**7. Microperimetry**

Micoperimetry is able to quantify macular sensitivity and fixation pattern in an exact, fundus-related fashion, thus adding detailed information about the degree and pattern of macular function alteration (**Figure 4k**). It has been successfully used in the diagnosis and follow-up of different macular disorders, including age-related macular degeneration, myopic maculopathy, macular dystrophies, and diabetic macular edema. Vujosevic S et al. have demonstrated in a series of studies that macular sensitivity is significantly affected when diabetic macular edema develops and it deteriorates further in eyes at more severe stages of macular edema even in the absence of ischemia. The stability of the fixation is decreasing late in the disease and indicates advanced photoreceptor damage and chronicity [19].

## **8. Glaucoma in eyes with DME**

In a recent meta-analysis of prospective cohort studies the pooled risk ratio of the association between primary open-angle glaucoma (POAG) and diabetes was 1.36 [20]. The prevalence of glaucoma in diabetics ranges from 4.96% to 14.6% with significant variations in geographic regions and racial groups. Moreover, there is a statistically significant association between the duration of diabetes and glaucoma [21]. Hou et al. compared rates of visual field (VF) loss and retinal nerve fiber layer thinning for patients with POAG and found no difference in progression between patients without and with type 2 diabetes and no detectable diabetic retinopathy. They also found that treated diabetes was linked to significantly slower loss of RNFL thickness [22].

The risk of ocular hypertension in a patient presenting with DME needs to be considered in the treatment choice. While anti-VEGF agents are generally safe, a key DRCR.net report on eyes with center-involved DME and no preexisting openangle glaucoma treated on ranibizumab and monitored for 3 years demonstrated increase in the risk of sustained IOP elevation or the need for ocular hypotensive treatment after anti-VEGF treatment [23]. In patients with POAG and DME treated with ranibizimab and monitored for 24 months, Fursova et al. report a decrease in the functional and structural parameters of the retina and optic nerve, and a higher rate of progression of glaucomatous optic neuropathy compared to patients without DME. Long-term results have not revealed a significant deterioration in the structural parameters of the optic disc and retina as a consequence of anti-VEGF therapy [24].

Intravitreal steroids will induce hypertensive response in up to 50% of the eyes with DME. The MEAD Study reported that over 40% of eye required initiation of a topical ocular hypotensive agent and 0.3% of eyes required incisional glaucoma surgery after Ozurdex [25]. In the FAME Studies, 18.4% of eyes that were injected with the 0.2 μg Iluvien-FA per day implant developed an IOP higher than 30 mmHg and 4.8% underwent incisional glaucoma surgery [26]. After a follow-up of 5 years, 9% of eyes that had multiple injections of triamcinolone acetonide required a trabeculectomy [27]. An eye that does not develop substantial IOP elevation after a challenge course with a topical steroid may still respond with an IOP rise after Ozurdex or Iluvien, however in most cases it is well controlled on antiglaucoma medications [28].

Patients with refractive DME and well compensated glaucoma on one or two antiglaucoma drops responded favorably to both Ozurdex and Iluvien in our practice (**Figure 4**). An eye with advanced glaucoma on more than 2 medications is at a high risk of uncontrollable IOP and severe vision loss after intravitreal steroid, and glaucoma surgery has to be performed prior to the switch from anti-VEGF.

Neovascularization of the iris or neovascularization of the angle that ultimately lead to neovascular glaucoma is a consequence of long-standing ischemia in patients with PDR. The incidence of neovascular glaucoma is further increased in patients who have undergone vitrectomy and lensectomy. Breach of the posterior capsule from a complicated cataract extraction or even from Nd: YAG laser capsulotomy may allow angiogenic factors to gain access to the anterior segment more readily, accelerating formation of neovascularization. The management of DME in these eyes with intravitreal anti-VEGF provides temporary regression of the iris neovascularization, decrease in the PDR severity and facilitates the panretinal photocoagulation [29]. Early glaucoma surgery significantly improves the visual prognosis of DME in eyes with neovascular glaucoma, however they remain at high risk of IOP decompensation, reactivation of the PDR and recurrences of the macular edema and need prompt, often urgent treatment (**Figure 2**).

