Retinopathy, diabetic E14.30+H36.0*

Jaeger was the first to describe a condition corresponding to today's diabetic macular edema in 1856. He described the finding as a "retinitis in glucosuria" (Wolfensberger 1999).

These findings were very controversial at the time and it was not until 1876 that Edward Nettleship succeeded in proving a link between cystoid degeneration of the macula and diabetes mellitus (Kampik 2008).

In 1978, Mc Nair described for the first time the connection between magnesium deficiency and the severity of diabetic retinopathy (v. Ehrlich 2006).

Diabetic retinopathy (dRP or DR) is a microvasculopathy in the retinal capillaries caused by a diabetogenic metabolic condition (Kellner 2008).

According to the ETDRS classification, dRP is clinically divided into:

• 1. non-proliferative form

This usually occurs at the end of the 1st decade or at the beginning of the 2nd decade of diabetes mellitus (Kasper 2015).

One differentiates between mild, moderate and severe form.

• mild form:
  • Microaneurysms
• moderate form:
  • Microaneurysms plus
  • sporadic intrarenal hemorrhages
  • Caliber fluctuations of the retinal veins, so-called pearl cord-like vein changes
• severe form (so-called 4 - 2 - 1 - rule):
  • > 20 microaneurysms and / or
  • in all 4 quadrants intraretinal hemorrhages and / or
  • in at least 2 quadrants calibre pearl cord veins and / or
  • in at least 1 quadrant intraretinal microvascular anomalies (IRMA) (Diederich 2020)
• 2. proliferative form

Here one differentiates between mild, moderate and high-risk form:

• mild form:
  • non papillary vascular neoplasms (NVE) in less than 0.5 of the optic disc area
• moderate form:
  • non papillary vascular neoplasms (NVE) in more than 0.5 of the optic disc area
  • papillary vascular neoplasms (NVD) in less than one third of the optic disc area
• High-risk form:
  • papillary vascular neoplasms (NVD) in more than one third of the optic disc area
  • Vitreous hemorrhage

The transition is characterized by preretinal neovascularization. In addition, fibrovascular membranes, traction amotio, rubeosis iridis are frequently found.

(Diederich 2020)

The proliferative form represents an advanced, irreversible state of a dRP (Herrmann 2007).

The Global Diabetec Retinopathy Project Group presents another classification of dRP.

• Stage 0: no diabetic retinopathy
• Stage 1: mild non-proliferative diabetic retinopathy (NPDR)
• Stage 2: Moderate NPDR
• Stage 3: severe NPDR
• Stage 4: proliferative diabetic retinopathy (Nentwich 2010)

In Western countries, dRP is the most common cause of both severe visual impairment and blindness in working age (Kellner 2008), although documented retinopathies have almost halved since 2009 (Haag 2018).

There is no gender predilection, except in Japan, where more female than male patients are affected (Diederich 2020).

The disease does not count as a late symptom; it can be present early (Herold 2020). There is also no lower threshold of HbA1c at which the risk and progression of dRP would not occur or would regress (Haag 2018).

Signs of retinopathy are found in >95% of patients in type 1 diabetes after 15 years of disease, 50% of which are at the proliferative stage (Herold 20210). In type 2 diabetes , this figure is up to 60% over the same period.

At diagnosis, however, up to 20 % of diabetes 2 patients already show signs of retinopathy. The occurrence of macular edema (DME), for example, is - according to epidemiological studies - dependent on the type of disease, the duration of the disease and the treatment concept.

In the USA, dRP is a leading cause of blindness between the ages of 20 and 74 (Kasper 2015).

Causally, RP is caused by diabetes mellitus disease. However, there are certain risk factors that make retinal complications more likely. These include, for example:

• Type of diabetes
• Adjustment of the blood glucose level
• Duration of the disease
• concurrent cardiovascular risk factors such as:
  • Hyperlipidemia
  • arterial hypertension
  • anemia
  • diabetic nephropathy
  • smoking (Kellner 2008)
• male gender
• Pregnancy with existing diabetes mellitus (gestational diabetes does NOT lead to dRP (Agostini 2018).
• Obesity
• Thiazolidinediones (orally active antidiabetic drug) (Diederich 2020).

Although there is evidence of a genetic predisposition to retinopathy, this has less influence on the disease than the duration of diabetes mellitus and the degree of glycemic control (Kasper 2015).

DRP with microvasculopathy of the retinal capillaries occurs due to:

• Occlusion of capillaries with resulting
  • Ischemia
  • release of proangiogenic cytokines
• disturbances of vessel wall permeability (Kellner 2008)

The underlying mechanism of action in the pathogenesis of a dRP has not yet been fully elucidated. Main factors for retinopathy are damages of the basement membrane and the vascular endothelium. Especially the latter leads to a functional breakdown of the inner blood-retinal barrier, which favors the occurrence of microaneurysms and neoangiogenesis.

These neovascularizations grow into the vitreous cavity and cause the typical vitreous proliferation (Kellner 2008).

In the non-proliferative form, the following changes are found in particular:

• Loss of pericytes
• Increase of vascular permeability
• changes in retinal blood flow
• abnormal retinal microvascularization
• ischemic nerve fiber infarcts, so-called cotton-wool spots (Diederich 2020/Kasper 2015)

The dRP can occur at any stage of diabetes (Nassiri Ansari 1990). In type 1 diabetes mellitus, it is found on average approx. 21 - 24 years after the initial diagnosis (Diederich 2020), in type 2 it often already exists at the time of diagnosis (Gries 2013).

