, Edwards AR, Aiello LP, Bressler NM, Ferris F, et alDiabetic Retinopathy Clinical Research Network (DRCR-net). 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