GUIDELINES OF CLINICAL PRACTICE OF THE SERV: … · management of ocular complications of diabetes....

GUIDELINES OF CLINICAL PRACTICE OF THE SERV:MANAGEMENT OF OCULAR COMPLICATIONS OF

DIABETES. DIABETIC RETINOPATHY AND MACULAROEDEMA

GUÍAS DE PRÁCTICA CLÍNICA DE LA SERV: MANEJO DE LASCOMPLICACIONES OCULARES DE LA DIABETES. RETINOPATÍA

DIABÉTICA Y EDEMA MACULAR

PAREJA-RÍOS A1, SERRANO-GARCÍA MA1, MARRERO-SAAVEDRA MD2, ABRALDES-LÓPEZ VM3, REYES-RODRÍGUEZ MA4, CABRERA-LÓPEZ F5, LÓPEZ-GÁLVEZ M6,CARDONA-GUERRA P5, ABREU-REYES P7, QUIJADA-FUMERO E1, CORONADO-TOURAL A8,

GUTIÉRREZ-SÁNCHEZ E9, GIL-HERNÁNDEZ MA7, VALLS-QUINTANA P4, MARÍN-OLMOS F10,NAVARRO-ALEMANY R11

Received: 20/7/09. Accepted: 18/9/09.Spanish Retina and Vitreous Society.

1 Ph.D. in Medicine. University Hospital of Canarias, La Laguna. Tenerife. Spain.2 Ph.D. in Medicine. University Hospital of Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria. Spain.3 Ph.D. in Medicine. University Hospital complex of Santiago de Compostela. Ophthalmology Technological Institute. Santiago de Compostela.

Spain.4 Graduate in Medicine. University Hospital of Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria. Spain.5 Ph.D. in Medicine. Maternal Island Hospital Complex. Las Palmas de Gran Canaria. Spain.6 Ph.D. in Medicine. University Clinical Hospital of Valladolid. Institute of applied Ophthalmobiology. Valladolid. Spain.7 Ph.D. in Medicine. University Hospital Sra. de Candelaria. Tenerife. Spain.8 Ph.D. in Medicine. Ocular Surgery Clinic (CCO). Madrid. Spain.9 Graduate in Medicine. Piñero Clinic. Sevilla. Spain.

10 Ph.D. in Medicine. University Clinical Hospital of Valencia. Valencia. Spain.11 Graduate in Medicine. Ocular Microsurgery Institute (IMO). Barcelona. Spain.The authors have no commercial interest or received any financial support.

Correspondence:Alicia Pareja RíosHospital Universitario de CanariasC/. Ofra, s/n38320 La Laguna (Tenerife)SpainE-mail: [email protected]

ABSTRACT

Objective: Diabetes mellitus is considered the mostcommon cause of blindness in the working popula-tion of industrialized countries, with diabetic macu-lar edema being the most common cause of decrea-sed visual acuity and proliferative diabetic retino-pathy (PDR) being responsible for the most severevisual deficits. We have therefore tried to establisha guide for clinical intervention whose purpose is toprovide orientation on the treatment of diabetic reti-nopathy and its complications. This is necessary at

RESUMEN

Objetivo: La diabetes mellitus está consideradacomo la causa más frecuente de ceguera en lapoblación activa en los países industrializados,siendo el edema macular diabético la causa más fre-cuente de disminución de la agudeza visual y laretinopatía diabética proliferante la responsable delos déficit visuales más severos. Por ello hemosintentado establecer una guía de actuación clínicacuyo propósito es proporcionar unas directrices quesirvan de orientación para el tratamiento de la reti-

ARCH SOC ESP OFTALMOL 2009; 84: 429-450 REVISION

1. OBJECTIVES

The purpose of this guide for managing the ocu-lar complications of diabetes is to present generalguidelines for treating diabetic retinopathy (DR)and/or macular edema (ME) at a time when we arewitnessing the emergence of new therapeutic alter-natives which as yet do not have well-defined roles.

To establish the differences we have carried out alarge revision of literature and existing protocols.The task was entrusted to a committee set up forthat purpose by the Spanish Retina and VitreousSociety, which has discussed the therapeuticoptions available at present and their most acceptedindications according to the degree of DR exhibitedby patients. Discussions focused on procedures tobe applied with a slight or moderate non-prolifera-tive DR (both controlled by the area ophthalmolo-gist) or a severe DR (susceptible to photocoagula-tion on some occasions) or a proliferative DR

(requiring hospital control). In addition, the com-mittee suggested how to proceed with diabeticmacular edema and discussed the role of varioussupplementary explorations.

The adaptation of these guidelines to differenthealth systems could involve variations in someprocedures. For instance, the autonomous commu-nities of Spain where Specialized Care Centers areequipped with laser devices, the treatment of diabe-tic retinopathy and macular edema can be executed,referring only surgical cases to hospitals. In com-munities where said Centers do not have laser, theentire treatment must necessarily be done at hospi-tals.

