Review Article
Laser, intravitreal drug application, and surgery to treat diabetic eye disease Anselm Kampik Professor and Chairman, Department of Ophthalmology, Ludwig Maximilians University, and Secretary-General, Deutsche Ophthalmologische Gesellschaft (DOG), Munich, Germany
Diabetes mellitus is affecting more and more persons. The mere damage from diabetes mellitus to eye sight accounts for almost 5% of total blindness worldwide[1] and for 10-13% of total visual impairment.[2] Projecting to the year 2030 there is a 51% global increase of persons affected by diabetes mellitus. For the region Middle East and North Africa currently 14.7 million people are diseases from diabetes mellitus. For the year 203 the prevalence is increasing by 83% to almost 60 million people suffering from the disease diabetes mellitus.[3] Worldwide, approximately 35% of those with diabetes mellitus have some form of diabetic retinopathy (DR), about 7% proliferative DR, and 6.8% diabetic macular edema (DME). More than 10% of diabetic patients have a vision threatening DR (VTDR). Duration of the diabetic disease and a poorer glycemic and blood pressure control are strongly associated with DR. A meta-analysis demonstrated the high burden of the disease diabetes mellitus on visual function in addition to the enormous economic burden of this disease worldwide. Modifiable risk factors include blood sugar control and also blood pressure control. In type 1 diabetics the prevalence of DR is higher as compared to type 2 diabetics.[4] Most persons, health professionals and lay-people alike, are not aware how frequently this metabolic disease affects eye sight. Thus, diabetic patients are not early enough screened for DR, which leads to vision loss only later in the disease stage and severe changes in the retina may precede the loss of visual acuity. DME is the leading cause of vision loss in the working age population. In
addition, medical expenses for people with diabetes are more than two times higher than for people without diabetes.[5] Diabetic damage to the eyes is the leading cause of new cases of blindness among adults aged 20-74 years, and occurs as a result of long-term accumulated damage to the small blood vessels in the retina and also to the neurons of the retina itself. After 15 years of diabetes mellitus, approximately 2% become blind, and about 10% develop severe visual impairment. These figures increase with longer duration of diabetes. It is known that patients suffering from diabetes mellitus fear blindness most out of all complications from diabetes, which include also kidney disease, neuropathy, and a two- to three-fold increase in risk for stroke. Optimum metabolic control and control of systemic blood pressure are the most important modifiable parameters to prevent late occurring damage to the eye, involving the retina, the vitreous, and sometimes the intraocular pressure and the lens of the eye; leading to earlier cataract formation. Even if patients are affected from these late sequelae of diabetes mellitus, ophthalmology today is able to prevent blindness from this disease, and is able to even improve vision with the help of intravitreal injection of drugs, laser surgery, and the application of appropriate microsurgical techniques. For all of these treatment options there is good scientific evidence of effectiveness and safety.
Diabetic Retinopathy: Disease Severity Level as Guide for Management
Access this article online Quick Response Code: Website: www.ojoonline.org DOI: 10.4103/0974-620X.122291
Clinical findings in DR may be classified for describing the severity of the disease, screening for visual impairing conditions, and the need for appropriate treatment. In 2003, as part of a global project a simplified and clinically useful classification has been proposed,[6] which is able to give a guideline for health professionals even outside ophthalmology and to understand the necessary management options of DR. This classification for DR
Copyright: 2013 Kampik A. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Correspondence: Prof. Anselm Kampik, Ludwig-Maximilian-University, Department of Ophthalmology, Mathildenstr. 8, 80336 Munich, DE. Email: [email protected]
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Kampik: Laser, IVT and surgery in DR and DME-1 on one side and the classification for DME still holds true.
DR” (PDR). As soon as this proliferative stage is approached, laser treatment is mandatory as evidence based treatment modality.
