Are light masks useful for early diabetic macular oedema? (2018)

Diabetic retinopathy is a leading cause of vision loss in middle-aged and economically active people.1Cheung N Mitchell P Wong TY Diabetic retinopathy.Lancet. 2010; 376: 124-136Summary Full Text Full Text PDF PubMed Scopus (1477) Google Scholar Roughly 7–10% of people with diabetes will have diabetic macular oedema, the most common cause of vision loss among patients with diabetic retinopathy.2Yau JW Rogers SL Kawasaki R et al.Global prevalence and major risk factors of diabetic retinopathy.Diabetes Care. 2012; 35: 556-564Crossref PubMed Scopus (2175) Google Scholar Diabetic macular oedema arises when fluid and blood leak into the centre of the retina (fovea), triggered by a combination of ischaemia, hypoxia, inflammation, and other factors.3Tan GS Cheung N Simó R Cheung GC Wong TY Diabetic macular oedema.Lancet Diabetes Endocrinol. 2017; 5: 143-155Summary Full Text Full Text PDF PubMed Scopus (100) Google Scholar Previously, the standard treatment for diabetic macular oedema was focal (or grid) laser photocoagulation.2Yau JW Rogers SL Kawasaki R et al.Global prevalence and major risk factors of diabetic retinopathy.Diabetes Care. 2012; 35: 556-564Crossref PubMed Scopus (2175) Google Scholar A major discovery in the past decade was that eyes with diabetic macular oedema have higher levels of vascular endothelial growth factor (VEGF).3Tan GS Cheung N Simó R Cheung GC Wong TY Diabetic macular oedema.Lancet Diabetes Endocrinol. 2017; 5: 143-155Summary Full Text Full Text PDF PubMed Scopus (100) Google Scholar This finding led to development of agents that block VEGF. Anti-VEGF agents are delivered by intraocular injection and are effective for diabetic macular oedema involving the foveal centre (termed centre-involving diabetic macular oedema) associated with vision impairment, as confirmed in clinical trials and in real-world settings.3Tan GS Cheung N Simó R Cheung GC Wong TY Diabetic macular oedema.Lancet Diabetes Endocrinol. 2017; 5: 143-155Summary Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 4Diabetic Retinopathy Clinical Research NetworkAflibercept, bevacizumab, or ranibizumab for diabetic macular edema.N Engl J Med. 2015; 372: 1193-1203Crossref PubMed Scopus (883) Google Scholar However, repeated intraocular injections and clinic visits (nine injections and 12 visits in the first year) are a substantial burden.4Diabetic Retinopathy Clinical Research NetworkAflibercept, bevacizumab, or ranibizumab for diabetic macular edema.N Engl J Med. 2015; 372: 1193-1203Crossref PubMed Scopus (883) Google Scholar The effect of such an intensive ocular treatment on patients with diabetes, who typically have multiple other comorbidities, and on health-care systems globally is substantial.3Tan GS Cheung N Simó R Cheung GC Wong TY Diabetic macular oedema.Lancet Diabetes Endocrinol. 2017; 5: 143-155Summary Full Text Full Text PDF PubMed Scopus (100) Google Scholar For a long time, clinicians and researchers have searched for an alternative, possibly non-invasive, therapy for diabetic retinopathy and diabetic macular oedema. Because diabetic macular oedema develops over many years, starting from outside the foveal centre (termed non-centre-involving diabetic macular oedema), potential treatments that prevent the progression of early, non-centre-involving diabetic macular oedema to centre-involving diabetic macular oedema are very attractive. Such a therapy should be simple to administer, non-invasive, and not require specialist ophthalmologists. The primary cells in the retina—rod photoreceptors—consume the most amount of oxygen during dark adaptation. The resultant hypoxia has been postulated as an initial trigger that contributes to the pathogenesis of diabetic retinopathy and diabetic macular oedema.5Linsenmeier RA Effects of light and darkness on oxygen distribution and consumption in the cat retina.J Gen Physiol. 1986; 88: 521-542Crossref PubMed Scopus (328) Google Scholar, 6Arden GB Gündüz MK Kurtenbach A et al.A preliminary trial to determine whether prevention of dark adaptation affects the course of early diabetic retinopathy.Eye (Lond). 2010; 24: 1149-1155Crossref PubMed Scopus (35) Google Scholar Thus, interventions to reduce dark adaptation of the retina could relieve hypoxia and potentially slow the onset and progression of diabetic retinopathy and diabetic macular oedema. Wearing a mask during sleep that emits light through the eyelids to disrupt the dark adaptation process, but not disturb sleep, might provide an elegant and novel solution.7Arden GB Jyothi S Hogg CH Lee YF Sivaprasad S Regression of early diabetic macular oedema is associated with prevention of dark adaptation.Eye (Lond). 2011; 25: 1546-1554Crossref PubMed Scopus (36) Google Scholar Preliminary clinical studies entailing small groups of patients suggest this idea could be possible.6Arden GB Gündüz MK Kurtenbach A et al.A preliminary trial to determine whether prevention of dark adaptation affects the course of early diabetic retinopathy.Eye (Lond). 2010; 24: 1149-1155Crossref PubMed Scopus (35) Google Scholar, 7Arden GB Jyothi S Hogg CH Lee YF Sivaprasad S Regression of early diabetic macular oedema is associated with prevention of dark adaptation.Eye (Lond). 