Pathophysiology from general breakdown of the blood–retinal

Pathophysiology of
diabetic macular oedema

Diabetic macular oedema
can be focal or diffuse. Focal oedema typically surrounds clusters of
microaneurysms, which have been demonstrated by fluorescein angio-graphy as
being a major cause of leakage (Ahmadi and Lim, 2009). Diffuse diabetic macular
oedema results from general breakdown of the blood–retinal barrier, which can
be induced by chronic hyperglycaemia (Ahmadi and Lim, 2009). Chronic
hyperglycaemia leads to accu­mulation of abnormal metabolites from multiple
overac­tive biochemical pathways, inducing oxidative stress and causing
vascular endothelial growth factor production to be upregulated. Vascular
endothelial growth factor is a potent endothelial-specific mitogen that induces
vasodila­tation, endothelial cell proliferation, production of pro-inflammatory
cytokines and increased vascular permeabil­ity (Ferrara et al, 1992), which
ultimately results in breakdown of the blood–retinal barrier with extravasation
of fluid that accumulates as macular oedema. This process is often further
compounded by associated conditions such as hypertension, dyslipidaemia and
vascular inflam­mation (Bloomgarden, 2007; Morello, 2007).

 

 

 

 

 

 

 

 

 

 

 

 

G.R. Barile, S.I.
Pachydaki, S.R. Tari, et al.The RAGE axis in early diabetic
retinopathy

Invest Ophthalmol
Vis Sci, 46 (8) (2005), pp. 2916-2924

https://www.ncbi.nlm.nih.gov/pubmed/16043866  &  

http://iovs.arvojournals.org/article.aspx?articleid=2182667 (accessed on 09/01/2018)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Diabetic retinopathy (DR) and diabetic maculopathy or diabetic macular
oedema (DMO) are well characterised complications of DM associated with changes
within the retinal vasculature and retinal thickening respectively, which can
ultimately result in permanent loss of vision. The development of these complications
correlates with the duration of diabetes so earlier onset of diabetes,
increasing life expectancy, in addition to the growing number of patients with
type 2 DM, is likely to result in a significantly higher prevalence of DR
globally. DR has been declared a priority eye condition by the World Health
Organization as timely intervention can prevent or delay loss of vision.

World Health Organization. Priority eye disease – diabetic retinopathy.
http://www.who.int/blindness/causes/priority/en/index6.html (accesssed
01/01/2018)

https://www.eyescreening.org.uk/userFiles/File/DiabeticEyeJournal/DEJ4-1a34to38.pdf

http://www.who.int/blindness/causes/PreventionofBlindnessfromDiabetesMellituswithcoversmall.pdf

http://bjo.bmj.com/content/84/8/871.full

http://bmjopen.bmj.com/content/3/3/e002269.full

http://bmjopen.bmj.com/content/bmjopen/3/3/e002269.full.pdf

https://www.wjgnet.com/1948-9358/full/v4/i6/324.htm

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3874493/

https://cellandbioscience.biomedcentral.com/articles/10.1186/2045-3701-4-27

https://cellandbioscience.biomedcentral.com/articles/10.1186/2045-3701-4-27

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4046142/

http://onlinelibrary.wiley.com/doi/10.1111/j.1444-0938.2012.00723.x/full

 

Screening and diagnosis

Recognizing the cost of
diabetic eye disease to individuals and society prompted the launch of
screening pro­grammes across the world aimed at early detection and
intervention. Patients in the UK with diabetes mellitus aged 12 years and over
have been systematically screened on an annual basis using digital fundus
photography for over 10 years (Peto and Tadros, 2012). Some 2.3 million
patients were offered screening in 2011–12, with a nationwide uptake of 81%
(NHS Diabetic Eye Screening Programme, 2013). Strict grading criteria for
diabetic maculopathy have been defined alongside criteria for referral to the
hospital eye service (Table 1).