DR as one major form of retinal involvement from diabetes mellitus is described and classified in Table 1 and is the major cause of blindness or severe visual loss, if not treated adequately. The reason for this is the formation of new vessels in the retina, finally growing into the vitreous, leading to hemorrhage into the vitreous and later to eventual scar formation and destruction of the retina [Figures 1 and 2]. The severity of this form of involvement of the retina is characterized by the presence and numbers of microaneurysms (seen as red dots in the retina), followed by intraretinal hemorrhages, and later by the formation of new blood vessels, first as intraretinal microvascular abnormalities (IRMA). Up to this stage the retinopathy is termed as “nonproliferative”. Later new blood vessels growing out or the retinal plane into the vitreous, either at the optic nerve head (NVD) or elsewhere at the retina (NVE), may occur. This later stage is called “proliferative
The other form of retinal involvement is DME, which is most prominent cause of less severe, but significant loss of visual acuity, meaning reading disability, and loss of the ability to drive a car, etc., Both modalities of retinal involvement may occur at the same time or may develop independently at different time points. Fluorescein angiography of the retina and its vasculature allows differentiating the origin of the fluid, which is responsible for the thickening of the retina in the macular area, which is then called DME [Figure 3]. Fluorescein angiography also allows for detection of avascular areas of the retina, which may exclude successful treatment of macular edema in case of severe ischemia in the center of the macula and is also useful to evaluate unexplained visual loss in these patients. Optical coherence tomography (OCT) allows high resolution (10 microns) imaging of the vitreoretinal interface, intraretinal differentiation of
Figure 1: Diabetic retinopathy with intraretinal bleedings, new vessels, microaneurysms, and venous beading
Figure 2: Severe proliferative diabetic retinopathy with scar formation and bleeding into the vitreous
Table 1: International diabetic retinopathy disease severity scale Disease severity level No apparent retinopathy Mild nonproliferative DR Moderate nonproliferative DR
Findings observable upon dilated ophthalmoscopy No abnormalities Microaneurysms only More than just microaneurysms but less than severe nonproliferative DR (NPDR)
Severe nonproliferative DR
Any of the following Extensive (>20) intraretinal hemorrhages in each of four quadrants Definite venous beading in 2+quadrants Prominent IRMA in 1+quadrant and no signs of proliferative retinopathy
Proliferative DR
One or more of the following Neovascularization Vitreous/preretinal hemorrhage
Management options Optimize medical therapy of glucose, blood pressure, and lipids Optimize medical therapy of glucose, blood pressure, and lipids Refer to an ophthalmologist Optimize medical therapy of glucose, blood pressure, and lipids Refer to an ophthalmologist Optimize medical therapy of glucose, blood pressure, and lipids Consider scatter (panretinal) laser treatment for patients with type 2 diabetes Optimize medical therapy of glucose, blood pressure, and lipids
Strongly consider scatter (panretinal) laser treatment, without delay for patients with vitreous hemorrhage or neovascularization within one disc diameter of the optic nerve head Optimize medical therapy of glucose, blood pressure, and lipids
DR: Diabetic retinopathy, NPDR: Non proliferative diabetic retinopathy
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Kampik: Laser, IVT and surgery in DR and DME-1 different types of DME, subretinal space, and thickness measurements of the retina during follow up [Figure 4]. OCT-examination in conjunction with careful ophthalmoscopy allows to detect the important differentiation between DME not involving the center of the macula (moderate DME), and the severe form of DME involving the center of the macula. The differentiation of center involving or not center involving DME leads to the appropriate treatment of DME. The current treatment modalities of diabetic eye disease include for DR and DME the current options: 1. Laser treatment for PDR and center not involving DME 2. Intravitreal drug administration for center involving DME and eventual additional later laser treatment 3. Vitrectomy as a microsurgical approach for traction induced DME, and later changes in PDR such as vitreous hemorrhage, and tractional retinal detachment, sometimes in conjunction with prior intravitreal anti-vascular endothelial growth factor (VEGF) treatment
Laser Treatment of DR and Center not Involving DME Laser treatment remains the gold standard for treatment of PDR and DME not involving the center of the macula [compare Tables 1 and 2]. Currently studies are under way to explore the additional benefit of primary intravitreal anti-VEGF treatment also for PDR. Results of randomized studies are not available so far. For PDR the multicentered DR study (DRS)[7] has given evidence that scatter laser photocoagulation or panretinal laser coagulation (PRP) [Figure 5] of the retina may lead to regression of new vessels and helps to avoid severe visual loss in 50% of
treated patients. In PRP large areas of the retina outside the center of the retina are treated with numerous laser spots, which destroy severely altered retina and RPE in order to help the remaining areas of the retina to survive for better function. Depending on the severity of PDR several hundreds of laser burns have to be applied to the retina, sometimes in several sessions of laser treatment. In DME, classified as moderate or center not involving, laser treatment proved to be the treatment of choice.[8] In this situation areas with retinal thickening are treated focally with only a limited number of laser spots in order to reduce the leaking of retinal vessels and thus improving visual acuity as much as possible. In this case mostly less than 100 spots at one session are given to the altered areas of the posterior pole of the eye. As seen in Figure 6, especially treatment of focal areas of retinal thickening apart from the center of the macula benefit from this treatment. Laser treatment of center not involving DME reduced visual impairment from DME statistically by 50%. The chances of improvement have been reported and seen less favorable in eyes with diffuse DME, in which the center of the macula is thickened from edema, and in cases in which the center of the fovea is ischemic at the time of laser treatment. The same is true for DME induced from tractional forces at the vitreoretinal interface, which can be detected by OCT. Therefore, in these severe forms of DME with involvement of the center of the macula the so-called grid laser treatment of DME is no longer applied and other treatment modalities such as intravitreal anti-VEGF treatment, intravitreal steroids, and if indicated vitreoretinal surgery are used to improve vision.
Table 2: International clinical diabetic macular edema disease severity scale Disease severity level Diabetic macular edema-apparently absent Diabetic macular edema-present
Figure 3: Diabetic macular edema as seen by ophthalmoscopy and fluorescein angiography
Findings observable upon dilated ophthalmoscopy No retinal thickening or hard exudates in posterior pole Mild diabetic macular edema Some retinal thickening or hard exudates in posterior pole but distant from the center of the macula Moderate diabetic macular edema Retinal thickening or hard exudates approaching the center of the macula but not involving the center Severe diabetic macular edema Retinal thickening or hard exudates involving the center of the macula
Figure 4: Differentiation of different types of diabetic macular edema as seen by optical coherence tomography
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Kampik: Laser, IVT and surgery in DR and DME-1 Screening of all patients with diabetes – even those with good visual acuity – is necessary to find those patients in which this described laser treatment is of benefit for the patient’s visual acuity even in cases of still good or very good visual acuity.