2. INTRODUCTION

Diabetes Mellitus is regarded as the most fre-quent cause of blindness in the active population of

430 ARCH SOC ESP OFTALMOL 2009; 84: 429-450

PAREJA-RÍOS A, et al.

a time when many treatment options have emergedwhose role is not yet fully defined. Method: A group of expert retina specialists selec-ted by the SERV (Vitreous-Retina Spanish Society)assessed the published results of different treatmentoptions currently available, suggesting lines ofaction according to the degree of diabetic retino-pathy present and the presence or absence of macu-lar edema. Results: PDR is primarily treated with pan-retinalphotocoagulation. For clinically significant diabeticmacular edema without signs of vitreomacular trac-tion, the treatment of choice continues to befocal/grid photocoagulation. Similarly, retinovitrealsurgery is indicated for both conditions. The use ofantiangiogenic drugs was also analyzed but remainsinconclusive. Conclusion: Laser therapy is effective in the mana-gement of diabetic retinopathy and diabetic macularedema. The role of antiangiogenics is not yet suffi-ciently defined (Arch Soc Esp Oftalmol 2009; 84:429-450).

Key words: Diabetic retinopathy, diabetic macularoedema, optic coherence tomography, photocoagu-lation, vitrectomy, intravitreal antiangiogenicdrugs.

nopatía diabética y sus complicaciones. Esto sehace necesario en un momento en el que han apare-cido numerosas alternativas terapéuticas cuyo papelaún no está completamente definido. Método: Un grupo de expertos retinólogos selec-cionados por la SERV han evaluado los resultadospublicados sobre las distintas opciones terapéuticasque existen en la actualidad, en base a lo cual sesugieren líneas de actuación según el grado de reti-nopatía diabética que presenta el paciente y la pre-sencia o no de edema macular. Resultados: El tratamiento princeps de la RDP esla panretinofotocoagulación (PFC). El tratamientode elección en el edema macular diabético clínica-mente significativo sin signos de tracción vítreomacular continúa siendo la fotocoagulaciónfocal/rejilla. La cirugía retinovítrea tiene así mismosus indicaciones en ambas afecciones. Se discute eluso de fármacos antiangiogénicos.Conclusión: La laserterapia es efectiva en el mane-jo de la RD y del EMD. El papel de los antiangio-génicos aún no está suficientemente definido.

Palabras clave: Retinopatía diabética, edemamacular diabético, tomografía de coherencia óptica,fotocoagulación, vitrectomía, fármacos antiangio-génicos intravítreos.

industrialized countries, while diabetic macularedema is the most frequent cause of visual acuityreduction in diabetics and proliferative diabetic reti-nopathy accounts for the most severe visual deficits(1).

Laser has been and continues to be the main tre-atment for the ocular complications brought aboutby diabetes.

Panretinophotocoagulation (PPC) avoids the pro-gression towards blindness in a significant percen-tage of patients. However, the results of laser aremuch more disappointing in macular edema, wherethe progression is only diminished in 50% ofpatients.

The search for new alternatives has become apriority objective and even though the pathogenicmechanisms involved in the development of thisprocess are not yet well known, the involvement ofthe endothelial vascular growth factor has opened anew line of research. A considerable number ofpublications discuss the usefulness of intra-vitreoustriamcinolone and anti-angiogenics (anti-VEGF)for controlling diabetic macular edema, and at pre-sent several clinical trials are ongoing in Europeand the United States to assess the safety and effi-cacy thereof. Anti-VEGF drugs are repeatedlyadministered through the intravitreal pathwaywhich, in a chronic diseases such as diabetes, invol-ves an important difficulty. For this reason, researchhas a role to assessing the possibility of utilizingsaid drugs in combination with laser treatment toachieve a longer effect.

In this situation of change and uncertainty, it isnecessary to establish a standard criteria to appro-ach said complications while we await the conclu-sion of these studies which will allow us to designthe new guidelines to improve the function of visualprognosis of these patients.

3. CLASSIFICATION OF DIABETICRETINOPATHY (DR) ANDMACULAR EDEMA (DME)

In accordance with the results of the large multi-centre studies, the prevention of blindness inducedby DR involves regular ocular fundus assessments inorder to treat in a timely manner the DR forms withthe highest risk of severe vision loss or even blind-ness. This requires the application of standard crite-ria for classification and treatment of diabetic retino-pathy. The classification proposed by the Early Tre-atment Diabetic Retinopathy Study (ETDRS) (2)pursued this goal and is considered as a reference tobe followed in clinical trials. However, it is not rou-tinely applied in clinical practice due to its comple-xity and the large amount of levels or stages and alsobecause there must be a correlation with the stereos-copic photographs of the seven Basic fields.

In an attempt to achieve a universal means of com-munication, a group of experts (Global Diabetic Reti-nopathy Project Group –GDRPG–) (3) proposed in2002 a new classification for diabetic retinopathy forimproved management. This is the International Reti-nopathy Severity Scale which this group believesshould be utilized in clinical practice. This new classi-fication is based on the ETDRS results and thereforeis based on scientific evidence. It does not aim toreplace the original classification but to provide a sim-ple management basis adequate for clinical practice.

3.1. International Clinical Classification of DR(GDRPG) (table I)

However, for approaching macular edema the clas-sification proposed by ETDRS seems more adequate.

431ARCH SOC ESP OFTALMOL 2009; 84: 429-450

Treatment of diabetic retinopathy and diabetic macular edema

Table I. DR classification by GDRPG

Without apparent DR Absence of microaneurysms (uA)Slight nonproliferative DR (NPDR) Only uA (fig. 8)Moderate NPDR µA associated to less than 20 intra-retina hemorrhages (H) in each of the four quadrants

(C), hard exudates (HE), cotton-like «exudates» (CE), venous circinate formations inonly 1 C (fig. 9)

Severe NPDR µA together with one of the following findings:– severe intraretinal hemorrhage (>20) in each one of the four C– Venous circinate formations in ≥ 2C– intraretinal microvascular anomalies (IMA) in ≥ 1 C (fig. 11)

Very severe NPDR uA together with at least two of the previous findingsPDR Neovessels (NV) and/or pre-retinal or hemovitreous hemorrhage (fig. 12)

3.2. Classification of Macular Edema (ETDRS)(1985)

– Without macular edema.– With macular edema (ME): retinal thickening

within one disc diameter (DD) from the centre ofthe macula, determined in the stereoscopic explora-tion with a slit lamp or color stereoscopic photo-graphs (30°) (ME is not the fluorescein diffusion influorescein angiography if there is no thickening).The ETDRS also defined ME with the presence ofhard exudates within one DD from the centre.

