Purpose
To investigate and compare the characteristics of colour Doppler ultrasound (CDUS) and contrast-enhanced ultrasound (CEUS) in degenerative retinoschisis (RS) and rhegmatogenous retinal detachment (RD).
Design
Prospective, observational case series.
Methods
We prospectively enrolled patients with degenerative RS, acute RD, or chronic RD at two tertiary centres from January 2024 to January 2025. Patients underwent clinical examination, ultrawide field photography and optical coherence tomography (OCT), and CDUS, followed by CEUS with Definity® microbubbles. Ultrasound characteristics between groups were compared.
Results
We included 65 eyes from 47 patients (25 male, median age 61.8). There were 51 eyes with RS, 6 eyes with acute RD, and 6 eyes with chronic RD. CDUS revealed no pre-contrast doppler flow in any RS, while all acute RD cases demonstrated doppler flow. CEUS displayed mild microbubble uptake in 18 RS cases (median bubble count of 2), whereas all RD cases exhibited florid uptake (median bubble count of 48.2). Compared to RS, acute RD cavities had significantly higher elevation from sclera (by 6.0 CI 2.8-9.2 mm), longer cavity lengths (by 9.8 CI 7.2-12.5), and greater membrane thickness (by 0.89 CI 0.6-1.2 mm). Chronic RD were significantly thicker than RS membranes (by 0.40 CI 0.2-0.6 mm) but were no longer or with greater elevation. Pixelated image analysis showed compared to RS, acute RD showed a higher average total particle count (by 45.83 units), larger particle size (by 66.3 pixels), and greater total particle area (by 3138 pixels). Chronic RD cases had mixed CDUS and CEUS findings.
Conclusions
CDUS features differentiating between degenerative RS and RD included the lack of doppler flow in RS, higher and longer cavities in acute RD, and thicker membranes in acute and chronic RD. CEUS features differentiating RS and RD included florid microbubble contrast enhancement in acute RD. These findings could aid in the investigation of cases with diagnostic uncertainty.
INTRODUCTION
D egenerative retinoschisis (RS) is a common age-related retinal degeneration characterised by the splitting of the neurosensory retina into inner and outer layers. The estimated overall prevalence is 3.9-7.1%, with the odds increasing with age. RS generally requires no intervention, however studies have demonstrated a progression rate to schisis-related retinal detachment (schisis-RD) in 0.05-8.3% of eyes. Schisis-RD confers a worse visual prognosis compared to rhegmatogenous retinal detachment (RDD). , , Additionally, RS can result in vitreous haemorrhage and vision-threatening posterior extension to the fovea. Accurate and timely discrimination between RD and degenerative RS can be challenging given both present as retinal layer elevation. There are cases of RS masquerading as RD upon optical coherence tomography (OCT) imaging, which may lead to unnecessary surgical intervention. Most cases of degenerative RS are identified incidentally on routine clinical examination. , However, clinical biomicroscopic examination can miss up to 36.3% of cases, with up to 65% of identified cases initially misjudged as RD. , Additionally, clinical exam has been shown to miss schisis-RD in up to 27.8% of eyes with known degenerative RS. ,
Existing retinal imaging options have limitations for diagnosing degenerative RS in certain settings. Spectral-domain optical coherence tomography (SD-OCT) is considered the gold standard for diagnosing RS, which can produce high-resolution images of individual retinal layers. , Previous studies have demonstrated a sensitivity of 94.6% in identifying RS cavities on OCT, with excellent visualisation of any associated retinal holes, detachments, and subretinal fluid. , However, in clinical practice OCT may be limited by media opacity, and its inability to visualise peripheral RS lesions, present in up to 20% of cases. , Ocular ultrasound (US) overcomes these issues but is limited by poor specificity in differentiating RS and RD, given the inability to visualise individual retinal layers. , , Additionally, existing studies are limited by very small samples sizes, and by inclusion of cases where US is guided by location on previous OCT imaging. ,
B-scan ultrasound (US) combined with colour doppler ultrasonography (CDUS) produces images by detecting blood flow in retinal vessels through acoustic signal. CDUS has demonstrated high accuracy in diagnosing RD, with a very high discrimination of RD from other vitreoretinal pathologies such as posterior vitreous detachment. , CDUS can be used with lipid coated microsphere contrast, which significantly increases the number of acoustic scatters from retinal vessels. Contrast enhanced doppler US (CEUS) is a relatively new imaging technique, and its use in retinal pathology is scarce. Emerging evidence shows it improves the sensitivity of CDUS in detecting RD from 57% to 100%. However, the evidence in this area is poor, and there remains no evaluation of the use of either CDUS or CEUS in the diagnosis of degenerative RS.
