Ординатура / Офтальмология / Учебные материалы / Retinal Vascular Disease Joussen Springer

No statistically significant difference in the outcome of progression of NPDR to proliferative DR was observed.

The favorable impact of ruboxistaurin on vision loss, compared to placebo, was observed irrespective of baseline DME level (Fig. 19.1.2.1.10) or baseline DR level (Fig. 19.1.2.1.11) or prior

19 III focal/grid laser photocoagulation at baseline (Fig. 19.1.2.1.12).

Ruboxistaurin had a statistically significant impact on DME progression, to within 100 μm from the center of macula, in eyes with clinically significant macular edema at baseline (p = 0.003).

Ruboxistaurin treatment resulted in a statistically significant reduction in the application of initial focal/grid laser photocoagulation, in eyes of patients which were laser-na¨ıve at baseline

(p = 0.008).

patients, as compared to placebo-treated patients, include: chalazion, posterior capsular opacification, dyspepsia, increased blood creatine phosphokinase levels, urgency of micturition and superficial thrombosis [12].

19.1.2.1.9 Conclusion

Protein kinase C enzyme upregulation appears to be a critical step in the pathogenesis of diabetic retinopathy. Selective inhibition of the PKC- enzyme, by ruboxistaurin, has been shown to be of benefit not only in animal models, but also in clinical trials. Although not aproved yet, ruboxistaurin, given once per day orally, appears to be well tolerated in the clinical trials so far and has shown benefit in the prevention of vision loss in patients with non-proliferative diabetic retinopathy, even when added to standard of care.

References

1.Aiello LP, Bursell S-E, Clermont A, et al. (1997) Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an

orally effective -isoform-selective inhibitor. Diabetes 46: 1473 – 1480

2.Aiello LP, Clermont A, Arora V, et al. (2006) Inhibition of

PKC- by oral administration of Ruboxistaurin is well tolerated and ameliorates diabetes-induced retinal hemodynamic abnormalities in patients. Invest Ophthalmol Vis Sci 47: 86 – 92

3.Beckman J, Goldfine A, Gordon M, et al. (2002) Inhibition of

protein kinase C- prevents impaired endothelium-depen- dent vasodilation caused by hyperglycemia in humans. Circ Res 90:107 – 111

4.Campochiaro PA; C99-PKC412 – 003 Study Group (2004) Reduction of diabetic macular edema by oral administration of the kinase inhibitor PKC412. Invest Ophthalmol Vis Sci 45(3):922 – 31

5.Ceolotto G, Gallo A, Miola M, et al. (1999) Protein kinase C activity is acutely regulated by plasma glucose concentration in human monocytes in vivo. Diabetes 48(6): 1316 – 1322

6.Curtis T, Scholfield C (2004) The role of lipids and protein kinase Cs in the pathogenesis of diabetic retinopathy. Diabetes Metab Res Rev 20:28 – 43

7.Danis R, Bingaman D, Jirousek M, et al. (1998) Inhibition of intraocular neovascularization due to retinal ischemia in

pigs by PKC- inhibition with LY333531. Invest Ophthalmol Vis Sci 39:171 – 9

8.Ishii H, Jirousek MR, Koya D, et al. (1996) Amelioration of

vascular dysfunctions in diabetic rats by an oral PKC inhibitor. Science 272:728 – 731

9.Jirousek M, Gillig J, Gonzalez C, et al. (1996) (S)-13-[(di- methylamino)methyl]-10,11,14,15-tetrohydro-4,9:16,21-di- metheno-1H,13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]-oxa- diazacyclohexadecene-1,3(2H)-d ione (LY333531) and

of protein kinase C, its isoforms, and endothelial cell growth. J Clin Invest 98:2018 – 2026

Core Messages

Synthetic analogues of the naturally occurring growth hormone inhibitor, somatostatin, are good candidates for pharmaceutical therapy of diabetic retinopathy (DR). They block production of growth hormone and insulin like growth factor 1

We have evidence so far that somatostatin analogues can reduce progression of DR and preserve visual acuity

Somatostatin analogues are safe and effective in the treatment of cystoid macular edema and proliferative diabetic retinopathy

Laser treatment and vitreoretinal surgery have markedly improved the prognosis for visual problems due to diabetic retinopathy (DR), but nevertheless DR is still the leading cause of blindness in industrialized countries in adults of working age. Therefore we need new therapeutic approaches in the treatment of DR.