– With Clinically Significant Macular Edema(CSME):

• Retinal thickening within 500 µm from thecentre (fig. 1).



Fig. 1: Retinal thickening within 500 µm from the centre.

Fig. 2: Hard exudates within 500 µm from the centreassociated to an adjacent retinal thickening.

Fig. 3: Retinal thickening of at least 1 DD, part of whichis less than 1 DD from the centre.

Fig. 4: Focal CSME.

• Hard exudates within 500 µm from the centrewhen associated to an adjacent retinal thickening(fig. 2).

• A retinal thickening area having the size of aleast one disc area, part of which is at less than 1DD from the centre (fig. 3).

The best corrected visual acuity (BCVA) is notpart of the macular edema definition and it can ran-ge between 1.2 to perception of light (PL), bothincluded, and exhibit CSME.

3.3. Angiographic Classification of ME

– Focal ME: a well defined diffusion area arisingout of individual or associated microaneurysms.The focal ME definition also includes diffusion are-as in which ≥ 67% is associated to microaneurysms(4,5). The characteristic funduscopic image is thatof a circinate ring which threatens or compromisesthe centre of the macula (fig. 4).

– Multifocal ME: with several diffusion areas(frequently confused with diffuse ME) (fig. 5).

– Diffuse ME: defined as an area of hyperfluores-cence with late diffusion ? 2 DD involving the fovea(6-11) or a hyperfluorescence in which ≤ 33% is asso-ciated to microaneurysms (3). Diffuse ME is usuallybilateral and asymmetric. Clinically, it is a poorlydefined edema area, with few microaneurysms andhard exudates. On some occasions, reflections andopacity of posterior hyaloids appear, with or withoutepiretinal membranes. It is frequently associated tocystic macular edema (CME) (fig. 6).

– Combined ME: both focal and diffuse edemas cancoexist, giving rise to the combined macular edema.

3.4. Classification based on Optic CoherenceTomography(OCT)

The classification of ME based on OCT (12) isdivided in:



Fig. 5: Multifocal CSME before and after laser treatment.

Fig. 6: Diffuse CSME.

1. Morphology-based (fig. 7a):E1: simple thickening (sponge-like, affecting

the outermost layers of the retina and withoutobserving cystoid spaces).

E2: cystoid thickening. Retina thickening asso-ciated to cysts, ranging in severity from «a» (betwe-en two and four small cysts) to «c» (coalescence ofseveral cysts).

E3: Neuroepithelial detachment. It can appearisolated or associated to simple or cystic retinalthickening.

2. Based on the existence of epiretinal traction(fig. 7b).

(Existence of a hyper-reflective continuous lineover the internal surface of the retina with at leastone point of adhesion to the retina in at least one ofthe six retinal map sections).

T0: absence of hyper-reflecting line.T1: Presence of continuous hyper-reflecting line

adhered to the retina but without distorting itT2: The continuous hyper – reflecting line has

multiple points of union with the retina, causing itsdistortion.

T3: anteroposterior traction with the typical«gull wing» configuration.

4. DIABETIC RETINOPATHYMANAGEMENT

Establishment of the first ophthalmic exploration

– Diabetes type 1: the first ophthalmologicalassessment must be made within 3-5 years after theDM diagnosis. If any sign of retinopathy appears, itis advisable to maintain ocular control in hospitalsdue to the high degree of complications and theiraggressive nature.

– Diabetes type 2: the first assessment must bemade at the time of diagnosis, with annual or bi-annual assessments being advisable if there are noassociated risk factors up to the appearance of somedegree of retinopathy. When the latter is detected,the advisable criteria are based on the degree ofinvolvement, the presence of edema and/or of com-plications secondary to advanced retinopathy. Spe-cial attention must be paid to diabetes Type 2patients of early appearance, more specifically bet-ween 30 and 50 years of age, due to the higher lifeexpectation and usually inadequate metabolic con-trol, as well as those in treatment with insulinbecause they could behave as type 1 diabetics inwhat concerns complications (13).

Follow up

To establish the frequency of subsequent chec-kups we must take into account the degree of reti-



Fig. 7a: ME Classification according to morphology in OCT.

Fig. 7b: ME Classification based on the existence of epi-retinal traction in OCT.

nopathy as well as the condition of the macula. Asregards the periodicity of the assessments, the hig-hest visual risk criterion must be followed. Forexample, if a patient with a slight NPDR withannual recommended assessment also exhibitsCSME, the frequency of the visits will be determi-ned by the latter condition (every three months).

In all DR stages, it is essential to maintain endo-crinological control, mainly of glycemia, glycosyla-ted hemoglobin, microalbuminuria in urine, higharterial blood pressure, overweight, lipids, condi-tion of the heart and kidneys. This has a twofoldconsequence: On the one hand, if the patient has animportant metabolic imbalance, the ocular controlmust be more frequent, and on the other hand wecan postpone ocular treatments (for example, amacular edema) until the patient reaches acceptablelevels of glycemia and/or blood pressure. In addi-tion, the patient must be advised to quit smoking.