Within the hospital eye
service there are a number of techniques available to ophthalmologists to
visualize and assess diabetic macular oedema. Clinical ophthalmoscopy with a
slit lamp and biomicroscopic lenses is a subjective and qualitative method
routinely used (Virgili et al, 2011). Fluorescein angiography can be useful in
identify­ing treatable lesions and areas of leakage. However, opti­cal
coherence tomography has become the key imaging technique. It produces
three-dimensional and cross-sec­tional images of the central retina, based on
optical reflec­tivity (Figure 2). This provides valuable information on
retinal structure and thickness (Virgili et al, 2011) and is used as an
objective and quantitative assessment of macu­lar oedema, both for initial
evaluation and, importantly, in monitoring response to treatment.

Management of diabetic
macular oedema

As chronic hyperglycaemia initiates and
propagates the succession of pathogenic events, the ultimate manage­ment of
diabetic macular oedema is strict glycaemic control (Turner et al, 1998).
Microvascular damage is compounded by hypertension, thus tight control of blood
pressure is essential (UK Prospective Diabetes Study Group, 1998). An emerging
body of evidence also supports a role for lipid-lowering agents in the manage­ment
of diabetic macular oedema, by reducing the sever­ity of hard exudates and
leakage of fluid (Panagiotoglou et al, 2010). However, despite efforts aimed at
early iden­tification and aggressive treatment of diabetes mellitus and these
associated risk factors, around a quarter of patients will develop diabetic
macular oedema within 10 years (Klein et al, 1995). Therefore, in addition to
these systemic modifications an array of intraocular treat­ment modalities have
been developed.

Laser photocoagulation

Macular laser photocoagulation has been the
unequivocal gold standard of treatment for diabetic macular oedema since
publication of the Early Treatment Diabetic Retinopathy Study in 1985. This
large multi-centre, rand­omized trial of nearly 4000 patients showed that focal
application of laser to leaking aneurysms and grid treat­ment of diffuse
macular leakage provided a 50% reduction in moderate visual loss after 3 years
compared with untreat­ed patients (Early Treatment Diabetic Retinopathy Study,
1985) (Figure 3). This study, which predates optical coher­ence
tomography imaging, recommended laser photoco­agulation for all patients with
clinically significant macular oedema, as defined by the following criteria:
retinal thick­ening within 500 ?m of the macula centre, hard exudates with
associated retinal thickening within 500 ?m of the macula centre, or a zone of
retinal thickening one disc area in size within one disc diameter of the macula
centre (Early Treatment Diabetic Retinopathy Study, 1985, 1991).

Unlike panretinal photocoagulation, which
treats pro­liferative diabetic retinopathy by reducing oxygen require­ments of
the retina through tissue destruction, the precise mechanism by which macular
photocoagulation treats diabetic macular oedema remains unknown. It is likely
that focal laser occludes leaking microaneurysms, con­tributing in part to its
efficacy (Royster et al, 1988). Grid laser treatment is thought to work through
the influence of macular tissue damage on autoregulation of retinal blood flow,
reducing it and consequently any associated fluid shift (Wilson et al, 1988).

Although effective at
slowing or preventing further loss of vision, laser photocoagulation is not
effective at restor­ing vision. Potential complications include visible scars
that can enlarge and encroach towards the fixation point (Bailey et al, 1999),
reduced contrast sensitivity and col­our vision (Morgan and Schatz, 1989), as
well as compli­cations such as choroidal neovascularization (Roider et al,
2000) and subretinal fibrosis (Stanga et al, 1999).

Efforts to reduce the
risks associated with thermal laser have led to the development of the
micropulsed diode laser that delivers laser energy in short pulses rather than
as a continuous wave. The relative absorption of diode laser is 40% of that of
conventional argon lasers, yet it remains therapeutically effective (Ohkoshi
and Yamaguchi, 2010) and with fewer side effects. Nevertheless, it still
produces its clinical effect by causing iatrogenic retinal damage, and is still
associated with vis­ual stabilization rather than improvement.

Corticosteroids

Corticosteroids are anti-inflammatory agents
effective at reducing the permeability of retinal capillaries by enhanc­ing
endothelial cell tight junctions and downregulating the vascular endothelial
growth factor metabolic pathway (Sears and Hoppe, 2005). This reduces leakage
of plasma proteins into the interstitial space, helping to restore the osmotic
gradient and resolve the oedema (Sivaprasad et al, 2006).

