Macular oedema occurs when fluid and protein deposits collect within the macula, leading to thickening and swelling which distorts central vision. It is a common final pathway for many ocular diseases, including diabetic retinopathy, vascular occlusions, postsurgical conditions and uveitic diseases.
The pathophysiological process is a breakdown of the blood-retinal barrier (BRB), which normally prevents water movement in the retina, thus allowing fluid to accumulate in the retinal tissue. Inflammatory processes and an increase in vascular permeability play a central role. Different mechanisms, complicated by ischaemic conditions, interact in a complex manner. Key factors are angiotensin II, prostaglandins and the vascular endothelial growth factor (VEGF).
The macula is the part of the retina responsible for sharp, central vision due to its high density of cone photoreceptors. It is situated at the back of the retina (the posterior pole), lying about 3 mm lateral to the optic disc. It has a central depression known as the fovea centralis. The fovea contains tightly packed cone photoreceptors in the fovea with no overlying blood vessels. This is the area of the retina where visual acuity is ultimately determined, where reading takes place and where form, shape and colour are most accurately detected. Macular fluid accumulation alters cell function in the retina as well as provoking an inflammatory reparative response.
The severity of macular oedema is determined by:
- The extent of the oedema.
- The distribution in the macular area (ie focal versus diffuse).
- Central foveal involvement.
- Evidence of alteration of the BRB and intraretinal cysts.
- Signs of ischemia.
- Presence or absence of vitreous traction.
- Increase in retinal thickness and cysts in the retina.
- Chronicity (ie time elapsed since initial diagnosis).
Macular oedema is usually described as two or three subtypes, depending on the underlying pathophysiology and on the structural changes which result.
- Cystoid macular oedema (CMO) with fluid accumulation in cyst-like spaces in the outer plexiform layer of the macula. This condition is an endpoint for many intraocular conditions.
- Diabetic macular oedema (DMO) caused by leaking macular capillaries. DMO may lead to CMO.
- Macular oedema associated with age-related macular degeneration (AMD), which may also lead to CMO.
Cystoid macular oedema (CMO)
CMO is characterised by intraretinal oedema contained in honeycomb-like (cystoid) spaces filled with clear fluid. The underlying cause is thought to be disruption to the BRB. Retinal cells are displaced by the cysts, so the fluid affects both cell function and cell architecture.
Depending on the aetiology, CMO is usually self-limiting and spontaneously resolves within 3-4 months. Resolution may be helped via medical or surgical options. If the oedema is chronic (more than 6-9 months) permanent damage to photoreceptors with retinal fibrosis can occur.
CMO is a common 'endpoint' pathological response to a variety of insults to the macular area:
- Ocular inflammatory diseases - eg, uveitis, pars planitis, Behçet's syndrome, toxoplasmosis and HIV-related cytomegalovirus (CMV) uveitis. It seems likely that inflammatory mediators, particularly CD4+ T cells, are an integral part of the pathological process, causing focal areas of BRB breakdown.
- Postoperative CMO following cataract surgery. This is known as the Irvine-Gass syndrome - after Irvine, who first reported it.It is thought to occur as a result of release of inflammatory mediators within the eye. If prolonged, permanent damage can occur. Approximately 20% of patients who undergo phacoemulsification or extracapsular extraction develop angiographically proven CMO. However, significant decrease in visual acuity is seen only in about 1%. If cataract extraction is complicated there is a significantly higher incidence. Cataract surgery in patients with diabetes may result in dramatic acceleration of pre-existing diabetic macular oedema (DMO).
- Central and branch retinal vein occlusions. In these conditions a rise in intravenous and capillary pressure leads to stagnation of blood, hypoxia of the affected structures and damage to the capillary endothelial cells, with extravasation of plasma constituents.
- Other causes of CMO include retinal vascular disease (eg, idiopathic retinal telangiectasia), retinal dystrophies (eg, retinitis pigmentosa) and drug-induced changes (as can occur with topical adrenaline (epinephrine) 2%, particularly in patients without a lens).
- CMO can also occur following injury to the eye and in association with choroidal tumours.