4.1. Without apparent Diabetic Retinopathy

Six-monthly ophthalmological assessment if thepatient has good metabolic control (Hb A1c < 7%)and absence of associated risk factors (high bloodpressure, dyslipemia, etc.). In these cases, an oph-thalmological exploration twice a year (14) seemssufficient for a timely detection of macular edemaas well as PDR. This would reduce 25% the num-ber of first visits to the ophthalmological practiceand thus allow a considerable saving in health costsas well as avoiding unnecessary explorations for thediabetic patient.

The ophthalmological explorations should becarried out annually in the presence of associated riskfactors or doubtful or deficient metabolic control.

4.2. With Slight NPDR

Annual ophthalmological checkup.Bring the check-up forward if µA appear in large

amounts or threaten the fovea, first exploration of apoorly controlled patient, recent step from oral anti-diabetics to insulin, pregnant patients (quarterlyexplorations and every six months the first yearafter labor).

In this stage it is crucial to inform the patient andmake him aware about the importance of metaboliccontrol. According to the DCCT (Diabetes Control

and Complications Trial) (15-18) in type 1 diabeticswho maintain a mean level of 7.2% of Hb A1c theprevalence of retinopathy is reduced 76% and theprogression of diabetic retinopathy 54%.

The UKPDS (United Kingdom Prospective Dia-betes Study) (19) verified similar findings in type 2diabetics. In addition, it demonstrated that strictcontrol of blood pressure reduces the progression ofDR 34% and the deterioration of visual acuity in47% (20) (fig. 8).

4.3. With Slight NPDR

Ophthalmological control every six months.Fluorescein angiography and panphotocoagula-

tion (PPC) are not required as the yearly risk of pro-



Fig. 8: Slight NPDR.

Fig. 9: Moderate NPDR.

gression to PDR ranges between 5.4% and 26.3%.It must be taken into account that a large variety ofconditions are comprised here, from those that onlyexhibit µA with hard exudates up to cotton-like«exudates», intraretinal hemorrhage and evenvenous circinate patterns. Therefore, the precisefollow up periodicity remains at the criterion of theophthalmologist (fig. 9).

4.4. With Severe NPDR

Severe NPDR must be analyzed with caution dueto the probability of progression to PDR which is ofabout 50.2% within one year [14.6% with high riskcharacteristics (21)].

– DM 2: Hospital control every 3-4 months.– DM 1 with poor metabolic control: Hospital

checkup every 2 months.Consider early PPC in patients having a high risk

of progression: DM 2 with poor metabolic control,patients who do not usually comply with the chec-kups, PDR in the other eye, patients with cataractswith obvious visual significance which could limitPPC in the near future, prior to cataract surgery,actual or intended pregnancy and generalizedangiographic ischemia areas.

In the above cases, the recommended photocoa-gulation order is to carry out one quadrant in eachsession, beginning with the nasal or inferior andending with the temporal (fig. 10). As regards fre-quency, one session every 2-3 weeks is recommen-ded (if time is not of the essence,3 weeks is betterthan two). This is because the macula does not reco-ver in one week (22). Before beginning photocoa-gulation, we must take into account the differentdegrees of magnification of the available lenses(table II).

Some papers propose the use of anti-VEGF as acoadjutant of PPC in an attempt to minimize thepost-laser macular edema (23-25).

It is important to emphasize that in severe NPDRcases in which we have decided to perform PPC andwhich also exhibit clinically significant macularedema, we must treat the edema prior to carryingout the PPC (fig. 11).

4.5. PDR and transparent media

PPC in 1 or 1.5 months: 300-500 impact sessions(if traction exists, the sessions should be of 200-300impacts) starting with the inferior quadrant. Reas-sessments every 3-6 months. When PPC is propo-



Table II. Lens magnification degrees

Magnification factors of contact lenses which do not induce Münster focal grid (1.05), Volk area centralis (1.0) and the 3-mirror a significant increase of the laser burn size Goldmann lens (1.08)

Magnification factors of contact lenses which induce a Quadraspheric (1.92), superquadrant 160 (2) and Ultrafield (1.89), significant increase of the laser burn size which induce a double magnification of the spot size.

For this reason, the size of the laser burn must be halved.

Fig. 10: Photocoagulation sequence based on quadrants. Fig. 11: Severe NPDR.

sed, it is advisable to explain the following points tothe patient:

a. scientific evidence demonstrates that PPC canhalt the progression of PDR but not in all cases.

b. the risk of hemorrhage persists after PPCbecause the regression of neovascularization is slow.

c. PPC can produce a moderate reduction ofvision, of the visual field or adaptation to darkness,but the benefits considerably exceed the collateraleffects.

It is convenient to insist with the patient aboutthese points emphasizing that, if vitreous hemorrha-ge occurs, it is a consequence of the disease and notof the laser treatment.

If the treatment does not respond (proliferationprogresses, bleeding occurs) the PPC level it mustbe reassessed, considering if both the confluenceand the extension towards the extreme periphery areadequate. After this verification we have twooptions: 1. Anti-VEGF (the use of triamcinolone(TAIV) and anti-VEGF in diabetic retinopathy is inthe clinical trial stage. Therefore its use in a diffe-rent context must have the informed consent of thepatient, which must warn about the lack of long-term experience and the possible complications. Italso must have the authorization of the MedicationAgency of Spain (for compassionate use). Theapplication must be submitted to the General Direc-tion of Pharmacy and Health Products of the Healthand Consumer Ministry): every 4-6 weeks. 2. Reti-novitreous Surgery (CRV) (figs. 12 and 13).