Intravitreal Drug Administration and Later Laser Treatment for Severe DME So far, no systemic medical therapy has proven to be effective for DR DME besides the preventive effect of optimum metabolic control and blood pressure control. There are sufficient data available that center involving severe DME is best and primarily treated with intravitreal application of anti-VEGF substances. Anti-VEGF agents act against the increased permeability of diseased blood vessels and against the formation of new blood vessels. Most data in DME are available for the drug ranibizumab, but also for bevacizumab and VEGF-trap are promising data published.[9-13] Monthly injections of anti-VEGF substances lead to rapid improvement of vision and decrease in retinal thickness if no major avascular areas are present in the macular area. This treatment is continued until no further improvement is seen and the retina is back to its normal configuration as best seen by OCT. During the 1st year of treatment about seven intravitreal injections are necessary in most cases. In the 2nd and 3rd year of treatment the numbers of injections needed are decreasing: Fewer than four injections at year 2 and fewer than three injections at year 3 is the usual finding in order to maintain the treatment effect. This decreasing number of injections is remarkable in contrast to the treatment of AMD with the same drugs. Thus, the burden of disease is decreasing with time if proper treatment is performed. Laser treatment was less effective for the treatment of center involving DME. Thus, only a deferred laser treatment for changes remaining outside the center of the macula is advisable.
Probably, additional carefully planned laser treatment after initial anti-VEGF-treatment is able to reduce the number of injections needed.[14] Additional data suggest also the use of intravitreal application of steroids, such as triamcinolone or dexamethasone for the treatment of DME in conjunction of instead of treatment with laser.[15,16] Clinical experience has demonstrated that intravitreal injection of 4 mg of triamcinolone is able to reduce macular edema and to improve visual acuity. Further results of the effect of steroids on DME are expected in the coming years as a result of further randomized clinical trials. Therefore, the role of steroids as primary treatment in severe DME, center involving, is not clear. However, a randomized trial has demonstrated the effectiveness of a potent steroid (fluocinolone implant) into the vitreous in chronic cases of severe DME not responding to anti-VEGF-therapy.[17] Thus, this steroid implant may serve as a second line treatment for very severe and chronic DME. One drawback of treatment with steroids is a potential increase of intraocular pressure, which needs pressure monitoring and eventually treatment. Potentially, further refinement in OCT-technology and multimodal imaging of the retina may guide the treatment in a way to reduce the burden of treatment and to find prognostic parameters for treatment of DME.[18] One potential new option for prevention of diabetic changes pharmacologic vitreolysis. This treatment aims at the induction of a separation of vitreous fibrils from the retinal surface, which can act as a scaffold for new vessels growing into the vitreous. This new approach is currently under investigation[19] and is considered experimental so far.
Vitreoretinal Surgery for PDR and DME The third therapeutic option for treatment of diabetic eye disease is vitreoretinal surgery, which can be combined with anterior segment cataract surgery, if necessary. The indications for this surgery in DR and DME are summarized in Table 3.
Figure 5: Scatter laser coagulation scars at the retina leading to regression of new vessels at the optic nerve head and elsewhere
Oman Journal of Ophthalmology, Vol. 6, No. 3, Supplement 2013
Figure 6: Laser treatment for focal diabetic macular edema, resolving after focal treatment
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Kampik: Laser, IVT and surgery in DR and DME-1
Figure 7: Vitreoretinal microsurgery (vitrectomy), intraocular laser therapy, and intravitreal tamponade with gas for treatment of vitreous hemorrhage and retinal detachment
Table 3: Indications for vitreoretinal surgery for diabetic eye disease Severe non-clearing vitreous hemorrhage Dense preretinal hemorrhage (subhyaloidal hemorrhage) Tractional retinal detachment ± involvement of the macula Ghost cell glaucoma Macular edema (especially with tractional component)
By techniques of vitrectomy opacities or blood within the eye, and fibrovascular or fibrous scar tissue acting as tractional force on the retina can be removed. These severe forms of PDR may develop in patients having not being identified for timely anti-VEGF-treatment or laser surgery for PDR. In addition, some eyes with PDR do not respond to appropriate laser treatment. With the help of manipulating substances, such as the heavy liquid perfluorocarbon (PFCL) detached retina can be brought back into its normal position in cases of retinal detachment. At the same time of this procedure necessary laser treatment to the retina can be applied endoscopically [Figure 7]. In most cases of PDR the eye is filled with balanced salt solution or air. Long acting tamponades such as silicone oil are restricted to the most severe cases of combined rhegmatogenous and tractional retinal detachment. The silicone oil remains usually within the eye for a very prolonged period of time and has to be removed later, if possible. Today there is agreement to combine cataract surgery with implantation of an artificial intraocular lens and vitreoretinal surgery whenever indicated. The typical diabetic patient for vitrectomy has suffered from visual loss after vitreous hemorrhage and/or associated retinal detachment. Most of these patients are type 2 diabetic, which means they are usually of older age and therefore have lens opacities at the same time. Mostly these eyes have already severe damage from retinal vascular changes. Because of limited diagnostic possibilities due to hemorrhage within the eye, individual chances for improvement are difficult to predict and depend largely also on the individual skills of the vitreoretinal surgeon. However, despite such very complex situations, useful visual acuity can be restored, almost as a rule for most patients. Large trials have underscored the evidence for the use of this surgical procedure in DR.[20] Anti-VEGF-substances are S30