Given the current limitations in existing practice of diagnosing degenerative RS and differentiating it from RD, other options may be useful. We sought to explore the characteristics of doppler (CDUS) and microbubble-enhanced studies (CEUS) in cases of degenerative RS and RD in a prospective series of eyes. The implications of this research could assist in cases of diagnostic uncertainty.
METHODS
Study Design
This prospective, observational clinical study was approved by the Central Adelaide Local Health Network Human Research Ethics Committee (Reference number 13556) and the study adhered to the tenets of the Declaration of Helsinki. We prospectively enrolled patients identified on clinical exam to have degenerative RS, acute rhegmatogenous retinal detachment or chronic retinal detachment presenting to the Royal Adelaide Hospital and The Queen Elizabeth Hospital between January 2024 and January 2025. Written informed consent was gained for all enrolled participants.
Selection of Patients
We included patients aged 18 years or older confirmed to have degenerative RS or RD by SD-OCT imaging. Patients were initially identified either in outpatient ophthalmology clinics, after routine clinical examination or after presenting to the emergency department. All patients underwent clinical biomicroscopic examination, fundus photography (Nikon OPTOS®, USA) and OCT imaging (ZEISS CIRRUS® 5000 or Nikon OPTOS®, USA if peripheral lesion) to confirm and diagnose either degenerative retinoschisis or retinal detachment. The diagnostic criteria previously proposed by Ness et al. for degenerative RS were used including a relatively immobile transparent smooth or bullous elevation, lack of retinal tears, vitreous pigment cells or demarcation lines; presence of an absolute scotoma on automated perimetry (Humphrey Visual Field Analyser), failure to re-appose with scleral depression, and ability for retinal blanching upon laser photocoagulation. On OCT imaging, RS was characterised by a break in the outer plexiform layer, unlike RD which involved detachment of retina from RPE. We excluded all patients with myopic macular schisis, vitreo-schisis or previous retinal surgery or procedures including pneumatic procedures, cryopexy, panretinal photocoagulation and vitrectomy. Retinal barrier laser was allowed. The inclusion for RRD involved any adult patient with primary RRD defined as retinal detachment posterior to the equator with a definite associated causative retinal break (s) observed by fundoscopy. Both acute and chronic retinal detachments were included. RRD was classified as chronic if both of the following criteria were satisfied: a history of persistent retinal detachment on fundus exam for a minimum period of 30 days, and subretinal demarcation lines which were confirmed by an experienced vitreoretinal consultant. , The exclusion criteria for RD cases included secondary retinal detachment such as tractional, traumatic or exudative retinal detachment, macular hole induced RRD; those with previous retinal surgery or procedures such as pneumatic procedures, cryopexy, panretinal photocoagulation and vitrectomy (retinal barrier laser for chronic detachment was allowed).
Myopia was defined as mild (0 D to −1.5 D), moderate (−1.5 D to −6.0 D), high myopia (−6.0 D or more), and pathological (−8.0 D or more).
Doppler Ultrasound Imaging
All participants underwent a colour Doppler ultrasound of the eye performed by a single expert radiologist trained in ultrasound of the retina using a CDUS unit (GE LOGIQ TM E10) with a 21-MHz G6-24 Hockey Stick transducer. Patients were instructed to lie in a supine position with closed eyes and an initial resting gaze straight ahead with restriction of voluntary ocular movements. A 1-2cm thick layer of coupling gel was then applied to the closed eyelid and lashes to minimise air trapping. The examiner’s hand was cautiously not rested on the patient’s eyelid to minimise pressure on the eye.
Schisis cavities were first located on B-scan US in greyscale mode using horizontal, vertical, oblique scans coupled with directed ocular gaze movements. The cavity elevation, schisis membrane thickness, cavity length, and distance from optic nerve head (ONH) were measured. Colour doppler US was then performed with the colour box set at a size which covered the entire area of the site of inner retinal elevation and posterior pole of the eye, at the following settings: colour gain from 68% to 82%, wall filter at “low” or “medium” level, pulse repetition frequency (PRF) at 700-1000 Hz, and flow option in the “medium velocity” (MedV) or “high resolution” (HRes) mode. Real-time duplex US doppler examinations with colour and pulse doppler were recorded. The blood flow velocity and spectral waveforms in the central retinal artery were identified and recorded with a sample volume length of 2 mm. A significant Doppler finding in the RS or RD membrane was defined as whether continual waveforms with the same rates as in the central retinal artery could be observed.
