Diabetic Eye Disease

Microscopically, the primary pathology is loss of pericytes and basement membrane thickening.

Ocular manifestations of diabetes

• Anterior segment

  • Reduced corneal sensation
  • Reduced corneal healing (neurotrophic ulcers)

• Iris

  • Poor dilation
  • Argyll robertson pupils

• Glaucoma: increased risk of POAG and neovascular glaucoma

• Cataract

• Posterior segment

  • Diabetic retinopathy
  • Retinal vascular occlusions

• Neurological

  • Cranial nerve palsies
  • Ischaemic optic neuropathy

• Periorbita

  • Xanthelasma
  • Orbital muccormycosis

Prognosis

• 25% of type 1 diabetics and 16% of type 2 diabetics develop proliferative disease within 15 years of diagnosis

Risk factors for diabetic eye disease (RCOphth guidelines based)

• Non-modifiable

  • Gender (male)
  • Duration of diabetes
  • Genetic factors

• Modifiable

  • BP
  • BMI
  • Smoking
  • Glycaemic control
  • Pregnancy
  • Renal impairment
  • Lipid levels
  • Carotid artery disease

Clinical features by severity

Causes of visual loss

• Diabetic macular oedema
• Ischaemic maculopathy
• Sequelae of neovascularisation: vitreous haemorrhage, traction, RD

Mild non-proliferative (NPDR)

• Microaneurysms: a saccular or fusiform swelling of a capillary
• Dot haemorrhages: it is generally not possible to differentiate these from MAs.
  • Haemorrhages in superficial retinal layers

Moderate non-proliferative (NPDR)

• Microaneurysms, plus

• Haemorrhages (dot or blot):

  • Blot haemorrhages develops where a capillary cluster has occluded (representing a deep retinal infarct) and are present in the outer plexiform layer (therefore do not mask overlying retinal circulation)

• Hard exudates

• Cotton wool spots: representing axonal swelling

• Venous beading: veins running through areas of capillary closure

• Venous loops and reduplication: rare

• Arteriolar narrowing

• Intraretinal microvascular abnormalities

  • Occlusion of a capillary-venule bed leads to dilation of the capillary remnants
  • Seen as spiky tortuous microvascular abnormalities in areas of capillary occlusion

Severe non-proliferative (NPDR)

• 4-2-1 rule
• At least one of the following
  • At least 20 blot haemorrhages in all 4 retinal quadrants
  • Venous beading in at least 2 quadrants
  • Prominent IRMA in at least 1 quadrant

Very severe non-proliferative (NPDR)

• 2 or more of the above features

Proliferative diabetic retinopathy

• New vessels usually arise from veins and always loop back on themselves (normal small vessels taper to an end)

• Early

  • New vessels at disc or within 1 disc diameter of disc (NVD) or elsewhere (NVE)

• High risk (based on Diabetic Retinopathy Study)

  • NVD with vitreous haemorrhage
  • NVD of ⅓ disc area or more
  • NVE of ½ disc area or more with vitreous haemorrhage

• Other features

  • Tractional RD
  • Neovascular glaucoma

Clinically significant macular oedema (from ETDRS study)

• Retinal thickening within 500 microns of the centre of the macula

• Exudates within 500 microns of the centre of the macula AND associated adjacent retinal thickening

• Retinal thickening >1500 microns, any part within 1DD of the centre of the macula.

• Poor prognosis

  • Significant macular ischaemia
  • Foveal exudation
  • Diffuse oedema
  • Cystoid oedema
  • Uncontrolled HTN
  • Poor BM control
  • Renal disease
  • Smoking

• Alternatively, Proposed International Clinical Diabetic Macular Oedema Severity Scale (2003)

  • Mild: thickening/exudates distant from posterior pole
  • Moderale: thickening/exudates near centre of macula
  • Severe: thickening/exudates involving centre of macula

Other

• Optic disc swelling: diabetic papillopathy (rare)
• New vessels at the iris: represents advanced ischaemia (and perhaps associated carotid disease)
• New vessels on anterior hyaloid surface
• Subretinal fibrosis
• Spontaneous regression of new vessels (auto-infarction): causes reduction in size and gliosis
• Macular ischaemia: central (enlarged FAZ) vs peripheral

Advanced retinopathy

• (from Diabetic Retinopathy Vitrectomy Study)
• High-risk PDR with tractional RD involving macular or vitreous haemorrhage

Tests

• Fundus photography
• OCT
• FFA: petalloid leakage from DMO and enlarged FAZ in ischaemic maculopathy
  • Only FFA can map areas of capillary non-perfusion

Management

Depends on stage.

Non-proliferative

Mild-Moderate NPDR

• Observation (if no macular oedema)
• Management of systemic risk factors: glycaemic control, blood pressure, lipidaemia

Severe (or Very Severe) NPDR

• Increased frequency of monitoring
• Consider FFA if uncertainty about presence of new vessels
• Scatter laser treatment as proliferative stage approaches (Very Severe NPDR had approximately 50% risk of progression to High-Risk PDR within 1 year in ETDRS)
• Consider PRP, especially if:
  • Older patients with type 2 diabetes
  • Poor retinal view
  • Cataract surgery needed soon
  • Only eye due to fellow eye advanced DR
  • Likely poor clinic attendance
  • Difficult examination of other reasons (eg. poor mobility etc)
  • Perhaps prior to pregnancy?