Figure 8: Removal of epiretinal tissue to release distortion of the retina and to treat macular edema from tractional forces at the macula
sometimes used as an adjunct to vitrectomy in situations in which marked active neovascularizations at the retina or iris are present. With the injection of anti-VEGF one or a few days before vitrectomy intravitreally the risk of hemorrhage during and after vitrectomy can be markedly reduced. Surgery in such severe cases of neovascularization has become easier with this addition of the drug prior to surgery. However, it has to be taken into account that in most severe situations rapid increase of traction from a fibrotic switch of the newly formed vessels in the vitreous may occur.[21] Besides the use of vitrectomy for PDR, vitrectomy techniques are also used to treat certain types of DME involving the center of the macula. Apparently vitrectomy with removal of epiretinal tissue and also the inner limiting membrane of the retina[22] can resolve this type of macular edema and lead to improvement of visual acuity. In this surgery, the vitreous is separated from the retinal surface and epiretinal membranes are removed. In addition, many surgeons prefer to remove at the same time the inner limiting membrane of the retina for optimum results [Figure 8]. However, there is no clear cut indication for vitrectomy in severe DME. It is in general agreement that in situations with vitreoretinal traction and DME surgery is useful. Perhaps in these situations pharmacologic vitreolysis will be an option in the future. Oman Journal of Ophthalmology, Vol. 6, No. 3, Supplement 2013
Kampik: Laser, IVT and surgery in DR and DME-1 The indication and the decision whether laser surgery, pharmacologic intravitreal therapy, or vitrectomy is superior in a given patient depends on the results of the clinical findings, and the individual surgeons experience and preference.
10.
Conclusions
11.
Diabetic eye disease needs attention from the patient and the physician as well. So far, the current treatment possibilities, but also the dangers of this devastating eye disease are underestimated. With proper metabolic control and control of the blood pressure much of the eye complications from diabetes can be prevented. Screening of all diabetic patients for the presence or absence of DR and DME is mandatory in order to apply a timely and personally adjusted therapy according to the clinical findings in an individual patient. Ophthalmology today gives for each individual diabetic patient with eye complications hope to avoid visual impairment or even blindness from diabetic eye disease and even to improve vision in situations where the disease is advanced.
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14.
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Resnikoff S, Pascolini D, Etya’ale D, Kocur I, Pararajasegaram R, Pokharel GP, et al. Global data on visual impairment in the year 2002. Bull World Health Organ 2004;82:844-51. Buch H, Vinding T, La Cour M, Appleyard M, Jensen GB, Nielsen NV. Prevalence and causes of visual impairment and blindness among 9980 scandinavian adults: The Copenhagen City Eye Study. Ophthalmology 2004;111:53-61. International Diabetes Federation, Diabetes Atlas 5th ed. Avaialable from: http://idf.org/diabetesatlas. [Last accessed 2013 Jul 31]. You JW, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T, et al. Meta-Analysis for Eye Disease (META-EYE) Study Group. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 2012;35:556-64. CDC. National Diabetes Fact Sheet, 2011. Available from: http://www.cdc. gov/diabetes/pubs/pdf/nfs_2011.pdf [Last accessed 2013 Jul 30]. Wilkinson CP, Ferris FL 3rd, Klein RE, Lee PP, Agardh CD, Davis M, et al. Representing the Global Diabetic Retinopathy Project Group. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology 2003;110:1677-82. Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study (DRS) findings, DRS Report Number 8. The Diabetic Retinopathy Study Research Group. Ophthalmology 1981;88:583-600. Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report Number 2. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 1987;94:761-74. Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, Massin P, Schlingemann RO, et al. RESTORE study group. The RESTORE