Special Cases

– With extended non active vitreoretinal adhe-rences, without traction and without threatening themacular area and good visual acuity: Regular chec-kups

– With extensive vitreoretinal adherences whichcompromise the macula: CRV with PPC. anti-VEGF + CRV can be utilized before the third day ±anti-VEGF at the end of the surgery.

– PDR with active traction but without severehemovitreous: anti-VEGF prior to surgery: 1 or 2days before to minimize bleeding during the sur-gery.

– Tractional diabetic papillopathy: CRV.– Tractional maculopathy: CRV.– PDR + rubeosis with medium transparency:

immediate PPC

– PDR + rubeosis + neovascular glaucoma:immediate PPC ± anti-VEGF + valve.

After the intravitreal injection of bevacizumab(IVB) a fast contraction of the neovascular mem-brane has been described (26) which tractions theroot of the iris, producing a permanent synechialangular closure. This undesirable situation can beprevented avoiding the use of intravitreal anti-VEGF in eyes exhibiting broad areas of peripheralanterior synechiae. Gonioscopic exploration isessential because the involvement of the angle canproceed the involvement of the iris and this may gounnoticed in biomicroscopic exploration only. Theablation of an ischemic retina by means of laserPPC, or cryo-ablation –when laser is not feasible–will achieve the same effect as anti-VEGF but itwill be longer lasting.



Fig. 12: PDR.

Fig. 13: PDR after PPC.

4.6. PDR with Hemovitreous

If the ocular fundus cannot be explored, ocularechography is required.

Limiting the activity of PDR diabetic patients isnot efficient to prevent hemovitreous. If bleedingexists, prescribing rest is not efficient either. There-fore, in both cases, the patient may carry out theactivity allowed by the visual limitations.

– If DR is regmatogenous or combined (tractio-nal/regmatogenous): urgent CRV.

– In non pan-photocoagulated patients: prefe-rably CRV

– In panphotocoagulated patients without DR:wait two months. VA/ echography controls every 15days. Defer surgery (2-3 months) if no improve-ment is demonstrated. In these cases it is useful toassess the condition of the contralateral eye.

Some authors (27-29) recommend consideringthe use of anti-VEGF in case of persisting or seve-re hemorrhage after discarding the presence of trac-tional DR. If the patient is not vitrectomized we canconsider the use of anti-angiogenic therapy prior tosurgery. It is advisable to perform this therapy bet-ween day 3 and 1 prior to the operation. If thepatient is already vitrectomized, the duration of theanti-VEGF action shortens considerably. Injectionscould be done every four weeks, maintaining closescrutiny due to risk of tractional retinal detachment.It is important to remember that the use of anti-VEGF is under the compassionate use principle.

Special Cases

PDR + rubeosis + media opacity:– If there are no peripheral anterior synechiae

(the presence of peripheral anterior synechiae at theangular level brings into question the use of anti-VEGF because the severe contraction of the tissuein response to the intravitreous injection may indu-ce acute angular closure and the development ofneovascular glaucoma with very negative conse-quences. Therefore, in the case of patients withPDR where the anti-VEGF therapeutic option isconsidered, angular gonioscopy is a requirement):anti- VEGF + surgery to resolve the media opacityand treat PDR

– If there are peripheral anterior synechiae: Sur-gery for treating media opacity and PDR. If the caseevolves to neovascular glaucoma: Valve implant.

4.7. PDR with Premacular-Retrohyaloidhemorrhage

Early CRV, preferably before one month.

4.8. PDR with recurring hemovitreous afterCRV

Immediate bleeding (within the first month)

This bleeding arises from remains of desiccatedfibrovascular tissue during the CRV or dispersion ofresidual blood (30), although it could also be due tothe existence of DR or peripheral tears, althoughsometimes in relation to sclerotomies. Both possibi-lities should be discarded.

The large majority of immediate bleedings areresolved spontaneously within days or weeks. Waitfor 1-2 months with VA and echographic control. Ifthe bleeding does not disappear, we have twooptions:

– Fluid-air exchange and, if there is no improve-ment, perform CRV.

– CRV directly.The surgery aims at restoring the vision and elimi-

nating products which could stimulate proliferation.If recurring hemovitreous appears, echographic

control every 15 days is recommended. We havetwo options:

– New CRV in 2-4 months. (anti-VEGF pre- orintra-op).

– Anti-VEGF every 4-6 weeks.If there is improvement, complete PPC/ cryothe-

rapy in extreme periphery.Late bleeding (after the first month).Late bleeding appears in a significant percentage

of cases (13% - 50%), and can have different cau-ses, the most frequent being the following.

– Bleeding of the peripheral proliferative tissuepresent in sclerotomies: the origin of these neoves-sels is not the anterior retina (as in anterior fibrovas-cular proliferation) but the ciliary body. This fibro-vascular tissue can be extended towards the anteriorvitreous because of its proximity. It is associated toincarceration of the vitreous in sclerotomies. Thediagnostic can be made by means of scleral depres-sion. Sometimes an epi-scleral sentinel vessel mayexist when entering the sclerotomy (although itsexistence does not ensure the existence of fibropro-liferative tissue therein).