Contrast Enhanced Doppler Ultrasound Imaging
Intravascular access was gained in the antecubital fossa via 20-G cannulation. Definity® Perflutren lipid microsphere 1.1 mg/ml was activated using VIALMIX® for 45 seconds. The contrast was then drawn into a 1 mL syringe, and 0.5 mL of contrast agent was administered followed by 10 mL saline flush. Imaging was then taken in contrast mode with mechanical index set at 0.9-1.3 for optimal visualisation of microbubble cavitation. Dual screen imaging was used so that a B-mode image could be used as a reference image for the CEUS image. Recording of contrast uptake for a minimum duration of 2 minutes, and an US cineclip was taken for retrospective viewing and analysis. Post-contrast infusion doppler studies were then repeated with colour doppler. The CDUS and CEUS data was collected from a formal radiology report with standardised data parameters for study purpose including cavity length, maximum cavity depth, membrane thickness, distance from optic nerve head, qualitative assessment of doppler flow (“low,” “moderate,” “florid”). Flow was qualitatively categorised from single radiologist (WL) interpretation, based on doppler flow compared to the central retinal artery. Pulse wave generation was attempted in all eyes with doppler signal, with peak systolic velocity (PSV) recorded if measurable. The microbubble study was quantified through counting of individual bubbles that appeared within the RS membrane over a 2-minute period. Microbubble uptake was categorised as “mild” (1-9 bubbles in membrane), “moderate” (10-49 bubbles) and “florid” (50+ bubbles), which was quantified by counting individual microbubbles. For all cases in which there was microbubble flow identified, a commercial software application (ImageJ, US National Institutes of Health, packages, Custom Particle Analyzer v0.1.54) was used to measure the total pixel area (TPA) in a region of interest drawn around the membranous with microbubble uptake, representing the signal intensity. Image colour threshold settings were as follow: Hue 0-255, Saturation 0-255 and Brightness set to 80. The brightness setting was determined by calibration to the maximal level achieved without capturing background artefactual vitreous colour pixels, ensuring that only microbubble-associated pixelation within the vitreous cavity was included. A region of interest surrounding the membrane was drawn to encompass all illuminated pixels, while a line was drawn parallel to the sclera to exclude any contributions from scleral microbubble uptake. Figure 1 demonstrates the particle counting process on NIH ImageJ. The greatest TPA from all CEUS image frames from 0-120 seconds post-contrast injection was recorded and used for further analysis. The mean pixel size, and pixel count was also recorded.
Statistical Analysis
Descriptive analysis summarises demographic, clinical and qualitative US findings. Continuous variables such as age were described using mean and standard deviation (SD) or median and interquartile range (IQR). Categorical variables were summarized using frequencies and percentages. The degree of vascularity on CDUS and CEUS between RS and RD cases was compared using generalised estimating equations generalised linear regression. All statistical analyses were performed using the statistical programming language R (packages geepack), and a p-value <.05 was considered statistically significant.
RESULTS
We included 51 cases of the degenerative RS from 33 patients, consisting of 18 males (55%) and 15 females (45%) with a median age of 63 years (range 27-78, IQR 55-70.5) ( Table 1 ). There were 31 cases involving the left eye (60.8%), and 20 involving the right eye (39.2%), and 18 of these patients presented with bilateral disease (35.3%). The median BCVA was 0.1 (IQR 0-0.2) LogMAR, i.e. 6/7.5 (IQR 6/6-6/9). The location of schisis lesion was inferotemporal in 74.5% of cases (38/51), and supertemporal in 25.5% (13/51). There were 2 eyes classified as medium myopia (3.92%), and no cases of high myopia.
| Characteristic | Degenerative RS (N = 51) | Acute RD (N = 6) | Chronic RD (N = 6) |
|---|---|---|---|
| Demographic | |||
| Male | 18 (55%) | 5 (83.3%) | 2 (33.3%) |
| Age | 63 (range 27-78) | 73 (range 62-78) | 55 (range 49-63) |
| Clinical features | |||
| BCVA (logMAR) | 0.1 (6/7.5) | 1.32 (6/120) | 0.05 (6/7.5) |
| IOP (mmHg) | 14 | 13 | 14.5 |
| Location | |||
| Inferotemporal | 38 (74.5%) | 0 | 5 (83.3%) |
| Superotemporal | 13 (25.5%) | 3 (50%) | 1 (16.7%) |
| Superonasal | 0 | 2 (33%) | 0 |