The first intravitreal
corticosteroid to be widely used in the treatment of diabetic macular oedema
was triamci­nolone acetonide. Its benefits in treating diabetic macular oedema
refractive to laser photocoagulation and as pri­mary therapy have been well
documented (Sutter et al, 2004). Intravitreal triamcinolone provided greater
short-term improvements in visual acuity than laser photo-coagulation, but this
was not sustained beyond 16 months (Beck et al, 2009). In practice, patients
require re-injec­tion every 3–6 months as the effect diminishes.

As with systemic
corticosteroids, intravitreal triamci­nolone causes both cataract (Beck et al,
2009) and glau­coma (Beck et al, 2009), and with each subsequent injec­tion the
risk increases. Furthermore, intravitreal injection itself carries risk of
endophthalmitis, retinal detachment and vitreous haemorrhage. Therefore the
need for regular repeat injections is a major drawback of intravitreal tri­amcinolone
therapy.

More recently,
sustained-release steroid intraocular implants have been developed that
lengthen the reinjec­tion interval and reduce side effects. Ozurdex is a sus­tained-release
dexamethasone injectible device currently licensed for use in macular oedema
following retinal vein occlusion and uveitis. Its short-term benefits in the
man­agement of diabetic macular oedema are well document­ed, but effects are
rarely sustained beyond 3–4 months (Pacella et al, 2013). A multi-centre
randomized control­led trial comparing laser plus Ozurdex with laser plus sham
in patients with diffuse diabetic macular oedema found that although a
significant improvement in visual acuity was reported for the first 9 months in
those treated with Ozurdex, this was not maintained and significance was lost
at 12 months (Callanan et al, 2013). Rates of raised intraocular pressure and
cataract were higher in eyes receiving Ozurdex, but lower than that associated
with intravitreal triamcinolone.

Iluvien is a second-generation injectable
fluocinolone acetonide device that has entered phase III trials for dia­betic
macular oedema. In patients with diabetic macular oedema previously treated
with laser photocoagulation, a maxiumum of one Iluvien insert per year provided
greater improvement in visual acuity after 3 years when compared with sham.
Rates of adverse effects were high; almost all phakic eyes developed cataract
after 3 years, and incisional glaucoma surgery was required in 8.1% of the high
dose group (Campochiaro et al, 2012). Iluvien is currently approved by the
National Institute for Health and Care Excellence for use in pseudophakic
patients with diabetic macular oedema refractive to other therapies.

Together, these trials demonstrate a valid
role for ster­oid therapy in diabetic macular oedema, with well-docu­mented
improvements in vision. However, despite the development of sustained delivery
systems the duration of effect is limited. With the risk of side effects being
high, a more effective and safer treatment modality is required.

Vascular endothelial growth factor inhibitors

As previously discussed, vascular endothelial growth fac­tor plays
a central role in the pathogenesis of diabetic macular oedema and is therefore
a key therapeutic target. Indeed, multiple drugs that target vascular
endothelial growth factor have been developed and tested in large phase III randomized trials for safety and efficacy in treating

diabetic macular oedema. These drugs are effective at

reducing diabetic macular oedema and restoring vision,

but require regular intravitreal injection. This exposes

patients to higher risk of injection-related adverse events

and places a strain on both eye clinics and budgets.

Ranibizumab (Lucentis) is a humanized monoclonal

anti-vascular endothelial growth factor antigen binding

fragment specifically designed for use in the eye. It

potently inhibits the activity of all known isoforms of

vascular endothelial growth factor. There is a large body

of robust evidence from multiple large phase III trials

demonstrating its efficacy in reducing diabetic macular

oedema, and three major trials have demonstrated its

superiority over laser therapy (Nguyen et al, 2012). The

3-year results of one trial highlight the importance of

early treatment with ranibizumab (Brown et al, 2013). To

maintain these effects, patients required an average of

seven injections with 12 monitoring visits in year one and

three injections with ten monitoring visits in year two,

with a total cost of around ?10 000 per
patient (Mitchell

et al, 2012).

Bevacizumab (Avastin) is a monoclonal anti-vascular

endothelial growth factor antibody that binds and inhibits

all isoforms of vascular endothelial growth factor-A.