The dRP is usually initially asymptomatic. A slowly deteriorating visual acuity is often hardly noticed by the patient, especially if it occurs unilaterally.

Acute visual deterioration may occur in the course of the disease (Herrmann 2007). According to Kellner (2008) this is mostly caused by:

• Macular edema
• Macular ischemia
• Complications of proliferative retinopathy such as
  • Traction ablation
  • vitreous hemorrhage

Other symptoms may include (Diederich 2020):

• occurrence of rubeosis iridis with acute open-angle glaucoma
  • Pain
  • acute onset of visual deterioration
  • Nausea
  • vomiting
  • reddened and hardened eye
  • headache

The diagnosis of dRP is made by ophthalmic examination (Herold 2020).

Binocular ophthalmoscopy in mydriasis is used to examine the posterior pole of the eye and indirect ophthalmoscopy is used to examine the fundus periphery. The staging is done funduscopically (Kellner 2008).

Another diagnostic option is fluorescein angiography (which can be used to visualize areas of ischemia and vascular leakage), gonioscopy of the chamber angle (for neovascularization), and optical coherence tomography (OCT) for diagnosis of macular edema.

(Diederich 2020)

Since initially there are often no symptoms of the disease, regular prophylactic examinations are necessary (Herold 2020).

• Central venous thrombosis
• hypertensive retinopathy
• radiation retinopathy after radiotherapy in the head region

(Herrmann 2007)

Therapeutically, optimal blood glucose and blood pressure control are of great importance. However, in the case of an existing proliferative dRP, the HbA1c should not be lowered too quickly with medication, as otherwise there is a risk of vitreous haemorrhage. Reductions of approximately 1% per quarter are ideal (Herold 2020).

Nicotine should be avoided at all costs, as it correlates with the development and progression of retinopathy and the occurrence of microvascular complications (Kleinwechter 2014).

Other therapeutic measures consist of early laser coagulation or vitreous surgery (Herrmann 2017).

• dRP during pregnancy

Patients with diabetes mellitus may develop non-proliferative retinopathy during pregnancy. In this case, there is a 50% chance of regression without laser therapy (Kleinwechter 2014).

Glucocorticoids:

Intravitreal glucocorticoids are preferred for macular edema but may also improve proliferative dRP. Glucocorticoids have anti-inflammatory and antiangiogenic effects. However, due to the blood-retinal barrier, systemically administered drugs do not reach the retina well; therefore, intravitreal surgical drug (IVOM) application is recommended (Nentwich 2012).

The dosage recommendation is between 4 mg - 25 mg per IVOM.

Temporally, the effect is limited to 3 months, which requires repeated injections.

Side effects (Kollias 2010): secondary cataract, glaucoma (the latter occurs in about one third of patients, which is why dexamethasone has been established as an alternative).

A possibly existing magnesium deficiency should be corrected (v. Ehrlich 2006).

Surgical measures for dRP consist primarily of laser coagulation and vitreous surgery.

Laser coagulation:

Laser coagulation is the evidence-based treatment for proliferative dRP and diabetic macular edema according to randomized, prospective, controlled EDTR- study (Kollias 2010).

It finds application in:

• Pearly veins
• intraretinal microvascular abnormalities (IRMA)
• Microaneurysms
• intraretinal hemorrhages
• vascular proliferations both in the optic disc and remote from it

The goal of treatment is regression of the newly formed vessels triggered by normalization of the partial pressure of oxygen in the avascular areas of the retina (Kollias 2010).

Vitreous surgery:

Vitreous surgery (pars- plana- vitrectomy) can remove cloudy vitreous, membranes and cicatricial strands, and can also be used to annex the retina in cases of retinal detachment and appropriate laser photocoagulation (Kollias 2010).

Indications for vitreous surgery are (Kollias 2010):

• train-induced macular edema
• train-induced retinal detachment
• subhyaloid hemorrhage
• non-resorbing vitreous hemorrhage
• ghost cell glaucoma
• preservation of orienting vision in an advanced stage of proliferative dRP

As shown in the prospective, randomized controlled DRVS (Diabetec Retinopathy Vitrectomy) study, surgery should be performed as early as possible because significantly better vision is then achieved in patients (Kollias 2010).

As early as 1976, the DRS study (Diabetic Retinopathy Study) demonstrated that the risk of severe vision loss can be more than halved by timely laser treatment. However, the laser treatment does not lead to an improvement of the existing visual acuity, it only serves to maintain the visual acuity. Any deterioration is irreversible (Kollias 2010).

According to the DCCT study, intensified insulin therapy in type 1 diabetes can reduce the risk of dRP by approximately 75% (Herold 2020).

If RP occurs in a pregnancy with known diabetes mellitus, minor changes usually regress to pre-pregnancy levels postpartum in the first year (Kleinwechter 2014).

An aspirin dose of 650 mg / d given in studies does not seem to affect the disease course of a dRP (Kasper 2015).

Diffuse macular edema is associated with a poor prognosis overall. The outcome of focal laser treatment at baseline visual acuity of > 0.2 - 0.7 has a good prognosis, but below this it is poor (Diederich 2020).

An ophthalmologic examination should be performed prophylactically at least every 2 years according to the GBA resolution of 2017 (Herold 2020); in the presence of retinopathy, these intervals should be shortened (Kellner 2008).

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