The treatment will consist in a new CRV extrac-ting this tissue. Gas can be left as a tampon.Recently the use of anti-VEGF has been proposedin late recurring vitreous hemorrhages (31).

– Anterior fibrovascular proliferation (32). Inthese cases, the hemovitreous occurs between thefirst and seventh month after retino-vitreous surgeryin the form of neovascular proliferation originatingin the peripheral retina and extends through the ante-rior hyaloids to the posterior face of the lens capsule.An exploration with scleral depression and indirectbiomicroscopy reveals neovascularization. Rubeosisin the iris appears occasionally. The echography mayshow thickened tissue strips from the peripheral reti-na to the cilliary body and the posterior surface of theiris, tractional detachments of the anterior retina andcilliary body (frequently associated to hypotonia). Astreatment is discouraging, prevention is more impor-tant, mainly in patients at risk such as young peoplewith DM type 1, severe retinal ischemia, tractionaland/or combined DR, above all if extra-scleral cer-clage has been fitted, multiple surgeries, PDR whichhas not been treated or does not respond to PPC,PDR with extended fibrovascular posterior prolifera-tion, post-op rubeosis iridis, recurring hemovitreous,etc. In these patients, aggressive PPC must be carriedout. If even so they continue to evolve, the indicationis CRV with careful removal of the anterior vitreous(for which a lensectomy may be necessary) followedby extensive anterior photocoagulation.

If the anterior fibrovascular proliferation is alre-ady present, it must be detected as early as possiblebefore a tractional detachment of the retina and/orcilliary body and the formation of cyclitic membra-nes occur. CRV must be performed, followed by len-sectomy, extracting the posterior lens capsule, dis-secting the vitreous base, endodiathermia of neoves-sels and endophotocoagulation with the broadestpossible extension (avoid cryotherapy because itcould cause a contraction of the fibrotic tissue andperipheral DR). If peripheral tractional detachmentof the retina and/or cilliary body exists, it is fre-quently necessary to perform peripheral retinoto-mies and use silicon oil to preserve the ocular globe.

4.9. PDR with retina detachment

Tractional, compromising or affecting the macu-la = CRV with or without the use of TAIV as amanipulator.

Regmatogenous/combined: CRV < 48 hr + longduration gas or silicon oil.

4.10. PDR with anterior ischemia

When faced with a condition comprising rubeo-sis and neovascular glaucoma it is important tostudy the chamber angle. As stated above, this isessential when considering the use of anti-VEGF.

4.11. PDR with rubeosis

Incipient: complete PPC and check-up at month2.

Evident: complete PPC, anti-angiogenic therapy,check-up at month 1.

In cases of iris rubeosis with cataract which pre-vents photocoagulation, we could consider the use ofanti-VEGF, to be injected 2-3 days prior to cataractssurgery after discarding the presence of angular neo-vessels. Subsequently PPC should be performed.

If the iris rubeosis is associated to vitreoushemorrhage which prevents photocoagulation: anti-VEGF followed by CRV (2-3 days after the injec-tion), trying to broaden the PPC to the extreme peri-phery.

4.12. Neovascular glaucoma (NG)

NG is a type of secondary glaucoma arising fromthe obstruction of the trabecular mesh by fibrovas-cular and/or associated synechiae. It usually cour-ses with ocular pain, severe visual acuity reduction,very high intra-ocular pressure, conjunctival hype-remia, corneal edema, tyndall, hyphema, iris rubeo-sis, chorectopia, uveal ectropion and significantgoniosynechiae.

It is likely that in the immediate future we willwitness changes in the prognosis of this disease dueto the anti-VEGF. Even though the results seemhighly encouraging in the short term, at present the-re are no prospective studies reporting the dosage ofchoice, secondary effects and long-term safety or thebest combination with other therapeutic measures.

In all patients at risk, a complete ocular assess-ment must be performed, including explorationwithout midriasis of the pupillary edge with largeincrease and gonioscopy.



Neovascular glaucoma treatment has three thera-peutic approaches (33-35).

1. Medical treatment

– Topical ocular hypotensors: beta blockers,alpha-adrenergics, carbonic anhydrase inhibitors.Pilocarpine is contraindicated and prostaglandinequivalents are under debate (access to the uveo-scleral pathway is blocked by the fibrovascular tis-sue in the angle and the inflammation increases).

– Systemic ocular hypotensor: osmotic diureticsand IV and oral carbonic anhydrase inhibitors.

– Controlling the inflammatory component(which is always present and is very intense) withmidriatics (Atropin or Cyclopegic) and topical cor-ticoids (Dexametasone or methyl prednisolone/3hours). The effect of this measure not only controlsthe inflammation, it also diminishes pain and intra-ocular pressure. If necessary, administer sub-con-junctival or subtenon corticoids.

2. Anti-vasoproliferative treatment

PPC is indicated (level A evidence): 1,200-1,600impacts produce the regression of rubeosis in70.4% of cases. The PPC destroys the ischemic reti-na responsible for the synthesis of vasoproliferativefactors and also increases the availability of oxygenin the untreated retina. PPC must be performedurgently and always complete up to the extremeperiphery. However, the regression of neovesselsafter PPC is slow (weeks). For this reason, we couldconsider the use of anti-VEGF as a supplementarymeasure (36) because it causes a nearly immediateregression of rubeosis (within 24-48 hours). Theseeyes must be closely followed up because, as men-tioned above, the anti-VEGF could cause the con-traction of existing fibrovascular tissue, generatingan angular closure. In any case, the patient must berequested to maintain close control of glycemiabecause the Hb A1c number is the most importantfactor in the recurrence of PDR after PPC.