19.1.2.2.1Pathogenesis of Diabetic Retinopathy

The pathophysiology of DR is complex. The principal causes of DR are biochemical, hemodynamic, and endocrine. Hyperglycemia results in the production of advanced glycation endproducts, activation of the polyol pathway and changes in the cellular signal transduction. The results are hyperviscosity, proinflammatory milieu, reduced flexibility of white and red blood cells, increased adhesion of leukocytes and increased oxidative stress. All stages of DR are characterized by the overexpression of a number of different growth factors, the most important being vascular endothelial growth factor (VEGF) and insulinlike growth factor 1 (IGF-1), leading to manifestation and progression of the disease [7].

Clinically DR is subdivided into nonproliferative and proliferative stages. Nonproliferative DR is characterized by the occurrence of microaneurysms, intraretinal hemorrhages, cotton wool spots, hard exudates, intraretinal microvascular abnormalities (IRMA), and venous beading. Proliferative DR exhibits preretinal neovascularization, vitreous hemorrhage and iris neovascularization leading to angle closure glaucoma. Macular edema can occur in any stage of DR.

Histological findings are early thickening of basement membranes and loss of intramural pericytes and vascular endothelial cells. Due to this cellular loss the vascular reactivity is reduced. Damage of the tight junctions of the retinal vascular endothelial cells results in a breakdown of the inner blood-reti- nal barrier, leading to the manifestation of a diabetic macular edema. The more advanced stages of DR show progressive occlusion of capillaries resulting in retinal hypoxia. The hypoxic retina produces angiogenic growth factors like VEGF and IGF-1. The result is the development of preretinal and iris neovascularization [14, 17, 18].

Diabetic retinopathy occurs after 20 years in 95 % of all type 1 and 50 – 80 % of all type 2 diabetic patients. Proliferative DR is found after 20 years in 50 % of type 1 and 10 – 30 % of type 2 diabetic patients. Clinically significant macular edema occurs after 15 years in 15 % of type 1 and 25 % of type 2 patients.

19.1.2.2.2Somatostatin and Somatostatin Analogues

Somatostatin (somatotropin-release inhibitory factor) is a cyclic tetradecapeptide which was isolated from hypothalamic extracts and regulates growth hormone secretion. This neuropeptide is also produced in different other human organs like hypophysis, gut, exocrine and endocrine glands and also in the retina. Somatostatin is distributed throughout diverse cells and its action affects several biological processes like neurotransmission, hormone secretion, cell proliferation, membrane stabilization and

inflammation. Native somatostatin has a short halflife of about 3 min. The synthetic somatostatin analogue Sandostatin® LAR® has been developed for patients requiring long-term therapy and consists of octreotide acetate microencapsulated by a biodegradable polymer.

Somatostatin acts via five G-protein coupled somatostatin receptor subtypes (SSTR1 – 5) (Fig. 19.1.2.2.1) that were identified by molecular cloning studies. Somatostatin inhibits the release of different hormones and enzymes [8]. The classical action of somatostatin to inhibit growth hormone (GH) release is mediated by SSTR2 and 5. After binding somatostatin, the somatostatin receptors generate a transmembrane signal. This results in a reduction of the calcium concentration and activation of tyrosine phosphatases. Somatostatin is a postreceptor antagonist of growth factors acting by inhibition of signal transduction [17]. Octreotide has high activity at SSTR2, good activity at SSTR5 and moderate activity at SSTR3. It is inactive at SSTR1 and 4.

Growth hormone is produced in the anterior pituitary, resulting in the synthesis of IGF-1. IGF-1 increases the cellular uptake of glucose in the tissue and acts as surviving, growth and progression factor. It presumably acts as a key signal for cells going into the mitotic cycle. IGF-1 stimulates somatostatin secretion and inhibits GH secretion [11].