Diabetic macular oedema (DMO)
DMO occurs in the context of diabetic retinopathy, both proliferative and non-proliferative types. If it occurs in a critical part of the macula or reaches a particular size, it is referred to as clinically significant macular oedema (CSMO).
DMO is the major cause of vision loss in diabetes. Alteration of the BRB is the hallmark. Studies indicate that DMO is an inflammatory disease involving multiple cytokines.
Macular degeneration leading to macular oedema
Patients with certain forms of AMD - exudative ('wet') AMD - are prone to macular oedema. AMD gives rise to formation of choroidal neovascular membranes which leak fluid and blood under the retina, so resulting in macular oedema. See separate Age-related Macular Degeneration article for more detail.The presence of CMO and foveal thickening is associated with worse visual acuity.
Cystoid macular oedema (CMO)
The vitreous, retina, retinal pigment epithelium (RPE) and choroid receive their circulation through the retinal and choroidal vasculature. This relies upon an intrinsic balance amongst the osmotic force, hydrostatic force, capillary permeability and tissue compliance in the vasculature.. Once imbalance occurs, an accumulation of fluid is seen in cystoid spaces within the inner layers of the retina. Vitreomacular traction is a common underlying factor which contributes to the release of inflammatory factors such as VEGF and platelet-derived growth factor (PDGF). This results in BRB breakdown, leakage and oedema.
Diabetic macular oedema (DMO)
Diabetic retinopathy is a neurovascular disease of the retina, and retinal neuronal abnormalities precede the retinal microvascular injury. Increased vasopermeability with breakdown of the BRB is due to many factors, including upregulation of the expression of VEGF and altered vitreo-retinal interface with persistent vitreo-macular traction (VMT). Blood vessel damage plays a significant role. Long-term hyperglycaemia leads to vascular basement membrane thickening, non-enzymatic glycosylation, free radical formation and pericyte death. These changes ultimately lead to vascular dilation, increased capillary hydrostatic pressure and microaneurysm formation. Duration and control of diabetes mellitus are of major significance in the development of DMO.
Previously, DMO was defined as CSMO or not, and focal laser treatment was initiated only for CSMO. More recently, DMO has been subcategorised into two main categories:
- Focal diabetic macular oedema (fDMO).
- Diffuse diabetic macular oedema (dDMO).
The term centre-involving diabetic macular oedema (ciDMO) is also now commonly used to describe DMO in which the central macula is involved.
Age-related macular degeneration (AMD)
The pathophysiology of this condition is covered in the separate related article. The prime pathological process seems to be degeneration of RPE cells, leading to a progressive irreversible degeneration of photoreceptors.
- CMO post-surgery: CMO occurs in only about 1% of cases of uncomplicated cataract surgery in a very mild form (in the past, with older techniques, up to 20% of patients developed CMO and the figure can be this high in more complex cases or where there is associated uveitis).
- Other causes of CMO: the incidence of other causes of CMO varies according to the specific pathology.
- CSMO/ciDMO: when diabetes is undiagnosed and untreated, there is a 25-30% chance of developing vision-threatening DMO. This drops by half in treated patients. It is more likely to occur in patients aged over 60 years with systemic vascular diseases such as hypertension.
- 'Wet' AMD: this tends to occur in patients aged over 60 and is the leading cause of severe sight impairment and partial sight impairment certification in the over-65s.
- In the less developed world a different picture is seen. A 2006 study of 4,800 patients in rural India found that 3.36% had bilateral severe sight impairment, about 75% of which were due to cataracts. Macular oedema accounted for 3.79% of cases.
The exact presentation will vary with the underlying pathology but patients will complain of painless impairment of central vision.
- There may be a scotoma (a black spot within the field of vision).
- Visual acuity is impaired, typically in the region of 6/12 to 6/60.
- Patients with Irvine-Gass syndrome usually experience a gradual blurring, with good initial vision.
- Patients with AMD may complain of visual distortion (metamorphopsia), particularly of straight lines).
- Some patients develop blue-yellow colour blindness.
- There may be loss of contrast sensitivity.
- Some patients note that colours in the central vision appear 'washed out'.