2011; 25: 1546-1554Crossref PubMed Scopus (36) Google Scholar In The Lancet Diabetes & Endocrinology, Sobha Sivaprasad and colleagues in the CLEOPATRA Study Group report findings of a multicentre randomised trial to assess the efficacy of a light-emitting mask (Noctura 400 Sleep Mask, PolyPhotonix Medical, Sedgefield, UK) in preventing progression of early non-centre-involving diabetic macular oedema.8Sivaprasad S Vasconcelos JC Prevost AT et al.Clinical efficacy and safety of a light mask for prevention of dark adaptation in treating and preventing progression of early diabetic macular oedema at 24 months (CLEOPATRA): a multicentre, phase 3, randomised controlled trial.Lancet Diabetes Endocrinol. 2018; (published online Mar 5.)http://dx.doi.org/10.1016/S2213-8587(18)30036-6Summary Full Text Full Text PDF PubMed Scopus (16) Google Scholar After 24 months of follow-up, the light mask did not differ from a sham (non-light) mask in the primary outcome of change in retinal thickness as measured by optical coherence tomography (OCT), nor in prespecified and post-hoc secondary outcomes, including need for treatment, progression of diabetic retinopathy, and visual acuity. Even if the light mask had shown a therapeutic benefit, compliance and patients' acceptability for long-term non-invasive treatments targeting asymptomatic patients is important. In this respect, analysis of such data suggests that use of light masks over 24 months is not sustainable, because compliance decreased over time. The light mask used in the CLEOPATRA study had in-built automatic recording of use, so objective documentation of compliance was easy. Median compliance (defined as using the light mask for 6 h/day over 24 months, 70% of the time) was 39·5% at 4 months, which fell further to 19·5% at 2 years.8Sivaprasad S Vasconcelos JC Prevost AT et al.Clinical efficacy and safety of a light mask for prevention of dark adaptation in treating and preventing progression of early diabetic macular oedema at 24 months (CLEOPATRA): a multicentre, phase 3, randomised controlled trial.Lancet Diabetes Endocrinol. 2018; (published online Mar 5.)http://dx.doi.org/10.1016/S2213-8587(18)30036-6Summary Full Text Full Text PDF PubMed Scopus (16) Google Scholar Thus, CLEOPATRA provides no evidence that a light-emitting mask used during sleep—based on a hypothesis that this approach can impede the dark adaptation cycle and reduce retinal hypoxia—is an effective treatment for early non-centre-involving diabetic macular oedema. Where does this finding leave such a potential therapy? Could limitations have biased the results of this trial? Sivaprasad and colleagues acknowledged some study limitations. For example, patients and clinicians were aware of study assignments because of the nature of the intervention (light mask vs sham [non-light] mask). Patients using the sham mask could opt not to use the mask at all. 62 patients did not complete the study and had no data for the primary outcome, although these patients did not differ in baseline characteristics from the 246 individuals who completed the study. Sivaprasad and colleagues argue that perhaps other light masks—emitting different wavelengths of light—would be more efficacious. Or perhaps inclusion criteria should focus on groups of patients who are more likely to adhere to the intervention because they are comfortable using masks while asleep as a matter of routine. Furthermore, would a larger and longer trial beyond 24 months, that not only assesses changes in OCT but also is powered to measure changes in visual acuity (the most important outcome for the patient) be useful? Unfortunately, the robustness of the CLEOPATRA trial and these overall data do not support the need for another trial. Large trials have shown that non-invasive interventions—eg, tight glucose and blood pressure control, possibly with oral drugs such as fenofibrate—reduce the long-term risk of diabetic retinopathy and diabetic macular oedema.9Mohamed Q Gillies MC Wong TY Management of diabetic retinopathy: a systematic review.JAMA. 2007; 298: 902-916Crossref PubMed Scopus (601) Google Scholar, 10Keech AC Mitchell P Summanen PA et al.Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial.Lancet. 2007; 370: 1687-1697Summary Full Text Full Text PDF PubMed Scopus (767) Google Scholar However, any clinician treating patients with diabetes will know these interventions are effective in theory, but are difficult to administer and monitor in real-world, busy clinical practices. Thus, the search for elegant, novel, non-invasive treatments for diabetic retinopathy and diabetic macular oedema continues. I have sat on advisory boards for Abbott, Allergan, Bayer, Novartis, Roche, and Pfizer and received honoraria for travel, service on advisory boards, and research support from these companies; I have also provided expert testimony to Novartis. Clinical efficacy and safety of a light mask for prevention of dark adaptation in treating and preventing progression of early diabetic macular oedema at 24 months (CLEOPATRA): a multicentre, phase 3, randomised controlled trialThe light mask as used in this study did not confer long-term therapeutic benefit on non-centre-involving diabetic macular oedema and the study does not support its use for this indication. Full-Text PDF Open Access