### **9. Uveitis**

History of a previous uveitis episode or evidence of a chronic intraocular inflammation in a patient with DME heralds high rate of complications and difficult management (**Figure 5**). A large database from the UK was analyzed for the prevalence of acute uveitis over a six-year period among populations without (n = 889,856) and with diabetes (n = 48,584) and evaluated the impact of glycaemic control on disease risk. Poor glycaemic control increases the risk of acute uveitis, with patients that have an HbA1c over >11.3% almost 5 times more likely to have an event. Acute uveitis was also more common in those with proliferative retinopathy. The odds ratio (OR) for acute uveitis was significantly higher in patients with type 1 DM (OR 2.01), Black (OR 20.17) or Asian (OR 2.09) ethnicity, proliferative disease (OR 2.42) and escalated with increasing HbA1c, however the association with maculopathy was less - OR 1.15 [30]. In a cohort of middle-aged diabetic patients with uveitis, who were followed up for 4 years, 42% had final visual acuity worse than 6/18. In 53% of the eyes, the poor visual acuity was thought to be uveitis related, and a half of these eyes had clinically significant macular edema. Progression of diabetic retinopathy to proliferative stage occurred in 10% of the eyes. In patients with available HbA1c data, the levels were over 7.0% on almost all cases in the quiescent period and rose by 1.5–4% in the acute episodes. The authors conclude that uveitis occurring in patients with pre-existing diabetes can be associated with numerous ocular complications and recurrences. Macular involvement related to both the uveitis and the diabetes appears to be the main cause of reduced vision [31].

*High-Risk Diabetic Maculopathy: Features and Management DOI: http://dx.doi.org/10.5772/intechopen.99748*

In clinical practice, diabetic patients with macular edema and uveitis have higher tendency to develop fibrinous exudates in the anterior chamber and posterior synechiae, particularly after intraocular surgery. They respond favorably to topical, periocular and intravitreal steroids and require close monitoring for intraocular pressure spikes. Interestingly, the IOP in many patients with uveitic glaucoma decreases in response to appropriate anti-inflammatory management; in the meantime the macular edema deteriorates, particularly if the patient is on systemic steroids or a biological agent and with significant fluctuations in the glucose levels. The recurrence of the edema may remain unnoticed in eyes with media opacities and active inflammation and is "discovered" once the uveitis subsides in the search for explanation of the poor vision - severe macrocysts in the macula are usually accompanied by exudative subsensory fluid collections. Early detection of the DME while the visual acuity is still reasonable and prompt intensive intravitreal treatment improve greatly the visual prognosis (**Figure 5**). These patients are very unstable - they present frequently with recurrent uveitis and macular edema in the course of each attack of their systemic inflammation or in periods of deteriorated metabolic control.

#### **10. Cataract surgery and DME**

Cataract surgery in diabetic patients has been associated with higher risk of complications, including postoperative macular edema (Irvine-Gass syndrome) and worsening of pre-existing DME (**Figure 4b**). The risk is high in patients with inconsistent previous treatment or chronic edema with incomplete response to intravitreal management. The prevalence is increased by intraoperative vitreous loss, vitreous traction at incision sites, vitrectomy for retained lens fragments, iris trauma, posterior capsule rupture, intraocular lens dislocation, early postoperative capsulotomy, iris-fixated intraocular lenses and placement of an anterior chamber intraocular lens and is further exaggerated by persistent postoperative inflammation [32, 33]. In clinical practice the edema is usually revealed late in the postoperative period and the differentiation between pseudophakic cystoid (Irvin-Gass) and macrocystic diabetic edema may not be very straightforward on OCT. The presence of hard exudates, atrophic changes and hypoperfusion in the posterior pole and some degree of retinopathy in an eye with low vision is more suggestive of a DME (**Figure 5**) while better vision and characteristic fluorescein angiography findings like retinal telangiectasis, capillary dilatation, and leakage from perifoveal capillaries in the early phase frames, and perifoveal hyperfluorescent spots classically described as a "petalloid" pattern in the late phase frames are suggestive of pseudophakic cystoid macular edema. While in most cases, acute pseudophakic CME spontaneously resolves with relatively good vision, the eyes with deteriorated DME after cataract surgery remain with low vision despite vigorous treatment on intravitreal anti-VEGF and steroids. There is a general consensus that DME and severe diabetic retinopathy should be stabilized before undergoing cataract extraction and proactive management is recommended in preparation for surgery. Recurrence or worsening of DME has been successfully prevented by preoperative or intraoperative ranibizumab [34] and triamcinolone acetonide (TA) [35], however the efficacy was short lasting and a sizable group of the eyes with TA develop elevated IOP. Dexamethasone implants have been used intraoperatively and postoperatively [36, 37], however if inserted 2 to 4 weeks prior to surgery they reach their peak activity at the time of the procedure and help control the postoperative inflammation. The initial improvement in visual acuity and decrease in the edema in the first 1–2 months start deteriorating in the next 2–3 months, yet these eyes respond favorably to repeated dexamethasone treatment [38].