- CSMO can be asymptomatic and only picked up in the diabetic screening clinic/unit.
The normal macula: what am I looking for?
The macula lies about 2 disc diameters temporally to the disc itself. It may be seen as a slightly darker area than the surrounding retina (more so in darker people) with blood vessels arching above and beneath it but not over it. Careful examination will reveal the foveal reflex, a small yellow-white shiny reflection in the centre of the macula - this is the fovea centralis.
Identifying macular oedema
It is not possible to diagnose macular oedema without the help of a slit lamp. A clue might be the loss of the foveal reflex compared to the fellow eye. In 'wet' AMD, there may also be an associated bleed, seen as a well-demarcated deep-red patch over the macular area. Even if the view is limited, the history and an abnormal Amsler grid will raise suspicions and should prompt referral.
This is a useful simple tool that can help screen for macular disease. The patient can use it at home to monitor progression.
It consists of a piece of paper on which a 10 cm x 10 cm box is printed, subdivided into 20 x 20 smaller squares and with a black dot in the centre. The patient is asked to wear any corrective lenses that they usually wear, hold the chart 33 cm away (arm's length) and cover one eye. They must then fix their gaze on the central dot. They are asked if they can see the four corners of the box. They are then told to comment on how straight the lines of the grid are and to draw over them as they see them in the parts that seem curved. Finally, they are asked to outline any areas missing within the box.
This should be repeated for the fellow eye. This gives a reasonable indication of macular function.
Once macular oedema is confirmed, the cause is likely to be one of those outlined above. In the young (typically type A personality male) patient, it could also be confused with central serous chorioretinopathy, a generally self-limiting condition which typically arises in times of acute stress, whereby there is a localised accumulation of fluid within the retina.
Macular oedema is usually diagnosed on slit-lamp examination.
- Using slit lamp, clinically significant foveal oedema and retinal thickening can be seen as a loss of foveal reflex; this is best seen using green light. Subclinical foveal oedema is better seen through retinal imaging.
- In DMO, macular thickening with or without hard exudates (consisting of lipoproteins) may be seen.
- CSMO is still extensively referred to in the literature and is defined as retinal thickening within 500 µm of the macular centre, hard exudates within 500 µm of the macular centre with adjacent thickening, or one or more disc diameters of retinal thickening, within one disc diameter of the macular centre. More recently the term centre-involving diabetic macular oedema (ciDMO) has been used to describe DMO in which the central macula is involved.
The diagnosis is often confirmed with optical coherence tomography (OCT), which is a sort of visual biopsy obtained in a similar fashion to an ultrasound scan but using light waves. It is a painless diagnostic imaging process performed in the outpatient setting, with the patient looking into the OCT machine for a few moments. OCT is useful both to confirm diagnosis (newer software is now able to distinguish between different patterns of CMO associated with different underlying pathology) and to monitor progress. Fluorescein angiography may also be required to further refine the diagnosis and guide management.
The management of macular oedema depends on its aetiology and extent. Many causes of macular oedema respond to treatment of the underlying condition (eg, CMO associated with CMV retinitis is treated by managing the retinitis with antiviral agents).
Current treatment of CMO
- Non-steroidal anti-inflammatory drugs (NSAIDS) - topical or systemic indomethacin decreases the production of prostaglandins. Ketorolac 0.5%, indomethacin 1%, and diclofenac 1% are used postoperatively for aphakic eyes and in other conditions where there is inflammation.
- Corticosteroids - topical, periocular, systemic, intravitreal injection or implant corticosteroids inhibit prostaglandin and leukotriene production. Steroids, particuarly intravitreal triamcinolone, help in uveitic macular oedema. Side-effects of steroid injection include glaucoma and cataract formation.
- Dexamethasone intravitreal implants are used for the treatment of macular oedema following central retinal vein occlusion and for branch retinal vein occlusion when laser treatment has not worked, or is not possible. It suppresses inflammation in the eye by inhibiting oedema, fibrin deposition, capillary leakage, phagocytic migration, expression of vascular endothelial growth factor and the release of prostaglandins. The treatment is effective but the duration of improvement is typically limited to 2 to 3 months and the treatment may need to be repeated. There is only limited published data on long term outcomes.[14, 15, 16]
- Carbonic anhydrase inhibitors - these alter ionic transport systems in the retinal pigment epithelial cells, moving fluid away from the intracellular spaces.