If the diagnostic was early, the application of theabove measure could suffice to resolve the condi-tion.

3. Surgical treatment

Whenever possible, we must try to postpone sur-gery until the disappearance of rubeosis.

– Trabeculectomy with antimetabolites.– Valve implant.– Cyclophotocoagulation (37) with diode laser.There is no consensus about which of these tech-

niques is more indicated. Filtrating surgery, with orwithout drainage valve, seems to be the best optionif the retina is panphotocoagulated, rubeosis hasregressed and there is angular blockage due to theperipheral synechiae. The use of anti-VEGF combi-ned with filtrating surgery could help to diminishvitreous hemorrhage and scarring of filtrationampoule, above all in rubeosis which remain active.Bevacizumab has been used as co-adjuvant treat-ment to filtrating surgery with good results (38,39).

In what concerns cyclo-destructive processes, thechoice process is laser diode. Occasionally theeffect can be transient but it usually suffices to com-plete the PPC. The procedure is quite safe in refrac-tory glaucoma cases but neovascular glaucomaseems to have a higher prevalence of post-treatmenthypotonia (15%).

Summarizing the above, the treatment guidelinefor NG we advise is in agreement with the guideli-nes recently published by the European GlaucomaSociety (40) and comprises:

– Stage 1: Atropin eye drops + topical corticoids+ antiglaucomatous: all except pilocarpine. Sugges-ted sequence: Brimonidin, betablockers, carbonicanhydrase inhibitors: topical or systemic. PPC:complete it as much as possible. Anti-angiogenictherapy has proved to be useful but its use for thisindication is not yet approved.

– Stage 2: without response in IOP. Trabeculec-tomy with anti-metabolites/valve implants/cycloa-baltion. Phenolization (if eye painful with amauro-sis)/evisceration /enucleation.

4.13. Cataracts

Diabetic patients under 65 have 3 or 4 times gre-ater risk of developing cataracts than the non-diabe-tic population (in younger groups the risk increasesup to 25 times). After age 65, the risk balances out.

Whenever the cataract allows to visualize theocular fundus and laser treat the progression ofretinopathy, the attitude should be of expectation.When said limits are overcome, phakoemulsifica-tion is indicated.

After surgery, the patient must be photocoagula-ted if applicable and placed in follow up for six



months in case the surgical trauma induces the reti-nopathy progression. It must be taken into accountthat diabetics without ME who submit to cataractsurgery an increase of the central macular thicknessmay appear in the first three months post surgeryalthough some resolve spontaneously (41).

In diabetics with ME, it must be treated beforecataract surgery if possible. If the cataract preventsthe treatment of ME, we can consider the use ofperi-op anti-VEGF/TAIV. At present there are clini-cal trials assessing its efficiency (42,43).

In summary, in the presence of diabetic retino-pathy without macular edema, regular controls mustbe established after cataract surgery. If ME appears,we must maintain an expectant attitude trying todiscard a pseudophakic ME, which usually has afavorable spontaneous evolution. Sometimes, dueto the clinic as well as angiographic aspect, it couldbe very difficult to differentiate between a diabeticME or an Irvine-Gass syndrome. However, if theedema persists through time, we should treat itaccording to the scheme proposed in this guide.

Due to the risk of progression of DR, simultane-ous cataract surgery in both eyes is not advised, aswell as within a short interval.

It is important to emphasize that, just like anypatient with macular pathology, in DME it is notadvisable to implant multifocal or diffractive intra-ocular lenses (Graph 1).

5. MANAGEMENT OF DIABETICMACULAR OEDEMA

As pointed out above, we use the EDTRS classi-fication and will consider treatment whenever thereis CSME. Similarly, the OCT result will be criticalto decide the treatment.

5.1. Assessment prior to the therapeutic action

If in diabetic retinopathy systemic control isparamount, in macular edema it is even moreobvious. The approach of this complication shouldbe multidisciplinary. It is necessary to insist inglycemia control (HbA1C), arterial blood pressure,overweight and lipids, referring the patient to theendocrinologist/ internist/ nephrologist whenevernecessary due to the important influence of theserisk factors. Deficient metabolic control could jus-

tify postponing the macular edema treatment awai-ting for improvement. It is desirable that HbA1Cnumbers should be below 7.5%.

The edema assessment must always include thebest corrected visual acuity, biomicroscopic assess-ment, retinography and OCT. Fluorescein angio-graphy can be considered in some clear cases of cir-cinates where the origin of exudation can be seen.In addition, it is a very useful test to determine thecondition of the perifoveal vascular network.

The tractional diabetic macular edema (TDME)is characterized in OCT by a macular thickeningwith loss of foveal depression and edema of theexternal retinal layers. In addition, the posteriorhyaloid is thick and hyper-reflected, tense andpartially detached from the posterior pole butremaining applied to the papilla and the cusp ofthe elevated macular surface. The tense and thic-kened posterior hyaloid exerts a vitreomaculartangential traction which induces or exacerbatesDME.

In contrast with OCT, biomicroscopy lacks suffi-cient precision to determine the condition of theposterior hyaloid when it is only slightly detachedfrom the macular surface. For this reason, OCT ismore sensitive to identify vitreo-macular adhesionand therefore allows an earlier diagnostic of a par-tial posterior vitreous detachment. In addition, itallows for a precise assessment of the macularthickness and is highly reproducible.