Somatostatin and SSTRstr have been identified in human retina and are produced in the retina.

Somatostatin analogues have been shown to exhibit pharmacological properties similar to the natural hormone somatostatin. Sandostatin (octreotide acetate) is a synthetic octapeptide analogue of somatostatin. Sandostatin is a potent and specific somatostatin receptor type 2 agonist. It is 45 times more potent in terms of inhibition of growth factor secretion relative to native somatostatin. The original injectable form of octreotide required a dosing regimen of three subcutaneous injections per day. Sandostatin LAR is a long-acting delivery system, administered i.m. once a month. After i.m. injection

of Sandostatin LAR, the serum octreotide concentration reaches an initial peak within 1 h and reaches a plateau concentration at around day 14. Steady-state octreotide serum concentrations are achieved after the third injection.

Somatostatin has an antiangigenic effect. Somatostatin is found in the vitreous and in diabetic patients reduced levels of somatostatin were reported [13]. Somatostatin does appear to also have an effect on fluid transport from the retinal pigment epithelium to the choroid, a process that is important in the development of macular edema.

19.1.2.2.2.1Role of Somatostatin, GH and IGF-1 in Diabetic Retinopathy

There is evidence that GH/IGF-1 excess and interactions between IGF-1 and VEGF play key roles in the development and progression of DR. The anterior pituitary secretes GH, which results in the synthesis of IGF-1 in multiple tissues. GH mediates both systemic and local IGF-1 production. IGF-1 acts as growth and progression factor.

Poulsen [20] found a relation of pituitary hormone and DR in a patient with proliferative DR, who suffered a postpartal pituitary insufficiency (Sheehan syndrome). Five years after the event retinopathy had regressed, indicating the important role of GH and IGF-1 in DR. In the following 20 years after the first description in 1953, diabetic patients underwent pituitary ablation for the treatment of proliferative diabetic retinopathy. These patients showed a regression of neovascularization and a significant reduction in the number of patients progressing to blindness. It is assumed that the treatment effect was related to postsurgical GH deficiency. Interestingly in diabetic patients with dwarfism due to GH deficiency, diabetic retinopathy is absent.

There is also strong evidence to indicate a hypersecretion of GH in diabetics. In patients with DR a substantial hypersecretion of GH was found. Further evidence for the important role of GH in the patho-

genesis of DR includes the case report of the development of retinal changes strongly mimicking diabetic retinopathy in two nondiabetic patients treated with GH [15].

The mitogenic effects of GH are mediated by IGF-1. Interestingly in patients with DR elevated serum levels of IGF-1 were found. Somatostatin reduces system-

19 III ic IGF-1 release via suppression of GH. Additional evidence for the role of IGF-1 in DR comes from studies of the normoglycemic reentry phenomenon. This term describes the worsening of DR occurring after rapid lowering of longstanding severe hyperglycemia in patients with DR. A rapid rise of serum IGF-1 levels has been found to accompany worsening of DR when insulin therapy is intensified and results in improved diabetic control [6]. It is further known that somatostatin, GH and IGF-1 play a role in the manifestation and progression of DR. Retinal hypoxia leads to an increased intraocular synthesis of both IGF-1 and VEGF. In eyes of diabetic patients increased vitreal IGF-1 levels were found. The highest levels of IGF-1 were present in patients with proliferative DR. In patients who had undergone vitrectomy after laser treatment the intravitreal VEGF levels were reduced but not the IGF levels [22], indicating the important role of IGF-1 in late stages of DR especially in cases where laser treatment alone is not effective.