- Laser photocoagulation - this uses a light source to coagulate retinal and retinal pigment epithelial cell tissue. It is thought that adjacent healthy RPE cells then replace necrotic cells. The other view it that a reduction of oxygen consumption in the outer retina allows diffusion of oxygen to the inner retina.
- Anti-VEGF agents - pegaptanib, ranibizumab and bevacizumab act by decreasing vascular permeability from disrupted endothelial cells. Marked reduction in retinal thickness and fluid accumulation has been noted in various studies with a significant improvement in visual acuity with minimal side-effects. A National Institute for Health and Care Excellence (NICE) technology appraisal in 2013 recommended ranibizumab for visual impairment caused by CMO following venous occlusion, although the appraisal specifies that it should only be used if purchased with the discount the manufacturer agreed for the NHS.
- Pharmacological vitreolysis agents - enzymatic vitreolysis with agents such as chondroitinase, dispase, hyaluronidase, plasmin and microplasmin can induce posterior vitreous detachment to relieve traction on the retina.
- Surgery - vitrectomy can help to relieve macula oedema refractory to medical therapy. It may also clear high levels of inflammatory mediators, although evidence remains inconclusive. Side-effects of vitrectomy include cataracts, retinal detachment, vitreous haemorrhage and a rise in intraocular pressure.
- Intravitreal pharmacotherapy has replaced macular laser photocoagulation as the gold standard in the care of DMO.
- Intravitreal fluocinolone is approved for use in the UK and Europe and has been shown to improve visual acuity in DMO.
- VEGF-A is believed to be one of the major mediating factors associated with the development of DMO.
- In August 2012, ranibizumab was approved by Food and Drug Administration (FDA) in the USA for the treatment of DMO.
- More recently, aflibercept was approved in the USA for the treatment of neovascular AMD and macular oedema secondary to central retinal venous obstruction.
- Treatment aims in DMO have changed from the maintenance or reduction in rate of visual loss, to reversal of the loss of visual acuity.
- The future is likely to involve a combination approach utilising anti-VEGF agents, laser and corticosteroids designed to address the multifactorial nature of the disease.
- Potential therapies targeting molecules other than VEGF are being developed and evaluated.
If macular oedema is prolonged, retinal thinning, scarring or a retinal hole can eventually ensue.
- CMO - this depends on the aetiology but in uncomplicated cases recovery is usually good after several months. 90-95% of these patients can expect a final visual acuity of 6/12 or better within 3-12 months of their operation. Severe cases can result in more permanent visual loss. In cases where irreversible processes have occurred (such as in central retinal vein occlusion), there may be little or no chance of recovery. Where there are inflammatory processes, the duration and severity of the condition will determine overall outcome.
- DMO - improvement of visual function remains rare where deterioration of central vision has occurred. Historically, treatment has focused on arresting deterioration. With the introduction of combination therapies this is beginning to change.
- 'Wet' AMD - these patients tend to have a poor outcome, even with therapy (which is long, may be painful and is very expensive). Most experience a sudden and rapid deterioration in visual function that is irreversible. Vision never fully disappears and peripheral vision will remain normal in the absence of concurrent disease.
Pre-operative NSAIDs are sometimes given to high-risk patients in cataract surgery. Patients with diabetes need intensive steroid cover for cataract surgery, in order to minimise the risk of deterioration.
Good glycaemic control, blood pressure and cholesterol control may stall the development of retinopathy and DMO in patients with diabetes. Progression of the condition once it has developed can be arrested with laser and other treatment modalities. Regular retinal surveillance will help detect changes and enable intervention before vision deteriorates..
Patients with a known diagnosis of AMD are often issued with an Amsler grid in order to try to catch any macular changes early. AMD patients with 'wet' macular disease may be monitored in outpatients. AMD patients may also be advised to take multivitamin supplements to prevent progression of the disease in the other eye. The use of these supplements remains somewhat controversial and is more fully discussed in the separate Age-related Macular Degeneration article.