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Study: Ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophtalmology 2011;118:615-25. Nguyen QD, Brown DM, Marcus DM, Boyer DS, Patel S, Feiner L, et al. RISE and RIDE Research Group. Ranibizumab for diabetic macular edema: Results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology 2012;119:789-801. Do DV, Nguyen QD, Boyer D, Schmidt-Erfurth U, Brown DM, Vitti R, et al. da Vinci Study Group. One-Year Out-comes of the DA VINCI Study of VEGF trap-eye in eyes with diabetic macular edema. Ophthalmology 2012;119:1658-65. Haritoglou C, Kook D, Neubauer A, Wolf A, Priglinger S, Strauss R, et al. Intravitreal bevacizumab (Avastin) therapy for persistent diffuse diabetic macular edema. Retina 2006;26:999-1005. Rajendram R, Fraser-Bell S, Kaines A, Michaelides M, Hamilton RD, Esposti SD, et al. A 2-year prospective randomized con-trolled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema: 24-month data: Report 3. Arch Ophthalmol 2012;130:972-9. Neubauer AS, Langer J, Liegl R, Haritoglou C, Wolf A, Kozak I, et al. Navigated macular laser decreases re-treatment rate for diabetic macular edema: A comparison with conventional macular laser. Clin Ophthalmol 2013;7:121-8. Bandello F, Polito A, Pognuz DR, Monaco P, Dimastrogiovanni A, Paissios J. Triamcinolone as adjunctive treatment to laser panretinal photocoagulation for proliferative diabetic retinopathy. Arch Ophthalmol 2006;124:643-50. Soheilian M, Ramezani A, Obudi A, Bijanzadeh B, Salehipour M, Yaseri M, et al. Randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus macular photo-coagulation in diabetic macular edema. Ophthalmology 2009;116:1142-50. Pearson PA, Comstock TL, Ip M, Callanan D, Morse LS, Ashton P, et al. Fluocinolone acetonide intravitreal implant for diabetic macular edema: A 3-year multicenter, randomized, controlled clinical trial. Ophthalmology 2011;118:1580-7. Otani T, Yamaguchi Y, Kishi S. Correlation between visual acuity and foveal microstructural changes in diabetic macular edema. Retina 2010;30:774-80. Gandorfer A, Rohleder M, Sethi C, Eckle D, Welge-Lussen U, Kampik A, et al. Posterior vitreous detachment induced by microplasmin. Invest Ophthalmol Vis Sci 2004;45:641-7. Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy. Two-year results of a randomized trial. Diabetic Retinopathy Vitrectomy Study report 2. Diabetic Retinopathy Vitrectomy Study Research Group. Arch Ophthalmol 1985;103:1644-52. Arevalo JF, Wu L, Sanchez JG, Maia M, Saravia MJ, Fernandez CF, et al. Intravitreal bevacizumab (avastin) for proliferative diabetic retinopathy: 6-months follow-up. Eye (Lond) 2007;23:117-23. Gandorfer A, Messmer EM, Ulbig MW, Kampik A. Resolution of diabetic macular edema after surgical removal of the posterior hyaloid and the inner limiting membrane. Retina 2000;20:126-33.
Cite this article as: Kampik A. Laser, intravitreal drug application, and surgery to treat diabetic eye disease. Oman J Ophthalmol 2013;6:S26-31. Source of Support: Nil, Conflict of Interest: None declared.
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Laser, intravitreal drug application, and surgery to treat diabetic eye disease Anselm Kampik Professor and Chairman, Department of Ophthalmology, Ludwig Maximilians University, and Secretary-General, Deutsche Ophthalmologische Gesellschaft (DOG), Munich, Germany
Diabetes mellitus is affecting more and more persons. The mere damage from diabetes mellitus to eye sight accounts for almost 5% of total blindness worldwide[1] and for 10-13% of total visual impairment.[2] Projecting to the year 2030 there is a 51% global increase of persons affected by diabetes mellitus. For the region Middle East and North Africa currently 14.7 million people are diseases from diabetes mellitus. For the year 203 the prevalence is increasing by 83% to almost 60 million people suffering from the disease diabetes mellitus.[3] Worldwide, approximately 35% of those with diabetes mellitus have some form of diabetic retinopathy (DR), about 7% proliferative DR, and 6.8% diabetic macular edema (DME). More than 10% of diabetic patients have a vision threatening DR (VTDR). Duration of the diabetic disease and a poorer glycemic and blood pressure control are strongly associated with DR. A meta-analysis demonstrated the high burden of the disease diabetes mellitus on visual function in addition to the enormous economic burden of this disease worldwide. Modifiable risk factors include blood sugar control and also blood pressure control. In type 1 diabetics the prevalence of DR is higher as compared to type 2 diabetics.[4] Most persons, health professionals and lay-people alike, are not aware how frequently this metabolic disease affects eye sight. Thus, diabetic patients are not early enough screened for DR, which leads to vision loss only later in the disease stage and severe changes in the retina may precede the loss of visual acuity. DME is the leading cause of vision loss in the working age population. In
addition, medical expenses for people with diabetes are more than two times higher than for people without diabetes.[5] Diabetic damage to the eyes is the leading cause of new cases of blindness among adults aged 20-74 years, and occurs as a result of long-term accumulated damage to the small blood vessels in the retina and also to the neurons of the retina itself. After 15 years of diabetes mellitus, approximately 2% become blind, and about 10% develop severe visual impairment. These figures increase with longer duration of diabetes. It is known that patients suffering from diabetes mellitus fear blindness most out of all complications from diabetes, which include also kidney disease, neuropathy, and a two- to three-fold increase in risk for stroke. Optimum metabolic control and control of systemic blood pressure are the most important modifiable parameters to prevent late occurring damage to the eye, involving the retina, the vitreous, and sometimes the intraocular pressure and the lens of the eye; leading to earlier cataract formation. Even if patients are affected from these late sequelae of diabetes mellitus, ophthalmology today is able to prevent blindness from this disease, and is able to even improve vision with the help of intravitreal injection of drugs, laser surgery, and the application of appropriate microsurgical techniques. For all of these treatment options there is good scientific evidence of effectiveness and safety.
