Six Tips for Detecting Proliferative Diabetic Retinopathy

Diabetic retinopathy (DR) is a major cause of blindness globally and the leading cause of vision loss in adults aged 20–74 years.1 Vision loss is most commonly caused by the development of diabetic macular oedema or proliferative DR (PDR).¹ In clinical practice, new vessels may be overlooked when they develop outside the posterior pole, resulting in misdiagnosis and delayed treatment.^2,3

Advanced imaging modalities, such as OCT, OCTA and ultra-widefield imaging, have greatly enhanced detection of both early and vision-threatening DR

Figure 1a. Left Optos widefield image of a 58 year-old male with type 2 diabetes diagnosed more than 10 years earlier. He has a history of poor glycaemic control with recent improvement of his HbA1c. Imaging shows five areas of pre-retinal neovascularisation (yellow arrows) in the nasal and inferior midperiphery, not visible in the posterior pole photo. The inferior neovascular fronds are associated with early pre-retinal fibrosis. Other retinopathy signs include a ghost vessel nasally and dot/blot haemorrhages.

Advanced imaging modalities, such as OCT, OCTA and ultra-widefield imaging, have greatly enhanced detection of both early and vision-threatening DR. A recent systematic review⁴ concluded that OCT and widefield OCTA are invaluable in the diagnosis, staging and management of PDR. Compared to traditional ETDRS 7-standard field images (which encompass the posterior pole and some of the retinal midperiphery), ultra-widefield imaging has been shown to result in a higher retinopathy grade in 10% of patients due to the detection of more pathology.²

The following six key tips will enhance your ability to detect and diagnose PDR.

1. DILATE THE PUPILS AND CAREFULLY EXAMINE OUTSIDE THE POSTERIOR POLE

Figure 1b. Only microaneurysms and
dot haemorrhages are evident in
the posterior pole fundus photo.

The American Diabetes Association Position Statement on Diabetic Retinopathy (2017) states that retinal photos are not a substitute for a comprehensive eye exam, which should include dilated slitlamp biomicroscopy with a hand-held fundus lens, indirect ophthalmoscopy, and supplemental imaging as appropriate.⁵ Haemorrhages, intraretinal microvascular abnormalities (IRMA) and neovascularisation elsewhere (NVE) frequently develop outside the posterior pole. Silva et al found that 22% of eyes with PDR had no new vessels within the central region of the retina (within the region of the 7-standard fields).³ Talks et al found that nearly 12% of eyes in a retinal screening program had NV outside the region of two-field fundus photography.⁴ Clinically, this means that new vessels may be overlooked in around one-fifth of patients when only the posterior pole is examined.

Figure 2a. Right retinal photo of a 44-year-old male with type 2 diabetes diagnosed 15 years earlier and PDR. He has a history of amputation and renal disease. The photo demonstrates a pre-retinal and vitreous haemorrhage at the inferior vascular arcades. Numerous intraretinal haemorrhages and cotton wool spots are also present. NV and pre-retinal fibrosis at the optic disc are difficult to visualise.

2. CONSIDER WIDEFIELD IMAGING AS A SUPPLEMENT TO FUNDUSCOPY

New vessels can be easily overlooked during a dilated fundus examination due to their subtle appearance and often peripheral location (Figure 1). Additional factors impacting the ability to detect NVE with funduscopy include poorly dilating pupils, cataract, eye movements, patient photosensitivity and, more recently, lens fogging issues secondary to mask wear that have arisen during the COVID-19 pandemic. Widefield imaging devices can often overcome these limitations, due to the properties of scanning laser ophthalmoscopy and the ability to use filters (gamma and red-free), and magnification to allow for more accurate diagnosis of DR outside the posterior pole.

3. PERFORM OCT IMAGING WHEN NVD IS SUSPECTED

OCT is invaluable in confirming a diagnosis of NVD, particularly when our funduscopic view is impaired. Vaz-Pereira and colleagues4 described the OCT features of NVD as usually appearing as hyper-reflective tissue on the surface of the disc or protruding outwards and attached to the posterior hyaloid of the vitreous (Figure 2). In the advanced stages, the new vessels are associated with thick hyper-reflective fibrous tissue that can extend along the posterior hyaloid and over the parapapillary retinal surface. OCT studies have confirmed that the posterior hyaloid provides a scaffold for the new vessels and that active NVD is more frequent in eyes that have not undergone posterior vitreous detachment. Occasionally, the NVD will breach the posterior hyaloid and proliferate into the vitreous cavity.

Figure 2b. Spectralis OCT line scan through the right optic disc demonstrate NVD, seen as hyper-reflective tissue extending from the surface of the optic disc (white arrows) and extending along the posterior hyaloid of the
vitreous (yellow arrows).