Proliferative

Proliferative DR

• PRP: within 2 week of diagnosis of high-risk PDR

  • Full treatment means all four quadrants of pre- and post-equatorial retina upto major vascular arcades
  • DRS showed PRP reduced risk of severe visual loss by more than 50% at 2-5 years in high-risk PDR
  • Discontinue when/if:
    • NV regression evident (reduced size, gliosis)
    • NV stabilise

• Baseline FFA is ideal but should not delay PRP

Advanced retinopathy (as per DRVS)

• Early vitrectomy for type 1 diabetics

Complications of PRP

• Early

  • Iris burns
  • Macular burns
  • Retinal tears
  • Vitreous haemorrhage
  • CMO

• Late

  • Loss of VA
  • Visual field defects: may have implications for driving
  • Tractional RD: due to contraction of fibrovascular tissue
  • ERM
  • CNV
  • Reduced mydriasis

Maculopathy

ETDRS showed approximately 50% reduction in risk of moderate visual loss at 3 years with focal/grid laser in patients with CSMO. However this treatment is largely superceded by anti-VEGF.

Anti-VEGF:

• Aflibercept and ranibizumab are licenced for use in DMO patients
• NICE guideline:
  • Commence treatment if central macular thickness at least 400microns
  • Eylea: monthly injections for 5 months then reduce to 2-monthly for the first 12 months (VISTA and VIVID studies)
  • Lucentis: monthly injections until maximal VA achieved and stable for 3 months (RISE, RIDE and RESTORE studies)

Steroid implants

• Dexamethasone (Ozurdex)

  • NICE guideline:

    • Only in pseudophakic eyes
    • Only for DMO that has not responded to (or cannot tolerate) non-steroid treatments
    • Implant remains in vitreous for approx 270 days before dissolving

  • MEAD, BEVORDEX, PLACID studies

• Risk of cataract and glaucoma

PPV for diabetics

• Indications

  • Non-clearing vitreous hemorrhage

    • Within 3 months for type 2 diabetics
    • Within 1 month for type 1 diabetics

  • Tractional RD involving or threatening the macula (eg. small peripheral ones can be observed)

  • Diffuse macular oedema associated with posterior hyaloid traction

  • Combined tractional and rhegmatogenous RD

  • Recurrent vitreous hemorrhage despite maximal PRP

Pregnancy

• Diabetics require assessments before and during pregnancy

• Discontinue statins and RAAS blocking drugs before conception

• Optimisation of glycaemic control should be deferred until after first retinal assessment

• Retinal assessment

  • Fundus imaging after first antenatal clinic (usually around 8-12 weeks)
  • If DR present, repeat assessment at 16-20 weeks
  • Repeat assessment at 28 weeks

• Retinopathy is not a contraindication to vaginal delivery

• If NPDR diagnosed during pregnancy, the patient needs follow up for 6 months post-delivery

• Tropicamide should not be used for mydriasis during pregnancy

• Gestational diabetes does not increase risk of retinopathy and does not require monitoring

Screening

UK Diabetic Eye Screening Programme retinopathy grading

• R0: no diabetic retinopathy/normal fundus (non-referable)

• R1: mild, background: haemorrhages and macroaneurysms (non-referable)

• R2: moderate, pre-proliferative: venous beading, venous reduplication/loops, multiple blot haemorrhages, IRMA

• R3: proliferative

  • R3a: active. Newly presenting proliferative retinopathy or new features
  • R3s: stable. Evidence of peripheral retinal laser, or stable

• M0: no maculopathy

• M1:

  • Exudate within 1 disc diameter of centre of fovea
  • Circinate or group of exudates within macula

Referable disease is R2 or above, or M1.

• Patients with R3 should be seen within 2 weeks
• Others should be seen within 13 weeks

Summary of main trials

Early Treatment of Diabetic Retinopathy

• RCT ofnon-proliferativediabetic retinopathy eyes
• Focal laser reduced the risk of moderate visual loss at 3 years in CSMO
• Aspirin did not affect the progression of retinopathy
• Scatter PRP could be deferred in mild-moderate NPDR but considered in severe NPDR

Diabetic Retinopathy Study

• An RCT ofproliferativeretinopathy eyes
• PRP reduced the risk of severe visual loss by more than 50% at 2 years in high-risk PDR patients
• Defined PRP technique

Diabetic Retinopathy Vitrectomy Study

• In type 1 patients with non-clearing vitreous haemorrhage, early vitrectomy was beneficial

Diabetic Control and Complications Trial

• Tight glycaemic control reduced the risk of progression of retinopathy (by 76% if no preexisting disease)
• But tight control can lead to initial worsening of retinopathy after prolonged hyperglycaemia

UK Prospective Diabetes Study

• RCT of type 2 diabetics
• Intensive glycaemic and blood pressure control independently reduced the risk of complications: retinopathy, nephropathy, neuropathy.

Diabetic Retinopathy Clinical Research Network Protocols

• Protocol I
  • Ranibizumab with prompt or deferred focal/grid laser achieved superior VA and OCT outcomes compared to laser alone for central DMO
• Protocol T
  • No significant difference found between aflibercept, ranibizumab and bevacizumab
  • In subgroups with worse initial vision or thicker maculas, aflibercept performed better initially (1 year) but at 2 years was equal to ranibizumab