The absence of diabetic retinopathy in patients with retinitis pigmentosa: implications for pathophysiology and possible treatment

Arden, G B

doi:10.1136/bjo.85.3.366

Cited by 126 publications

(86 citation statements)

References 70 publications

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“…19,20 The mainstay of surgical treatment, laser pan-retinal photocoagulation, is thought to be successful because it reduces the number of highly active photoreceptors, thus increasing the pO 2 by destroying many rods, with improvement in the oxygen supply to the remaining rods. 9 Conditions under which rod activity is reduced also prevent DR. [21][22][23] The loss of hypoxic upregulation of VEGF is found in patients with long standing diabetes and no retinal changes 24 In diabetic patients who have sleep apnoea, with more than five 'dips' (episodes of reduction of oxygen saturation below 90%) per night, 25,26 the incidence and severity of DR is higher than that in control diabetic subjects. One common factor explains all these observations: the high metabolic rate of rods in darkness places a strain on the normal retina, which in diabetics is unsustainable and results in increased retinal hypoxia, stimulating the production of cytokines, especially vascular endothelial growth factor (VEGF), that contribute to DR.…”

Section: Relationship To Previous Work and Theories Of Pathogenesismentioning

confidence: 99%

A preliminary trial to determine whether prevention of dark adaptation affects the course of early diabetic retinopathy

Arden

Gündüz

Kurtenbach

et al. 2010

Eye

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This study was designed to determine whether a new form of treatment of diabetic retinopathy (DR) was acceptable to patients and whether reduction in the maximal activity of rods in diabetes could affect the progress of DR. Methods In 12 patients, trans-lid retinal illumination of one eye was employed during sleep to prevent the depolarisation of rods and thus reduce their metabolic activity. Techniques A headband was used to place a source of chemical light over one eye, with its fellow as a control. Measurements Colour contrast thresholds were measured before and after a period of treatment in treated eyes, and the changes were compared to those in untreated fellow eyes, and areas of 'dark retinal anomalies' (microaneurysms, dot haemorrhages) were measured at the same time points. Results Patients found this intervention to be acceptable, and no adverse effects were noted. In the majority of cases, and for each outcome measure, the treated eyes improved relative to their fellows. The intervention significantly reduced the tritan thresholds in treated eyes relative to their fellows (P ¼ 0.03), and the area of dark retinal anomalies decreased in treated eyes and increased in untreated eyes, with a similar probability.

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Section: Relationship To Previous Work and Theories Of Pathogenesismentioning

confidence: 99%

A preliminary trial to determine whether prevention of dark adaptation affects the course of early diabetic retinopathy

Arden

Gündüz

Kurtenbach

et al. 2010

Eye

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“…There is Fast Track Paper Fast Track Paper considerable evidence to support this view. [13][14][15][16][17][18] These and other observations have led to a different proposal about the pathophysiology of DR. 19,[20][21][22] The oxygen demand of rods, in the outer retina, is much increased in darkness 6,7,13,[23][24][25] and this in turn causes a reduction in inner retinal oxygen tension. 11,25 It has been suggested that the increasing inner retinal hypoxia in diabetes causes the upregulation of cytokines, most importantly VEGF, to a degree that produces damage to small retinal vessels, thus reducing local capillary blood flow and increasing hypoxia in a vicious circle.…”

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confidence: 99%

Regression of early diabetic macular oedema is associated with prevention of dark adaptation

Arden

Jyothi

Hogg

et al. 2011

Eye

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Hypothesis Dark-adapted rods consume oxygen at high rates and light adaptation decreases this oxygen burden and can have therapeutic effects on diabetic macular oedema (DMO). Methods Patients with mild nonproliferative diabetic retinopathy (DR) and early, untreated non-sight-threatening DMO slept for 6 months wearing masks that illuminated the eyelid of one closed eye by 505 nm light. Exclusion criteria were any concomitant eye disease, DR 4ETDRS grade 35, and other systemic diseases. Primary outcome: change of OCT retinal thickness in the local region where oedema was present. Results A total of 34 out of 40 patients completed the study. Mean baseline OCT macular cube thickness was equivalent for study and fellow eyes. But study eyes had a greater mean thickness in the central subfield zone 1 (282±53 lm) vs (256±19 lm) the fellow eyes. Twenty-eight study eyes showed intraretinal cysts compared with nine in the fellow eyes. At 6 months, only 19 study eyes had cysts while cysts were seen in 20 fellow eyes. After 6 months, the worst affected ETDRS zone and the central subfield zone 1 reduced in thickness in study eyes only by 12 lm (95% CI 20 to À7, P ¼ 0.01). The secondary outcomes of change in visual acuity, achromatic contrast sensitivity, and microperimetric thresholds improved significantly in study eyes and deteriorated in fellow eyes. Conclusions Sleeping in dim light that can keep rods light adapted may reverse the changes of DMO.