19.1.2.2.2.2 Experimental Studies

Several laboratory studies support the hypothesis of the modes of action of octreotide. Somatostatin and IGF-1 receptors have been demonstrated on retinal vascular endothelial cells [1]. In preclinical studies it was shown that GH can stimulate the proliferation of human retinal endothelial cells. Sall et al. [21] found in cultured human retinal pigment epithelial cells that IGF-1 induced a dose dependent increase in IGF1R phosphorylation and in VEGF mRNA levels. Somatostatin and octreotide inhibited IGF-1 receptor phosphorylation and decreased VEGF production. Both IGF-1R phosphorylation and accumulation of VEGF mRNA were inhibited by physiological levels of somatostatin and octreotide (1 nM). These results demonstrate a somatostatin and octreotide mediated attenuation of IGF-1R signal transduction and VEGF mRNA accumulation via somatostatin receptor type 2. The role of the GH-IGF-1 axis has also been studied in transgenic and MK678, an octreotide-like somatostatin analogue – treated mice models showing a significant reduction of retinal neovascularization. These studies indicate that the interactions between IGF-1 and its receptors are necessary for maximal induction of retinal neovascularization by VEGF. These findings also indicate the essential role for IGF-1 in the late stages of DR, being

a permissive factor in angiogenesis and indicating the relationship between VEGF and IGF-1 receptors.

It has been shown [9] that octreotide inhibits IGF- 1 or b-FGF stimulated endothelial cell proliferation at a low concentration of 10 nM of octreotide. In preclinical studies octreotide also directly inhibits endothelial cell proliferation, indicating additional mechanisms of antiangiogenic action, probably by direct SSTR mediated inhibition [1, 23].

These studies emphasize the importance of paracrine and autocrine effects of octreotide. These data from preclinical studies strongly suggest a role for the use of octreotide as a therapeutic option in diabetic retinopathy.

19.1.2.2.2.3Mechanism of Action of Octreotide in Diabetic Retinopathy

Because growth hormone and IGF-1 are important mediators of angiogenesis in the retina, the use of synthetic somatostatin analogues in the treatment of DR is at present a promising area of pharmacological research. DR develops as a result of imbalance of proand antiangiogenic factors. VEGF and IGF-1 are major players in the pathogenesis. But DR only develops if at the same time there is a lack of natural angiogenesis inhibitors like transforming growth factor (TGF-) and pigment epithelium derived factor (PEDF) [2, 4].

Octreotide acts via paracrine and autocrine effects on retinal endothelial cells [9]. It binds to the SSTR and inhibits endothelial cell growth stimulated by growth factors like VEGF and IGF-1.

Somatostatin analogues have two different clinical mechanisms of action. First they can stabilize the blood-retinal barrier in patients with diabetic macular edema. Second they inhibit the neoangiogenesis via IGF-1 inhibition in patients with advanced stages of DR, resulting in regression of preretinal neovascularization or iris neovascularization (Fig. 19.1.2.2.2). The synthetic somatostatin analogue octreotide has been proven to be effective in small series of patients and two phase III trials have been completed recently [18].

Fig. 19.1.2.2.2. Somatostatin analogues inhibit the IGF-1 induced neovascularization in diabetic retinopathy

19.1.2.2.3 Current Clinical Use of Octreotide

Octreotide is in clinical use for the treatment of tumors like GH producing pituitary adenoma. It is approved for the treatment of acromegaly, malignant carcinoma syndrome, VIPoma, and gastropancreatic neuroendocrine tumors. Octreotide inhibits the pituitary release of GH from the tumor and lowers IGF-1 plasma levels. As overproduction of GH and IGF-1 plays an important role in the pathogenesis of DR, octreotide is under investigation for the treatment of DR.

19.1.2.2.3.1Treatment of Diabetic Retinopathy with Somatostatin Analogues

According to the clinical experience described above, the idea of treating DR with somatostatin analogues was born more than 20 years ago. Somatostatin analogues were used up to now in prospective studies or on a compassionate basis.

Sandostatin and Sandostatin LAR are more selective and have enhanced activities in comparison to somatostatin. In vitro and in vivo studies have confirmed that somatostatin analogues are specific and potent inhibitors of GH and IGF-1. Octreotide reduces elevated levels of GH and IGF-1. Preliminary evidence suggests that octreotide provides clinical benefits in DR in terms of reduced progression of DR, improved visual acuity and regression of macular edema.