| Subtotal | 0 | 1 (17%) | 0 |
| B-mode Features | |||
| Elevation (mm) | 1.35 | 8.32 | 1.86 |
| Length (mm) | 7.39 | 17.79 | 10.7 |
| Membrane thickness (mm) | 0.34 | 1.19 | 0.74 |
| Distance from ONH (mm) | 13.4 | – | 11.6 |
| Doppler Features | |||
| Flow pre-CEUS | 0 | 6 (100%) | 2 (33.3%) |
| Flow post-CEUS | 2 (4.17%) | 6 (100%) | 2 (33.3%) |
| CEUS | |||
| No uptake | 30 (62.5%) | 0 | 2 (33.3%) |
| Mild | 18 (37.5%) | 0 | 0 |
| Moderate | 0 | 0 | 3 (50%) |
| Florid | 0 | 6 (100%) | 1 (16.7%) |
Within the acute RD group, there were 5 males (83%) and 1 female (17%), with a median age of 73 years (range 62 – 78, IQR 62.5-76). The median BCVA was 1.32 (IQR 0.25-2.1) LogMAR, i.e. 6/120 (IQR 6/12 – CF). The clinical location of detachment was superotemporal in 3 cases (50%), superonasal in 2 case (33%) and subtotal in 1 case (17%). There were 3 cases of macula-off RD and 3 cases of macula-on. There were no cases of medium or high myopia. Of the 6 cases of chronic RD, 2 were male (33.3%) and 4 were female (66.7%), with the left eye involved in 4/6 cases (66.7%) and right eye in 2/6 (33.3%). There was median age 55 years (IQR 49-63). The median BCVA was 0.05 (IQR -0.1-0.55) LogMAR, i.e. 6/7.5 (IQR 6/4.8-6/20). The average known duration of detachment was 1101 days (range 35-1461 days). There were 5 cases of inferotemporal detachment, 1 case of superotemporal detachment. Of chronic RD cases, there were two eyes with high myopia (33.3%). There were 2 cases of chronic RD that had barrier laser retinopexy. The demographic and clinical findings of included eyes are represented in Table 1 .
The RS lesion was found on B-mode US in 48/51 (94.1%) of cases. Of those characterised on US, there was mean elevation from sclera of 1.35 mm (range 0.1 mm – 4.2 mm), mean cavity length of 7.39 mm (range 3.3 mm-13.1 mm), mean RS membrane thickness of 0.34 mm (range 0.1 mm-0.9 mm), and average distance from ONH of 13.4 mm (range 7.1 mm-19.5 mm). Morphological characterisation for acute RD cases revealed mean elevation from sclera of 8.32 mm (range 3.02 mm-13.53 mm), mean detachment length of 17.79 mm (range 12.21 mm-21.2 mm), mean membrane thickness of 1.19 mm (range 0.6 mm-1.6 mm), with 5/6 cases crossing the ONH. The 6 cases of chronic RD had mean elevation from sclera of 1.86 mm (range 0.7 mm-3.24 mm), mean cavity length of 10.7 mm (range 12.2 mm-18.2 mm), mean membrane thickness of 0.74 mm (range 0.3 mm-1.21 mm), and mean distance from ONH of 11.6 mm (range 8.1 mm-15.3 mm).
On B-mode doppler interrogation there was no doppler flow evident in any RS cases. All 6 cases of acute RD revealed flow on doppler mode, with one case producing pulse wave PSV of 3 cm/s. Of the chronic RD, 2/6 displayed doppler flow, with mean PSV of 2 cm/s.
Upon CEUS, 18/48 RS cases displayed mild microbubble uptake, with a median bubble count of 2 (IQR 2-5). The average duration for the first evidence of microbubble uptake was 29.9 seconds (range 16-144). There were 2 cases that displayed post-CEUS doppler flow on B-mode US but were unable to produce pulse wave velocities. Only one of these cases displayed microbubble uptake on CEUS. All 6 cases of acute RD were described as florid microbubble uptake, with the average duration for first microbubble uptake being 12 seconds (range 11-19). All 6 cases showed post-CEUS doppler flow on B-mode, with one case producing a pulse wave PSV of 3 cm/s. There were 4/6 chronic RD cases that showed microbubble uptake on CEUS, with 3 cases of moderate uptake, and 1 case of florid uptake. The mean duration for first microbubble uptake was 25.3 seconds (range 7-44). There were 2 eyes that displayed post-CEUS doppler flow, with an average PSV of 2.5 cm/s. One of these eyes had moderate CEUS uptake, the other had florid uptake.
Upon pixelated image analysis, for the 18 RS cases that demonstrated microbubble uptake, there was a median particle count of 2 (IQR 2-4). The average particle size was 16.4 pixels (range 3-44 pixels), with an average TPA of 64.8 pixels (range 6-308 pixels). For the acute RD cases there was a median particle count of 48.2 (IQR 30.5-70.5). The average particle size was 66.3 pixels (range 43.3-111 pixels), with an average TPA of 3138 pixels (range 1332-5676 pixels). The 4 chronic RD cases with microbubble uptake had a median particle count of 11.5 (IQR 6.5-29), average particle size of 28.7 pixels (range 8.63-75.2 pixels), and an average TPA of 404 pixels (range 79-1053 pixels). CDUS and pixelated image analysis findings are displayed in Table 2 .
