Most cataracts are caused by age-related changes. However, cataract can also result from ultraviolet damage, smoking, dehydration crisis, metabolic disturbance such as diabetes, galactosemia, and steroid use. More women are affected by blindness and vision impairment due to cataract compared to men.1

Intraocular lens (IOL) implantation, a surgical procedure done usually under local anaesthesia, is a very effective treatment. The majority of patients (70%-90%) attain a best-corrected visual acuity of 6/18 or better by two months.1

Complications associated with cataract surgery

According to Lindstrom, one of the keys to successful cataract surgery is the prevention of complications. Complications affect about 5% of patients and range from mild and transient to vision-threatening.2

The two most common complications following cataract surgery are infection, in the form of endophthalmitis (infection of the tissues or fluids inside the eyeball), and inflammation, which can lead to cystoid macular oedema (CMO)- also known as Irvine-Gass syndrome. Patients with diabetes are at high risk of developing CMO.2,4

Endophthalmitis

Endophthalmitis can be caused by internal and external sources. Internal sources include microorganisms introduced into the eye from the patient’s conjunctival flora. External sources include contaminated instruments, disposable supplies, prepared solutions, the surgical field, or intraocular lenses.2

Risk factors for endophthalmitis include chronic bacterial blepharitis, active conjunctivitis, infections of the lacrimal drainage system, tear drainage obstruction, contaminated eye drops, contact lens wear, prosthesis in the fellow eye, and active non-ocular infections.3

Cystoid macular oedema

A study analysing the risk factors for CMO in 81 984 eyes from patients with diabetes, found that these patients had a relative risk (RR) of 1.8 of developing CMO following surgery – even in the absence of retinopathy. The risk was higher in patients with the presence of any diabetic retinopathy and rose proportionately with the increasing severity of DR.4

Inpatient with diabetes, CMO is induced by hyperglycaemia-induced oxidative stress, deposition of advanced glycation end products, impaired blood flow, hypoxia, pericyte loss, endothelial cell loss, upregulation of vesicular transport, downregulation of glial cell-derived neurotrophic factor and inflammation.5

Preventing complications

Anti-infectives are widely used for surgical prophylaxis in the prevention of endophthalmitis. The goal of a topical anti-infective is to reduce bacteria on the ocular surface as quickly and safely as possible in order to lessen the likelihood of bacteria entering the eye during surgery or through a poorly sealed wound.2

Fourth-generation fluoroquinolones, which target both intravenous bacterial topoisomerase and DNA gyrase, include besifloxacin, gatifloxacin, and moxifloxacin, have emerged in recent years as the most commonly used anti-infective agents during cataract surgery.2

Options for the prevention of CMO after cataract surgery in patients include preoperative treatment with steroids, intravitreal injections of anti-vascular endothelial growth factor (VEGF), laser treatment, and topical non-steroidal anti-inflammatory drugs (NSAIDs). It is recommended that all patients undergoing cataract surgery should be treated with topical NSAIDs to prevent CMO.6

Treating post-operative complications

Endophthalmitis

Postoperative endophthalmitis may be acute or have a delayed onset.  It can occur within the first week or depend on the causative pathogen, can manifest six weeks or even several months after surgery. Symptoms indicative of endophthalmitis include ocular pain, diminished vision, and headache.3,7

Acute endophthalmitis should be suspected when there is pain and an increase in anterior chamber reaction on slit-lamp examination on the first postoperative day. Decreased glow on distant direct ophthalmoscopy has high sensitivity but low specificity on the first postoperative day for diagnosing acute infectious endophthalmitis.3

On subsequent postoperative days, a decrease in vision following initial improvement along with pain should immediately raise the index of suspicion toward endophthalmitis. The presence of exudates in the vitreous on indirect ophthalmoscopy is 100% specific.3

Cystoid macular oedema

Although there is no universally accepted definition for post-operative CMO in either the historic or recently published literature, clinically significant CMO has traditionally been defined as an asymptomatic reduction in vision equivalent to 20/40 (6/12 Snellen) or worse, as observed in <1% of patients after cataract surgery in the absence of any treatment. Prolonged CMO is defined as the presence of macular oedema over three months since the original cataract surgery.8

Patients commonly experience good vision in the immediate postoperative period, followed by a painless central visual deterioration a few weeks later. The incidence of post-operative CMO peaks at four to six weeks, but most cases are self-limiting, though visual impairment can persist, with the duration of CMO reported to range between 72 and 249 days.8