Diabetic Retinopathy: Disease Severity Level as Guide for Management
Access this article online Quick Response Code: Website: www.ojoonline.org DOI: 10.4103/0974-620X.122291
Clinical findings in DR may be classified for describing the severity of the disease, screening for visual impairing conditions, and the need for appropriate treatment. In 2003, as part of a global project a simplified and clinically useful classification has been proposed,[6] which is able to give a guideline for health professionals even outside ophthalmology and to understand the necessary management options of DR. This classification for DR
Copyright: 2013 Kampik A. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Correspondence: Prof. Anselm Kampik, Ludwig-Maximilian-University, Department of Ophthalmology, Mathildenstr. 8, 80336 Munich, DE. Email: [email protected]
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Kampik: Laser, IVT and surgery in DR and DME-1 on one side and the classification for DME still holds true.
DR” (PDR). As soon as this proliferative stage is approached, laser treatment is mandatory as evidence based treatment modality.
DR as one major form of retinal involvement from diabetes mellitus is described and classified in Table 1 and is the major cause of blindness or severe visual loss, if not treated adequately. The reason for this is the formation of new vessels in the retina, finally growing into the vitreous, leading to hemorrhage into the vitreous and later to eventual scar formation and destruction of the retina [Figures 1 and 2]. The severity of this form of involvement of the retina is characterized by the presence and numbers of microaneurysms (seen as red dots in the retina), followed by intraretinal hemorrhages, and later by the formation of new blood vessels, first as intraretinal microvascular abnormalities (IRMA). Up to this stage the retinopathy is termed as “nonproliferative”. Later new blood vessels growing out or the retinal plane into the vitreous, either at the optic nerve head (NVD) or elsewhere at the retina (NVE), may occur. This later stage is called “proliferative
The other form of retinal involvement is DME, which is most prominent cause of less severe, but significant loss of visual acuity, meaning reading disability, and loss of the ability to drive a car, etc., Both modalities of retinal involvement may occur at the same time or may develop independently at different time points. Fluorescein angiography of the retina and its vasculature allows differentiating the origin of the fluid, which is responsible for the thickening of the retina in the macular area, which is then called DME [Figure 3]. Fluorescein angiography also allows for detection of avascular areas of the retina, which may exclude successful treatment of macular edema in case of severe ischemia in the center of the macula and is also useful to evaluate unexplained visual loss in these patients. Optical coherence tomography (OCT) allows high resolution (10 microns) imaging of the vitreoretinal interface, intraretinal differentiation of
Figure 1: Diabetic retinopathy with intraretinal bleedings, new vessels, microaneurysms, and venous beading
Figure 2: Severe proliferative diabetic retinopathy with scar formation and bleeding into the vitreous
Table 1: International diabetic retinopathy disease severity scale Disease severity level No apparent retinopathy Mild nonproliferative DR Moderate nonproliferative DR
Findings observable upon dilated ophthalmoscopy No abnormalities Microaneurysms only More than just microaneurysms but less than severe nonproliferative DR (NPDR)
Severe nonproliferative DR
Any of the following Extensive (>20) intraretinal hemorrhages in each of four quadrants Definite venous beading in 2+quadrants Prominent IRMA in 1+quadrant and no signs of proliferative retinopathy
Proliferative DR
One or more of the following Neovascularization Vitreous/preretinal hemorrhage
Management options Optimize medical therapy of glucose, blood pressure, and lipids Optimize medical therapy of glucose, blood pressure, and lipids Refer to an ophthalmologist Optimize medical therapy of glucose, blood pressure, and lipids Refer to an ophthalmologist Optimize medical therapy of glucose, blood pressure, and lipids Consider scatter (panretinal) laser treatment for patients with type 2 diabetes Optimize medical therapy of glucose, blood pressure, and lipids
Strongly consider scatter (panretinal) laser treatment, without delay for patients with vitreous hemorrhage or neovascularization within one disc diameter of the optic nerve head Optimize medical therapy of glucose, blood pressure, and lipids
DR: Diabetic retinopathy, NPDR: Non proliferative diabetic retinopathy
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Kampik: Laser, IVT and surgery in DR and DME-1 different types of DME, subretinal space, and thickness measurements of the retina during follow up [Figure 4]. OCT-examination in conjunction with careful ophthalmoscopy allows to detect the important differentiation between DME not involving the center of the macula (moderate DME), and the severe form of DME involving the center of the macula. The differentiation of center involving or not center involving DME leads to the appropriate treatment of DME. The current treatment modalities of diabetic eye disease include for DR and DME the current options: 1. Laser treatment for PDR and center not involving DME 2. Intravitreal drug administration for center involving DME and eventual additional later laser treatment 3. Vitrectomy as a microsurgical approach for traction induced DME, and later changes in PDR such as vitreous hemorrhage, and tractional retinal detachment, sometimes in conjunction with prior intravitreal anti-vascular endothelial growth factor (VEGF) treatment
Laser Treatment of DR and Center not Involving DME Laser treatment remains the gold standard for treatment of PDR and DME not involving the center of the macula [compare Tables 1 and 2]. Currently studies are under way to explore the additional benefit of primary intravitreal anti-VEGF treatment also for PDR. Results of randomized studies are not available so far. For PDR the multicentered DR study (DRS)[7] has given evidence that scatter laser photocoagulation or panretinal laser coagulation (PRP) [Figure 5] of the retina may lead to regression of new vessels and helps to avoid severe visual loss in 50% of