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“…These postmitotic cells have a very high metabolic rate, using more oxygen than other cells throughout the body. They are also considered as likely contributors to the eventual development of retinal hypoxia and subsequent neovascularization in advanced stages of diabetic retinopathy (13,14). The contribution of photoreceptors to early stages of diabetic retinopathy, however, has been less well investigated.…”

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“…Several recent reports have raised the possibility that photoreceptors could play an important role in the initiation of diabetic retinopathy. A survey of diabetic patients with photoreceptor degeneration and concomitant retinitis pigmentosa suggested that patients whose photoreceptors degenerated had less retinopathy than did diabetics with intact photoreceptors (13). Moreover, diabetic mice lacking photoreceptor cells (resulting from opsin deficiency) featured a lower density of retinal vessels than those with photoreceptors (15), suggesting that photoreceptors influence diabetes-induced degeneration of retinal capillaries.…”

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Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina

Veenstra

Palczewski

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Accumulating evidence suggests that photoreceptor cells play a previously unappreciated role in the development of early stages of diabetic retinopathy, but the mechanism by which this occurs is not clear. Inhibition of oxidative stress is known to inhibit the vascular lesions of early diabetic retinopathy, and we investigated whether the diabetes-induced oxidative stress in the retina emanates from photoreceptors. Superoxide generation was assessed in retinas of male C57BL/6J mice made diabetic for 2 mo (4 mo of age when killed) using histochemical (dichlorofluorescein and dihydroethidine) and bioluminescence (lucigenin) methods. Photoreceptors were eliminated in vivo by genetic (opsin −/− ) and chemical (iodoacetic acid) techniques. Immunoblots were used to measure expression of intercellular adhesion molecule 1 and the inducible form of nitric oxide synthase. Diabetes increased the generation of superoxide by diabetic mouse retina more at night than during the day. Photoreceptors were the major source of reactive oxygen species in the retina, and their deletion (either genetically in opsin −/− mice or acutely with iodoacetic acid) inhibited the expected diabetes-induced increase in superoxide and inflammatory proteins in the remaining retina. Both mitochondria and NADPH oxidase contributed to the observed retinal superoxide generation, which could be inhibited in vivo with either methylene blue or apocynin. Photoreceptors are the major source of superoxide generated by retinas of diabetic mice. Pharmaceuticals targeting photoreceptor oxidative stress could offer a unique therapy for diabetic retinopathy.T he pathogenesis of diabetic retinopathy remains unclear, but prior work by us and others has provided strong evidence in animal models that oxidative stress and inflammatory processes play important roles in the development of the vascular lesions characteristic of early stages of this retinopathy (1, 2). Inhibition of oxidative stress by feeding antioxidants or overexpressing antioxidant enzymes has reduced diabetes-induced degeneration of retinal capillaries (3-7). Moreover, oxidative stress has been reported to regulate expression of proinflammatory proteins (8-10), which also have been shown to play a critical role in the pathogenesis of this early retinopathy (2). However, which cells of the retina are the major sources of such oxidative stress in diabetes is unclear. In vitro studies of retinal endothelial cells or Müller cells incubated in elevated levels of glucose have demonstrated that these cells can contribute to oxidative stress (11, 12), but the contribution of other cell types and their relative importance has not been studied.Rod and cone photoreceptor cells are the most prevalent cells in the retina. These postmitotic cells have a very high metabolic rate, using more oxygen than other cells throughout the body. They are also considered as likely contributors to the eventual development of retinal hypoxia and subsequent neovascularization in advanced stages of diabetic retinopathy (13,14). Th...

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The absence of diabetic retinopathy in patients with retinitis pigmentosa: implications for pathophysiology and possible treatment

Cited by 126 publications

References 70 publications

A preliminary trial to determine whether prevention of dark adaptation affects the course of early diabetic retinopathy

A preliminary trial to determine whether prevention of dark adaptation affects the course of early diabetic retinopathy

Regression of early diabetic macular oedema is associated with prevention of dark adaptation

Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina

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