Several clinical studies with somatostatin analogues in patients with DR have been reported in the literature. Most of the studies have been small or open trials, case reports, and studies of short duration.

Mallet et al. [19] reported significant regression of retinal neovascularization in patients with severe proliferative diabetic retinopathy showing progression of DR despite panretinal photocoagulation. The patients were treated with SMS 201-995 (octreotide) by subcutaneous infusions for up to

20months.

Böhm et al. [3] treated 9 of 18 patients with persis-

tent proliferative DR with vitreous hemorrhage despite having received full scatter laser photocoagulation with octreotide as subcutaneous injections in a dose of 100 μg tid three times daily for up to 3 years; the other nine patients served as control. A significantly reduced incidence of vitreous hemorrhages and number of vitrectomies in the octreotide-treated group was found. In the octreotide group visual acuity remained stable; in the control group visual acuity significantly decreased. Neovascularizations regressed in 85 % of the patients in the treated group and were stable in 15 %; in the control group neovas-

cularizations increased in 42 % and were unchanged in 58 %. Octreotide was well tolerated throughout the 3 years. Insulin dosis had to be reduced up to 50 % in insulin-dependent patients. No patient had a severe hypoglycemic episode.

Grant et al. [10] studied the effect of octreotide in 23 type 1 and 2 diabetics with preproliferative and

early proliferative DR. The patients were treated with III 19 maximally tolerated doses of octreotide (200 –

5,000 μg/day subcutaneously). Patients were followed for 15 months or until laser photocoagulation was required for both eyes. In the treated group, significantly fewer patients developed high risk characteristics. In the octreotide treated group only one of 22 eyes required laser treatment due to high risk proliferative DR whereas 9 of 24 eyes in the control group had to be treated with laser. Octreotide treatment showed a significant reduction of progression of DR.

Kuijpers et al. [16] described a nondiabetic patient with idiopathic cystoid macular edema who was treated with octreotide 100 μg tid s.c. The cystoid macular edema improved during treatment period, but recurred after treatment cessation and responded again when octreotide treatment was recommenced.

In another case report, Sandostatin LAR showed a beneficial effect in the treatment of diabetic cystoid macular edema (CME). The CME in both eyes was refractive to vitrectomy and periocular steroids. The patient was treated with Sandostatin LAR 20 mg every 4 weeks. One year treatment resulted in complete resolution of CME in the right eye and marked improvement in the fellow eye. Corrected visual acuity was 20/40 in the right eye and 20/100 in the left eye [12].

Chantelau and Frystyk [5] reported patients in whom the progression of diabetic retinopathy during intensified metabolic control was treated with manipulation by administration of octreotide. Octreotide lowered total IGF-1 levels. Macular edema resolved partly and visual acuity improved. Intensified insulin therapy in poorly controlled type 1 patients is able to cause florid diabetic retinopathy with acute macular edema. These changes may improve by administration of octreotide by downregulation of IGF-1.

Octreotide was under investigation in two phase III (802 and 804) multicenter, double-masked, randomized, placebo-controlled trials initiated by Novartis in 1999. Included were type 1 and 2 diabetic patients with moderate to severe nonproliferative DR to early proliferative DR. The patients were treated with the long acting octreotide (Sandostatin LAR, Novartis), which was injected intramuscularly once a month for up to 6 years. In the treatment arms the

after panretinal laser photocoagulation or postvitrectomy respond well to octreotide treatment. Patients with iris neovascularization also benefit from octreotide treatment (Fig. 19.1.2.2.3). In patients pretreated with octreotide, surgical procedures seem to be easier to perform concerning removal of preretinal membranes that can be peeled off more easily and seem to be more fragile. This experience suggests that especially the neovascular stages respond well to octreotide treatment. The reason might be that the late stages of DR are most likely IGF-1 driven.

About 30 % of patients have mild to moderate diarrhea and gastrointestinal side effects at the beginning of treatment. The side effects usually resolve within 3 months. Pancreatic enzymes can be administered to reduce side effects. Rarely patients withdraw from treatment due to severe diarrhea. Gallbladder stones and thyroid problems are rare. Sandostatin LAR 20 mg or preferentially 30 mg once a month can be used for the treatment of DR. To reduce gastrointestinal side effects lower doses can be used at the beginning of treatment.