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- Aflibercept for treating diabetic macular oedema; NICE Technology Appraisal, July 2015
- Dexamethasone intravitreal implant for treating diabetic macular oedema; NICE Technology Appraisal, July 2015
- Coscas G, Cunha-Vaz J, Soubrane G; Macular edema: definition and basic concepts. Dev Ophthalmol. 2010 47:1-9. doi: 10.1159/000320070. Epub 2010 Aug 10.
- Scholl S, Augustin A, Loewenstein A, et al; General pathophysiology of macular edema. Eur J Ophthalmol. 2011 21 Suppl 6:S10-9. doi: 10.5301/EJO.2010.6050.
- Cunha-Vaz J, Coscas G; Diagnosis of macular edema. Ophthalmologica. 2010 224 Suppl 1:2-7. doi: 10.1159/000315156. Epub 2010 Aug 18.
- Rotsos TG and Moschos MM; Cystoid macular edema. Clin Ophthalmol. 2008 Dec 2(4): 919–930.
- Irvine SR; A newly defined vitreous syndrome following cataract surgery. Am J Ophthalmol. 1953 May 36(5):599-619.
- Das A, McGuire PG, Rangasamy S; Diabetic Macular Edema: Pathophysiology and Novel Therapeutic Targets. Ophthalmology. 2015 Apr 30. pii: S0161-6420(15)00305-X. doi: 10.1016/j.ophtha.2015.03.024.
- Nowak JZ; Age-related macular degeneration (AMD): pathogenesis and therapy. Pharmacol Rep. 2006 May-Jun 58(3):353-63.
- Jain A, Varshney N, Smith C; The evolving treatment options for diabetic macular edema. Int J Inflam. 2013 2013:689276. doi: 10.1155/2013/689276. Epub 2013 Sep 9.
- Vijaya L, George R, Arvind H, et al; Prevalence and causes of blindness in the rural population of the Chennai Glaucoma Study. Br J Ophthalmol. 2006 Apr 90(4):407-10.
- Wu WC, Cheng KC, Wu HJ; Intravitreal triamcinolone acetonide vs bevacizumab for treatment of macular oedema due to central retinal vein occlusion. Eye (Lond). 2009 Dec 23(12):2215-22. doi: 10.1038/eye.2008.429. Epub .
- Ford JA, Clar C, Lois N, et al; Treatments for macular oedema following central retinal vein occlusion: systematic review. BMJ Open. 2014 Feb 10 4(2):e004120. doi: 10.1136/bmjopen-2013-004120.
- Park YG et al; Laser-Based Strategies to Treat Diabetic Macular Edema: History and New Promising Therapies, Journal of Ophthalmology Volume 2014 (2014).
- Lopez-Lopez F, Rodriguez-Blanco M, Gomez-Ulla F, et al; Enzymatic vitreolysis. Curr Diabetes Rev. 2009 Feb 5(1):57-62.
- Dexamethasone intravitreal implant for the treatment of macular oedema caused by retinal vein occlusion; NICE Technology Appraisal Guidance, July 2011
- Kuppermann BD, Haller JA, Bandello F, et al; Onset and duration of visual acuity improvement after dexamethasone intravitreal implant in eyes with macular edema due to retinal vein occlusion. Retina. 2014 Sep 34(9):1743-9. doi: 10.1097/IAE.0000000000000167.
- Pelegrin L, de la Maza MS, Molins B, et al; Long-term evaluation of dexamethasone intravitreal implant in vitrectomized and non-vitrectomized eyes with macular edema secondary to non-infectious uveitis. Eye (Lond). 2015 Jul 29(7):943-50. doi: 10.1038/eye.2015.73. Epub 2015 May 22.
- Ranibizumab for treating visual impairment caused by macular oedema secondary to retinal vein occlusion; NICE Technology Appraisal, May 2013
- Rangasamy S, McGuire PG, Das A; Diabetic retinopathy and inflammation: novel therapeutic targets. Middle East Afr J Ophthalmol. 2012 Jan 19(1):52-9. doi: 10.4103/0974-9233.92116.