Treatment options

Steroids have been the cornerstone of therapy for controlling inflammation after cataract surgery for more than 50 years. Studies have shown them to be efficacious, tolerable, and safe. More recently, NSAIDs have been recommended as an adjuvant to steroids as adjuvant therapy because they act at a different and synergistic place in the inflammatory cascade, complimenting the action of steroids.2

Nepafenac (NPF) is a topical NSAID approved by the American Food and Drug Administration (FDA) in 2005. Kjaerbo describes NPF as a unique prodrug, that rapidly penetrates the cornea and is deaminated to form the active metabolite, amfenac, by intraocular hydrolases within the ciliary body epithelium, retina, and choroid. Nepafenac and amfenac are potent inhibitors of the cyclooxygenase enzyme isoforms 1 and 2.6,9

NPF is recommended for the management of pain, inflammation, and CMO following cataract surgery. NPF 0.1% is also approved in Europe for the reduction in the risk of CMO associated with cataract surgery in diabetic patients. NPF 0.3% formulation is now available in South Africa.6

The benefits of using NPF includes:6

  • NPFs has a prolonged activity in the vascularized tissues of the eye
  • Enhanced corneal permeability relative to diclofenac, allowing for greater intraocular drug accumulation
  • The rate of hydrolysis of NPF is much greater in the retina/choroid (about 20 times) than in the iris/ciliary body
  • The administration of NPF also produces sustained inhibition of prostaglandin synthesis relative to a conventional NSAID.
  • The increased absorption, targeted activation, and greater duration of action of nepafenac may lead to improved efficacy in the posterior segment over other NSAIDs lacking these properties.

The use of the 0.1% formulation given three times daily is supported by several key phases 2 and 3 clinical trials, in which prophylactic use resulted in a lower incidence of CMO, better visual outcomes and lower central subfield macular thickness than a vehicle alone.9

NPF 0.3% efficacy and safety studies

The 0.3% NPF formulation provides a more convenient once-daily dosing. Modi et al (2014) evaluated once-daily NPF 0.3% to prevent and treat ocular pain and inflammation following cataract surgery. The study involved 65 centres in the United States and Europe. This was a randomised double-masked vehicle- and active-controlled phase 3 study.9,10

Patients received NPF 0.3% once daily (n=817), NPF 0.1% (819) three times daily, or their respective vehicles (n=200 and n=206) from day -1 to day 14 after cataract extraction. An additional drop of study drug was administered 30 to 120 minutes preoperatively. The primary endpoint was the percentage of patients with a cure for inflammation (score of 0 for both aqueous cells and flare) at day 14.10

Significantly more NPF 0.3% patients had no inflammation (68.4% vs 34%) and were pain-free (91% versus 49.7%) at day 14 than vehicle patients. NPF 0.3% was non-inferior to NPF 0.1% for inflammation (95% confidence interval [CI], -5.73% to 3.17%) and pain-free rates (-3.08% to 2.70%). At all post-operative visits, fewer treatment failures and more clinical successes were observed with NPF 0.3% versus vehicle. NPF 0.3% was well tolerated and had a safety profile comparable to that of NPF 0.1%.10

Singh et al (2017) conducted two prospective, randomised, multicentre, double-masked, vehicle phase 3 studies to demonstrate the efficacy and safety of once-daily NPF 0.3% ophthalmic suspension in patients with diabetes post-operative cataract surgery. Study 1 enrolled 615 patients and study 2 and 605 patients.11

The primary endpoint was the percentage of patients in whom CMO developed (≥30% increase from pre-operative baseline central subfield macular thickness) within 90 days after cataract surgery and the patients (%) with a best-corrected visual acuity (BCVA) improvement of >15 letters from pre-operative baseline through day 14 maintained through day 90.11

Secondary endpoints included the percentage of patients with a BCVA improvement of >15 letters from pre-operative baseline through days 90 and 60 and safety over three months. Patients were randomised (1:1) to topical NPF 0.3% or vehicle once-daily starting the day before surgery and continuing for 90 days thereafter.11

A significantly lower percentage of patients demonstrated CMO within 90 days after surgery with NPF 0.3% versus vehicle (study 1: 2.3% vs 17.3%, study 2: 5.9% vs 14.3%. Pooled: 4.1% vs 15.9%.11