Sufficient evidence for GH and IGF-1 involvement in the progression of DR supports the potential utility of octreotide in the treatment of DR. However, not

*1 dense vitreous hemorrhage not requiring vitrectomy

†5 dense vitreous hemorrhages, 3 requiring surgery

Fig. 19.1.2.2.3. Risk of vitreous hemorrhage and vitreoretinal surgery was significantly reduced in patients with octreotide treatment [3]

Fig. 19.1.2.2.4. Decision making in the treatment with somatostatin analogues. CSME clinically significant macular edema, DR proliferative diabetic retinopathy, SA somatostatin analogues (off label)

all patients respond to octreotide treatment. There are unfortunately no hard criteria to identify who benefits from octreotide treatment. In patients with treatment failure somatostatin analogues may have inadequate penetration of the blood-retina barrier after intramuscular administration. Intravitreal administration might be more effective; however, Sandostatin LAR formulation is not suitable for intravitreal injection.

19.1.2.2.3.4 Follow-up and Monitoring

Sandostatin LAR is not approved for treatment of diabetic retinopathy. However, off-label treatment of diabetic retinopathy can be considered after failure of the gold standard treatment regimen, i.e., laser treatment and vitrectomy. This is in either patients with proliferative diabetic retinopathy or iris neovascularization or those with diabetic macular edema. Ophthalmological follow-up is recommended at 3- month intervals. Sandostatin LAR administration should be monitored by a diabetologist or endocrinologist because especially in insulin-dependent patients severe hypoglycemic episodes are possible. Therefore insulin dosis has to be adjusted appropriately. Other possible side effects like gallstones and hypothyroidism also have to be monitored by regular ultrasound and thyroid status checks. It is mandatory that patients are compliant and closely self-con- trol their blood glucose levels.

References

1.Baldysiak-Figiel A, Lang GK, Kampmeier J, Lang GE (2004) Octreotide prevents growth factor-induced proliferation of bovine retinal endothelial cells under hypoxia. J Endocrinol 180:417 – 424

2.Böhm BO, Feldmann B, Lang GK, Lang GE (1999) Treatment of diabetic retinopathy with long-acting somatostatin analogues. In: Lamberts SWJ (ed) Octreotide: The next decade. BioScientifica, Bristol, pp 241 – 257

3.Böhm BO, Lang GK, Jehle PM, Feldmann B, Lang GE (2001) Octreotide reduces vitreous hemorrhage and loss of visual acuity risk in patients with high-risk proliferative diabetic retinopathy. Horm Metab Res 33:300 – 306

4.Böhm BO, Lang GE, Volpert O, Jehle PM, Kurkhaus A, Rosinger S, Lang GK, Bouck N (2003) Low content of the natural ocular anti-angiogenic agent pigment epithelium-derived factor (PEDF) in aqueous humor predicts progression of diabetic retinopathy. Diabetologica 46:394 – 400

5.Chantelau E, Frystyk J (2005) Progression of diabetic retinopathy during improved metabolic control may be treated with reduced insulin dosage and/or somatostatin analogue administration – a case report. Growth Horm IGF Res 15: 130 – 135

6.Chantelau E, Kohner EM (1997) Why some cases of retinopathy worsen when diabetic control improves. Br Med J 315:1105 – 1106

Peptides 48:267 – 278

10.Grant MB, Mames RN, Fitzgerald C, Hahariwala KM, Coo- per-DeHoff R, Caballero S, Estes KS (2000) The efficacy of octreotide in the therapy of severe nonproliferative and early proliferative diabetic retinopathy. Diabetes Care 23: 504 – 509

11.Grant MB, Caballero S, Smith LEH (2002) Somatostatin in diabetic eye diseases. In: Lamberts SWJ, Ghigo E (eds) The expanding role of octreotide II: Advances in endocrinology and eye diseases. BioScientifica, Bristol, pp 165 – 184