4. USE OCT TO DIFFERENTIALLY DIAGNOSE BETWEEN IRMA AND NVE

Differential diagnosis of IRMA and NVE can be difficult due to the often-subtle and similar clinical appearance of these DR lesions. Structural OCT line scans, placed over the region of interest, can be useful to demonstrate the presence or absence of new vessels on the surface of the retina (Figure 3). Typically, NVE appear as homogenous hyper-reflective loops breaching the internal limiting membrane (ILM) and protruding into the vitreous (with the posterior hyaloid serving as a scaffold), whereas IRMA appears as hyper-reflective dots within the inner retinal layers. In case of NVD where vitreous traction is present, the new vessels remain tethered to the retina but are pulled anteriorly, creating a ‘tabletop’ appearance on structural OCT.⁴

Figure 3a. Right retinal photo of a 33-year-old female with type 1 diabetes diagnosed 17 years earlier. She has a history of poor glycaemic control. There is a neovascular frond in the superior mid-periphery.

5. LOOK CAREFULLY FOR SIGNS OF RETINAL ISCHAEMIA

Neovascularisation develops at the border of a relatively perfused and ischaemic retina. As a result, examining the retina carefully for accompanying signs of ischaemia (such as cotton wool spots, IRMA, venous beading, featureless retinal appearance, and retinal ghost vessels) may lead to an earlier diagnosis of PDR and/ or more frequent follow-up intervals where retinal ischaemia is suspected. Subtler signs of ischaemia, including ‘pruning’ of the retinal capillaries, capillary dropout and IRMA are more easily visualised with OCT angiography (Figure 4).⁴

6. CONSIDER OCT-ANGIOGRAPHY IN EYES WITH SIGNS OF RETINAL ISCHAEMIA

Figure 3b. Spectralis line scans confirmed the presence of NVE, seen as hyper-reflective neovascular tissue on the ILM and extending along the posterior hyaloid of the vitreous (yellow arrows).

OCTA enhances diagnosis of NV and IRMA but clinicians should keep in mind that these lesions may be missed if they fall outside the imaged region of the retina. Widefield angiography has been demonstrated to have excellent sensitivity for detecting NV due to the larger field of view.⁴ OCTA generally shows NVE as an irregular mass of vessels with positive flow above the ILM (Figure 5), whereas IRMA shows positive flow within the inner retina.

AN OPPORTUNITY TO IMPROVE OUTCOMES

Advances in retinal imaging are providing invaluable insights into proliferative diabetic eye disease. A multimodal approach (including retinal photography, ultra-widefield imaging, OCT imaging and dilated fundus examination) results in earlier diagnosis as well as more timely systemic interventions. In the case of severe NPDR and PDR, earlier referral to an ophthalmologist for treatment provides our patients with the best chance of maintaining good vision.

Figure 4. OCT angiography (montage) demonstrates areas of reduced capillary perfusion (yellow arrows), most marked in the retinal midperiphery, IRMA (blue arrows) and early NVE (white arrow).

Paula Katalinic BOptom, MOptom, GradCertOcTher is the Lead Clinician (Diabetes and Vascular Disease) at Centre for Eye Health Australia (CFEH). Ms Katalinic’s interest in the early diagnosis of ocular diseases, imaging and diabetic retinopathy began early in her career when she worked with the Joslin Diabetes Centre’s Beetham Eye Institute in Boston. Upon her return to Australia, she worked as a staff optometrist at UNSW and concurrently took on the role of Professional Services Manager at Optometry NSW/ ACT, a position she still holds today. Ms Katalinic joined CFEH at its inception in 2009 and during this time has had a strong focus on the provision of both clinical services and education while also being involved in clinical research. She has been invited to speak at conferences in Australia, New Zealand and the United States. 

Figure 5a. Left retinal photo of a 40-year-old male with type 2 diabetes and suspected NVD.

References 

1. Lee R, Wong TY et. al. Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss. Eye Vis (Lond) 2015 Sep 30;2:17.doi: 10.1186/s40662- 015-0026-2. eCollection 2015. 
2. Silva PS, Cavallerano JD, Haddad NMN, et al. Peripheral lesions identified on ultrawide field imaging predict increased risk of diabetic retinopathy progression over 4 years. Ophthalmology. 2015;122:949–956. 
3. Talks SJ, Manjunath V, Steel DHW,et al. New vessels detected on wide-field imaging compared to two-field and seven-field imaging: implications for diabetic retinopathy screening image analysis. Br J Ophthalmol 2015;99:1606–1609. 
4. Solomon SD et al. American Diabetes Association Position Statement on Diabetic Retinopathy (2017). Diabetes Care 2017 Mar; 40(3): 412-418. 
5. Vaz-Pereira et al. Optical coherence tomography features of neovascularization in proliferative diabetic retinopathy: a systematic review. Int J Retin Vitr (2020) 6:26 Photo source: CFEH Atlas.

Figure 5b. OCT angiography vitreous slab demonstrates the sea-fan morphology
of the neovascular network overlying the left optic disc.