The percentage of patients achieving a >15-letter improvement from baseline through day 14 maintained through day 90 with NPF 0.3% versus vehicle was 61.7% versus 43% in study 1, 48.8% versus 50.5% in study 2, and 55.4% versus 46.7% in the pooled analysis.11

A greater percentage of patients treated with NPF 0.3% versus vehicle in study 1 and a similar percentage in study 2 had a BCVA improvement of >15 letters from pre-operative baseline through day 90 (77.2% vs 67.7% and 65.4% vs 65.9%) and through day 60 (76.2% vs 64.7% and 68.9% vs 62.1%). No unanticipated adverse events were observed.11

More recently, (2020) Giarmoukakis et al assessed the effect of twice-daily NPF ophthalmic suspension 0.3% on postoperative CMO in 21 patients which acute or chronic postoperative CMO following cataract extraction.12

Patients were treated with twice-daily NPF 0.3% drops and followed for at least a four-month period. BCVA and spectral-domain optical coherence tomography-derived central retinal thickness (CRT) were measured.12

Eight of the 21 patients, presented with acute postoperative CMO and 13 with chronic CMO. Mean follow-up was 4.82±1.24 months. No adverse events were reported during the study. Baseline BCVA was 0.49±0.36 logMAR and improved to 0.36±0.42 logMAR at the last follow-up visit. CRT decreased from 450.40±90.74 μm at baseline to 354.60±81.49μm, following treatment.

Conclusion

Cataract surgery has been shown to be an efficacious and safe treatment modality. However, 5% of patients may develop complications such as inflammation and infection, which may result in CMO. Options for the prevention of CMO following cataract surgery in patients with diabetes include preoperative treatment with steroids, intravitreal injections of anti-VEGF, laser treatment, and topical NSAIDs. It is recommended that all patients undergoing cataract surgery should be treated with topical NSAIDs to prevent CMO. NPF is a potent topical NSAID recommended for the management of pain, inflammation, and CMO following cataract surgery. The NPF 0.3% solution was approved in South Africa recently.

REFERENCES:

1. Burton MJ, Ramke JR, Marques AP, et al. The Lancet Global Health Commission on Global Eye Health: vision beyond 2020. Appendix 1. The Lancet Global Health, 2021.

2. Lindstrom RL. Reducing the Risk for Inflammation and Infection Following Cataract Surgery. Medscape, 2021.

3. Verma L and Chakravarti A. Prevention and management of postoperative endophthalmitis: A case-based approach. Indian J Ophthalmol, 2016.

4. Chu CJ, Johnston  RL, Buscombe C, et al. Risk Factors and Incidence of Macular Edema after Cataract Surgery: A Database Study of 81984 Eyes. Ophthalmology, 2017.

5. Munk MR, Jampol LM, Simader C, et al. Differentiation of Diabetic Macular Edema From Pseudophakic Cystoid Macular Edema by Spectral-Domain Optical Coherence Tomography. IOVS, 2015.

6. Yuksel B, Karti O and Kusbeci T. Topical nepafenac for prevention of post-cataract surgery macular edema in diabetic patients: patient selection and perspectives. Clinical Ophthalmology, 2017.

7. Zagaria MAE. Postoperative Endophthalmitis After Cataract Surgery. US Pharm, 2016.

8. Erikitola O-O, Siempis T, Foot B and Lockington D. The incidence and management of persistent cystoid macular oedema following uncomplicated cataract surgery—a Scottish Ophthalmological Surveillance Unit study. Eye, 2021.

9. Kjaerbo H. Nepafenac in the Treatment of Ocular Inflammation Following Cataract Surgery (Pseudophakic Macular Oedema) – an Update. European Ophthalmic Review, 2018.

10. Modi SS, Lehmann RP, Walters TR, et al. Once-daily nepafenac ophthalmic suspension 0.3% to prevent and treat ocular inflammation and pain after cataract surgery: phase 3 study. J Cataract Refract Surg, 2014.

11. Singh RP, Lehmann R, Martel J, et al. Nepafenac 0.3% after cataract surgery in patients with diabetic retinopathy: Results of 2 randomized phase 3 studies. Ophthalmology, 2017.

12. Giarmoukakis AK, Blazaki SV, Bontzos GC, et al. Efficacy of Topical Nepafenac 0.3% in the Management of Postoperative Cystoid Macular Edema. Ther Clin Risk Manag, 2020.