5.2. Therapeutic options

5.2.1. Focal or multifocal CSME

The treatment of choice for this type of edemacontinues to be focal photocoagulation. It providesgood results in the long-term and is considered tobe the reference treatment (figs. 4 and 5).

The treatment will be carried out over the micro-aneurysms which fugue and are located in the cen-tre of the circinated crowns, between 500 and 3,000microns from the centre of ZAF, with 50-100micron spots and sufficient power to achieve a softwhitening thereof.

For the edemas which are generally of the com-bined type and not purely focal in which the centralmacular thickening makes laser therapy difficult(usually corresponding to OCT values above 400µ)(44) we could consider anti-angiogenic therapy or





Graph 1. Diabetic retinopathy management.

intravitreous corticoid therapy followed by laser(45-49). This subject is discussed in greater detail inthe diffuse CSME section.

If a vitreo-macular traction with functional reper-cussion is evidenced, we would proceed to CRV

(50-52) (figs. 7a and 7b) with or without this sec-tion of the internal limiting membrane (ILM) (53-55) and/or TAIV/anti-VEGF (44-48). If the patientexhibits a stable improvement, we can refer him tothe ophthalmologist for control.



Graph 1 (cont.). Diabetic retinopathy management.

5.2.2. Diffuse CSME

In case of diffuse CSME with vitreoretinal trac-tion, the therapeutic indication is CRV with hyaloi-dectomy (56-57), with the dissection of ILM beingunder debate (58-63) as well as the use of TAIVsurgery at the end (64, 65) (figs. 6, 14 and 15).

If there is no traction, the most widely usedoption which forms part of established protocols isthe application of modified grid laser. This optionutilizes less intense (mild grey) and smaller burns(50µm), treating microaneurysms directly butwithout trying to change their color. The OCT mapis useful for identifying the retinal thickening areas.According to the ETDRS criteria, the treatmentmust be repeated at 3-4 months if the edema has notbeen resolved (3 treatments maximum).

The results obtained with said technique are infe-rior to those of focal macular edema. Only a mode-rate loss of visual acuity is avoided (equal to or gre-ater than 15 ETDRS letters) in 50% of patients,while 26% continues to lose vision in the long termand only 3% experience a slight improvement oftheir visual acuity. For these reasons, new therapeu-tic alternatives are being considered of which weonly have preliminary data as they are at present inthe clinical research stage.

The pharmacological alternatives proposed forcontrolling diffuse macular edema include intravi-treal triamcinolone and the new anti-VEGF drugs.These therapies aim at reducing the diffusion, selec-tively carrying out laser therapy in specific areas.Both options require the submission of a compas-sionate use application to the health Ministry.

The complications described with the use ofTAIV (65-68) (glaucoma, DR, cataracts, endoph-thalmitis, etc) and the legal problems which may bederived from their use leads to an increasing scree-ning of patients. In diffuse CSME with large centralmacular thickening (fig. 16), its efficiency makes itthe most recommendable drug. The most extendedoption is the use of 4 mg TAIV in non-vitrectomizedpatients and 8 mg in a vitrectomized patients (69). Incases where the central macular thickening is not solarge, we would suggest the use of anti-VEGF(bevacizumab, ranimizumab, pegaptanib) as theirsecondary effects appear to be less important. As ithas been seen that the effect of TAIV is temporary(70-73), the possibility of beginning treatment witha TAIV injection followed by an anti-VEGF and/orlaser therapy has been considered (74-76).

If improvements are not obvious after the aboverecommended therapy, there are not many therapeu-tic options available. Only in a few selected cases aCRV can be performed (77,78) because some stu-dies did not find improvements (79,80).

5.2.3. Cystic Macular edema

In the case of a cystic macular edema (CME)with vitreomacular traction, the proposal is to utili-ze CRV without dissection of MLI when the evolu-tion time is unknown or exceeds 6 months (due tothe risk of inducing a macular hole). When under 6months the MLI dissection can be performed.



Fig. 14: Macular edema with vitreo-macular tractionsyndrome.

Fig. 15: The same case after retinal-vitreous surgery.Fig. 16: OCT E3 of a patient with diffuse CSME and lar-ge central macular thickening.

For CME patients who do not exhibit evidence oftraction the option is the use of TAIV optionallyfollowed by anti-VEGF and/or modified grid(81,83) (figs. 17-19).

By way of summary, we would like to emphasizethat in the presence of a tractional component withfunctional repercussion in any type of diabeticmacular edema we must assess the CRV indication.



Graph 2: Treatment algorithms for focal and multifocal macular edema.

5.2.4. Ischemic macular edema

Ischemic macular edema is defined by clinicalsigns such as:

– Increase of avascular foveal zone (ZAF)≥ 1.000 µm.

– Rupture of the perifoveal capillary ring in theZAF edge.

– Non-perfusion area within a disc diameterfrom the centre of the fovea.

In DME with ischemic tractional predominan-ce, the possibility of CRV is to be considered. The

use of anti-VEGF is initially contraindicatedbecause, even though the edema is reduced, visualacuity worsens due to the increase of ischemia(84).

5.2.5. Massive lipid deposit

In some patients with chronic macular edema,lipid deposits concentrate in the macular area, cau-sing irreversible damage to photoreceptors, andthus rendering any treatment inefficient.



Graph 3: Diffuse macular edema treatment algorithm.

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GUIDELINES OF CLINICAL PRACTICE OF THE SERV: … · management of ocular complications of diabetes....

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