treated patients. In PRP large areas of the retina outside the center of the retina are treated with numerous laser spots, which destroy severely altered retina and RPE in order to help the remaining areas of the retina to survive for better function. Depending on the severity of PDR several hundreds of laser burns have to be applied to the retina, sometimes in several sessions of laser treatment. In DME, classified as moderate or center not involving, laser treatment proved to be the treatment of choice.[8] In this situation areas with retinal thickening are treated focally with only a limited number of laser spots in order to reduce the leaking of retinal vessels and thus improving visual acuity as much as possible. In this case mostly less than 100 spots at one session are given to the altered areas of the posterior pole of the eye. As seen in Figure 6, especially treatment of focal areas of retinal thickening apart from the center of the macula benefit from this treatment. Laser treatment of center not involving DME reduced visual impairment from DME statistically by 50%. The chances of improvement have been reported and seen less favorable in eyes with diffuse DME, in which the center of the macula is thickened from edema, and in cases in which the center of the fovea is ischemic at the time of laser treatment. The same is true for DME induced from tractional forces at the vitreoretinal interface, which can be detected by OCT. Therefore, in these severe forms of DME with involvement of the center of the macula the so-called grid laser treatment of DME is no longer applied and other treatment modalities such as intravitreal anti-VEGF treatment, intravitreal steroids, and if indicated vitreoretinal surgery are used to improve vision.
Table 2: International clinical diabetic macular edema disease severity scale Disease severity level Diabetic macular edema-apparently absent Diabetic macular edema-present
Figure 3: Diabetic macular edema as seen by ophthalmoscopy and fluorescein angiography
Findings observable upon dilated ophthalmoscopy No retinal thickening or hard exudates in posterior pole Mild diabetic macular edema Some retinal thickening or hard exudates in posterior pole but distant from the center of the macula Moderate diabetic macular edema Retinal thickening or hard exudates approaching the center of the macula but not involving the center Severe diabetic macular edema Retinal thickening or hard exudates involving the center of the macula
Figure 4: Differentiation of different types of diabetic macular edema as seen by optical coherence tomography
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Kampik: Laser, IVT and surgery in DR and DME-1 Screening of all patients with diabetes – even those with good visual acuity – is necessary to find those patients in which this described laser treatment is of benefit for the patient’s visual acuity even in cases of still good or very good visual acuity.
Intravitreal Drug Administration and Later Laser Treatment for Severe DME So far, no systemic medical therapy has proven to be effective for DR DME besides the preventive effect of optimum metabolic control and blood pressure control. There are sufficient data available that center involving severe DME is best and primarily treated with intravitreal application of anti-VEGF substances. Anti-VEGF agents act against the increased permeability of diseased blood vessels and against the formation of new blood vessels. Most data in DME are available for the drug ranibizumab, but also for bevacizumab and VEGF-trap are promising data published.[9-13] Monthly injections of anti-VEGF substances lead to rapid improvement of vision and decrease in retinal thickness if no major avascular areas are present in the macular area. This treatment is continued until no further improvement is seen and the retina is back to its normal configuration as best seen by OCT. During the 1st year of treatment about seven intravitreal injections are necessary in most cases. In the 2nd and 3rd year of treatment the numbers of injections needed are decreasing: Fewer than four injections at year 2 and fewer than three injections at year 3 is the usual finding in order to maintain the treatment effect. This decreasing number of injections is remarkable in contrast to the treatment of AMD with the same drugs. Thus, the burden of disease is decreasing with time if proper treatment is performed. Laser treatment was less effective for the treatment of center involving DME. Thus, only a deferred laser treatment for changes remaining outside the center of the macula is advisable.
Probably, additional carefully planned laser treatment after initial anti-VEGF-treatment is able to reduce the number of injections needed.[14] Additional data suggest also the use of intravitreal application of steroids, such as triamcinolone or dexamethasone for the treatment of DME in conjunction of instead of treatment with laser.[15,16] Clinical experience has demonstrated that intravitreal injection of 4 mg of triamcinolone is able to reduce macular edema and to improve visual acuity. Further results of the effect of steroids on DME are expected in the coming years as a result of further randomized clinical trials. Therefore, the role of steroids as primary treatment in severe DME, center involving, is not clear. However, a randomized trial has demonstrated the effectiveness of a potent steroid (fluocinolone implant) into the vitreous in chronic cases of severe DME not responding to anti-VEGF-therapy.[17] Thus, this steroid implant may serve as a second line treatment for very severe and chronic DME. One drawback of treatment with steroids is a potential increase of intraocular pressure, which needs pressure monitoring and eventually treatment. Potentially, further refinement in OCT-technology and multimodal imaging of the retina may guide the treatment in a way to reduce the burden of treatment and to find prognostic parameters for treatment of DME.[18] One potential new option for prevention of diabetic changes pharmacologic vitreolysis. This treatment aims at the induction of a separation of vitreous fibrils from the retinal surface, which can act as a scaffold for new vessels growing into the vitreous. This new approach is currently under investigation[19] and is considered experimental so far.