Ocular use is currently unlicensed, yet numerous randomized

trials have demonstrated its superiority over laser

therapy, intravitreal steroids and combinations of these,

in treating diabetic macular oedema (Rajendram et al,

2012). Again, regular repeat injections of bevacizumab

were required for maintenance of effect.

Aflibercept (Eylea) is a fusion protein of human immunoglobulin

and vascular endothelial growth factor receptors

that binds multiple isoforms of vascular endothelial

growth factor with high affinity. A major benefit of

aflibercept is its longer duration of action meaning fewer

injections and monitoring visits are required. In the

phase II clinical trial, laser therapy was compared with an

aflibercept dosing regimen consisting of monthly injections

for 3 months followed by 2-monthly injections.

After 6 months, patients treated with aflibercept demonstrated

a significantly greater improvement in mean visual

acuity and retinal thickness. One year follow up demonstrated

that 2-monthly injections were sufficient to

maintain these effects, with seven injections required in

total (Do et al, 2012). Although this initial study is

promising, further data are required before drawing conclusions

on aflibercept.

Pegaptanib (Macugen) is PEGylated aptamer that

potently bind vascular endothelial growth factor-165.

When compared with sham injection, pegaptanib showed

only weak efficacy in treating diabetic macular oedema

and no further comparative trials were commenced

(Sultan et al, 2011).

These trials also demonstrated the safety of anti-vascular

endothelial growth factor agents for intraocular use.

The frequency of reported adverse events was low, with

raised intraocular pressure being the only consistently

reported side effect in a small proportion of patients

across all anti-vascular endothelial growth factor therapies,

excluding bevacizumab in which rates were comparable

with laser. As a result, anti-vascular endothelial

growth factor agents are now considered first-line management

for patients with diabetic macular oedema.

Enzymatic vitreolysis

The observation that patients with spontaneous or surgical

posterior vitreous detachment had significantly

reduced rates of diabetic macular oedema or improvement

of already established diabetic macular oedema

(Tachi and Ogino, 1996) led researchers to believe that

vitreoretinal relationships at the macula play a key role.

Plasmin is a protease active against fibronectin and laminin,

the proteins responsible for vitreous attachment to

the retinal surface. Researchers using intravitreal plasmin,

either in autologous or recombinant forms (Ocriplasmin),

to induce posterior vitreous detachment in patients with

diabetic macular oedema found that it effectively reduced

macular thickness and improved vision (Diaz-Llopis et al,

2013). When compared to intravitreal triamcinolone,

plasmin had a more sustained effect on both macular

thickness and visual acuity without the concomitant rise

in intraocular pressure (Elsawy, 2012). These therapies

represent a promising new approach to treating diabetic

macular oedema.

Discussion

The past decade has seen a significant evolution in the

treatment of diabetic macular oedema. Laser was once

the gold standard therapy, but now its role is debatable.

A robust evidence base supports anti-vascular endothelial

growth factor drugs as primary therapy for diabetic

macular oedema. Both ranibizumab and bevacizumab are

superior to laser, and adding laser confers no benefit.

However, laser may still be used to treat very focal areas

of leakage.

There are no direct head-to-head trials of ranibizumab

and bevacizumab, therefore choice is at the ophthalmologist’s

discretion. Bevacizumab is currently unlicensed for

intraocular use, but is considerably cheaper than licensed

ranibizumab. Anti-vascular endothelial growth factor

drugs represent a significant advance, but they are not the

solution; only half of patients gain ?10
letters in visual

acuity following treatment (Mitchell et al, 2011), and

regular injections are required to maintain effect.

Studies investigating the efficacy of steroid have mixed

results, but the association with cataract and raised

intraocular pressure is consistent. The effects of dexamethasone

implants peak at 3 months and then diminish,

requiring retreatment. Each retreatment increases the risk

of complications. Fluocinolone requires fewer administrations,

potentially one every 3 years, but rates of cataract

are high. Some patients may opt for infrequent steroid

injections, accepting the considerable risk of cataractand small risk of glaucoma, over frequent anti-vascular
endothelial growth factor injections, despite the differ­ence in potential
acuity gain. There also remains a place for steroids in patients not responding
to anti-vascular endothelial growth factor drugs. Furthermore, cataract is very
common in diabetes, and many patients are pseudo­phakic when treatment for
diabetic macular oedema is required.

As research continues,
the management for diabetic macular oedema will constantly evolve. A range of
prom­ising new treatment modalities is currently under devel­opment that target
various elements of the cascade lead­ing to diabetic macular oedema. Some are
topical agents (Callanan and Williams, 2008), which may play a major role in
the future.

The pathogenesis of
diabetic macular oedema is multi­factorial, so a combination of therapies
working synergis­tically to target multiple pathways is likely to be needed.
The presence of macular ischaemia, as evidenced by an enlarged foveal avascular
zone on fluorescein angiography (Figure 4), is thought to contribute to
poor visual out­comes following treatment (Chung et al, 2008). In the absence
of an effective therapy for macular ischaemia, complete resolution of visual
loss is unlikely to be achiev­able. Diabetic macular oedema is an ongoing
global prob­lem, and although recent years have seen a number of significant
advances, the problem is far from solved.

 

 

 

 

 

 

 

How is diabetic maculopathy / diabetic macular
oedema treated?

Mild
macular oedema may resolve itself without treatment but most people will need
the first line of diabetic maculopathy treatment which is laser
photocoagulation treatment.

Other
treatments include having injections of what are called anti-VEGF drugs
(anti-vascular endothelial growth factor), such as Lucentis or Avastin. At the time of
writing Avastin and Lucentis have not been approved for use in treating
diabetic macular oedema by NICE but an appeal is underway by health charities
to reverse the decision.

In
December 2012, Lucentis was approved for use in
treating diabetic macular oedema in Scotland.

Another treatment, which is rare because of the side effects that
can exist, is to have injections of intravitreal steroids.

 

 

Treatment

Treatment

Medical treatment by the primary care
physician or diabetologist

The
primary care physician or the diabetologist is

responsible
for the treatment of risk factors for retinal

complications,
including diabetes, arterial hypertension,

and
renal disease. It was concluded in a recent

review
that intense antihyperglycemic therapy in patients

with
type 2 diabetes leads to an approximately

3%
absolute reduction of the risk of retinopathy. Intensified

antihyperglycemic
therapy (e21) was associated

with a
higher risk of hypoglycemia. Patients with high

HbA1c
values stand to benefit more from such therapy;

for
patients with low HbA1c values, whose risk of diabetic

complications
is significantly lower, the benefits and risks of treatment intensification
must be jointly

discussed
by the patient and the physician. The effect of

intensified
treatment of either diabetes or hypertension

on
retinal complications is but one of many factors

(some
of them still inadequately defined) to be

considered
in weighing its benefits against its risks.

More
information on this topic can be found in the

evidence-based
guidelines on the individualized treatment

of
diabetes and its complications (www.diabetes.

versorgungsleitlinien.de,
www.awmf.org/leitlinien/detail/

ll/057–013.html).

Special ophthalmological treatment

The
ophthalmologist is responsible for appropriate

diagnostic
evaluation and treatment corresponding to

the
patient’s stage of disease, and for monitoring the

course
of diabetic retinopathy and/or maculopathy. The

treatment
options for diabetic retinal complications include

laser
therapy and intravitreal operative

medication
(IVOM). The most important considerations

for the
choice of treatment are the distinction between

proliferative
and nonproliferative retinopathy

and the
presence or absence of clinically significant

macular edema, with or without foveal involvement

Deutsches
Ärzteblatt International | Dtsch Arztebl Int 2016; 113: 816–23 | Supplementary
material

Diabetic maculopathy is often treated by laser
surgery.

For cystoid macular edema due to
diabetes or a stroke in the retina, laser treatment is usually recommended as
the first choice. … If the swelling does not go away after that
time or it comes back later, the laser treatment can be repeated.

When the macula swells with fluid, a
condition called macula edema, vision blurs and can be lost
entirely. Although non-proliferative retinopathy usually does not
require treatment, macular edema must be treated, but fortunately
treatment is usually effective at stopping and sometimes reversing
vision loss.

Try watching this video on www.youtube.com,
or enable JavaScript if it is disabled in your browser. Because macular
edema occurs inside the layers of retina tissue, you may have a test called
fluorescein angiography, or another called optical coherence tomography (OCT)
to help make an accurate diagnosis.