Vitreoretinal Surgery for PDR and DME The third therapeutic option for treatment of diabetic eye disease is vitreoretinal surgery, which can be combined with anterior segment cataract surgery, if necessary. The indications for this surgery in DR and DME are summarized in Table 3.
Figure 5: Scatter laser coagulation scars at the retina leading to regression of new vessels at the optic nerve head and elsewhere
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Figure 6: Laser treatment for focal diabetic macular edema, resolving after focal treatment
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Kampik: Laser, IVT and surgery in DR and DME-1
Figure 7: Vitreoretinal microsurgery (vitrectomy), intraocular laser therapy, and intravitreal tamponade with gas for treatment of vitreous hemorrhage and retinal detachment
Table 3: Indications for vitreoretinal surgery for diabetic eye disease Severe non-clearing vitreous hemorrhage Dense preretinal hemorrhage (subhyaloidal hemorrhage) Tractional retinal detachment ± involvement of the macula Ghost cell glaucoma Macular edema (especially with tractional component)
By techniques of vitrectomy opacities or blood within the eye, and fibrovascular or fibrous scar tissue acting as tractional force on the retina can be removed. These severe forms of PDR may develop in patients having not being identified for timely anti-VEGF-treatment or laser surgery for PDR. In addition, some eyes with PDR do not respond to appropriate laser treatment. With the help of manipulating substances, such as the heavy liquid perfluorocarbon (PFCL) detached retina can be brought back into its normal position in cases of retinal detachment. At the same time of this procedure necessary laser treatment to the retina can be applied endoscopically [Figure 7]. In most cases of PDR the eye is filled with balanced salt solution or air. Long acting tamponades such as silicone oil are restricted to the most severe cases of combined rhegmatogenous and tractional retinal detachment. The silicone oil remains usually within the eye for a very prolonged period of time and has to be removed later, if possible. Today there is agreement to combine cataract surgery with implantation of an artificial intraocular lens and vitreoretinal surgery whenever indicated. The typical diabetic patient for vitrectomy has suffered from visual loss after vitreous hemorrhage and/or associated retinal detachment. Most of these patients are type 2 diabetic, which means they are usually of older age and therefore have lens opacities at the same time. Mostly these eyes have already severe damage from retinal vascular changes. Because of limited diagnostic possibilities due to hemorrhage within the eye, individual chances for improvement are difficult to predict and depend largely also on the individual skills of the vitreoretinal surgeon. However, despite such very complex situations, useful visual acuity can be restored, almost as a rule for most patients. Large trials have underscored the evidence for the use of this surgical procedure in DR.[20] Anti-VEGF-substances are S30
Figure 8: Removal of epiretinal tissue to release distortion of the retina and to treat macular edema from tractional forces at the macula
sometimes used as an adjunct to vitrectomy in situations in which marked active neovascularizations at the retina or iris are present. With the injection of anti-VEGF one or a few days before vitrectomy intravitreally the risk of hemorrhage during and after vitrectomy can be markedly reduced. Surgery in such severe cases of neovascularization has become easier with this addition of the drug prior to surgery. However, it has to be taken into account that in most severe situations rapid increase of traction from a fibrotic switch of the newly formed vessels in the vitreous may occur.[21] Besides the use of vitrectomy for PDR, vitrectomy techniques are also used to treat certain types of DME involving the center of the macula. Apparently vitrectomy with removal of epiretinal tissue and also the inner limiting membrane of the retina[22] can resolve this type of macular edema and lead to improvement of visual acuity. In this surgery, the vitreous is separated from the retinal surface and epiretinal membranes are removed. In addition, many surgeons prefer to remove at the same time the inner limiting membrane of the retina for optimum results [Figure 8]. However, there is no clear cut indication for vitrectomy in severe DME. It is in general agreement that in situations with vitreoretinal traction and DME surgery is useful. Perhaps in these situations pharmacologic vitreolysis will be an option in the future. Oman Journal of Ophthalmology, Vol. 6, No. 3, Supplement 2013
Kampik: Laser, IVT and surgery in DR and DME-1 The indication and the decision whether laser surgery, pharmacologic intravitreal therapy, or vitrectomy is superior in a given patient depends on the results of the clinical findings, and the individual surgeons experience and preference.
10.
Conclusions
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Diabetic eye disease needs attention from the patient and the physician as well. So far, the current treatment possibilities, but also the dangers of this devastating eye disease are underestimated. With proper metabolic control and control of the blood pressure much of the eye complications from diabetes can be prevented. Screening of all diabetic patients for the presence or absence of DR and DME is mandatory in order to apply a timely and personally adjusted therapy according to the clinical findings in an individual patient. Ophthalmology today gives for each individual diabetic patient with eye complications hope to avoid visual impairment or even blindness from diabetic eye disease and even to improve vision in situations where the disease is advanced.
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Cite this article as: Kampik A. Laser, intravitreal drug application, and surgery to treat diabetic eye disease. Oman J Ophthalmol 2013;6:S26-31. Source of Support: Nil, Conflict of Interest: None declared.
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