12.Hernaez-Ortega MC, Soto-Pedre E, Martin JJ (2004) Sandostatin LAR for cystoid diabetic macular edema: a 1-year experience. Diabetes Res Clin Pract 64:71 – 72

13.Hernandez C, Carrasco E, Casamitjana R, Deulofeu R, Gar- cia-Arumi J, Simo R (2005) Somatostatin molecular variants in the vitreous fluid: a comparative study between diabetic patients with proliferative diabetic retinopathy and nondiabetic control subjects. Diabetes Care 28:1941 – 1947

14.Joussen AM, Fauser S, Krohne TU, Lemmen K-D, Lang GE, Kirchhof B (2003) Diabetische Retinopathie: Pathophysiologie und Therapie einer hypoxieinduzierten Entzündung. Ophthalmologe 100:363 – 370

15.Koller EA, Green I, Gertner JM, Bost M, Malozowski SN (1998) Retinal changes mimicking diabetic retinopathy in two nondiabetic, growth hormone-treated patients. J Clin Endocrinol Metabol 83:2380 – 2383

16.Kuijpers RWAM (1998) Treatment of cystoid macular edema with octreotide. N Engl J Med 338:624 – 626

17.Lang GE (2004) Therapie der diabetischen Retinopathie mit Somatostatinanaloga. Ophthalmologe 101:290 – 293

18.Lang GE (2007) Pharmacological treatment of diabetic retinopathy. Ophthalmologica 222 (in press)

19.Mallet B, Vialettes B, Haroche S, Escoffier P, Gastaut P, Taubert JP, Vague P (1992) Stabilization of severe proliferative diabetic retinopathy by long-term treatment with SMS 201 – 995. Diabete et Metabolisme 18:438 – 444

20.Poulsen JE (1996) Diabetes and anterior pituitary insufficiency: final course and postpartum study of a diabetic patient with Sheehan’s syndrome. Diabetes 15:73 – 77

21.Sall JW, Klisovic DD, O’Sorisio MS, Katz SE (2004) Somatostatin inhibits IGF-1 mediated induction of VEGF in human retinal pigment epithelial cells. Exp Eye Res 79:465 – 476

22.Spranger J, Mohlig M, Osterhoff M, Bühnen J, Blum WF, Pfeiffer AFH (2001) Retinal photocoagulation does not influence intraocular levels of IGF-1, IGFand IGF-BP3 in proliferative diabetic retinopathy – evidence for combined treatment of PDR with somatosatin analogues and retinal photocoagulation. Horm Met Res 33:312 – 316

23.Spraul CW, Baldysiak-Figiel A, Lang GK, Lang GE (2002) Octreotide inhibits growth factor-induced bovine choriocapillary endothelial cells in vitro. Graefes Arch Clin Exp Ophthalmol 240:227 – 231

Core Messages

Vitreous surgery for proliferative diabetic retinopathy can clear media opacities and relieve traction on the retina

Vitrectomy can posititvely influence the development of the retinopathy, since the schaffold for fibrovascular proliferations is removed and possible by improving oxygen supply to the inner retina

Laser treatment of the retina is essential to reduce the risk for complications of surgery

such as iris rubeosis, fibrovascular reproliferations and rebleeding

Functional outcome of surgery depends on the primary microvascular disease and the degree of retinal ischemia

Cataract surgery can have a negative influence on diabetic macular edema

Neovascular glaucoma requires aggressive surgical intervention with intense coagulation treatment, nevertheless the prognosis is guarded

19.2.1.1Rationale for Surgery in Diabetic Retinopathy

Diabetic retinopathy is a disease of the retinal microvasculature. Surgery does not treat the primary disease and is not a causative therapeutic approach; it can only address secondary complications of the primary microvascular problem. Complications of diabetic retinopathy which can be treated surgically and which are targets for surgery include [13, 15, 21, 30, 55]:

Removing media opacities, especially vitreous hemorrhage

Relieving traction on the retina by active or atrophic fibrovascular membranes

Reattachment of detached retina, tractional or rhegmatogenic

Enabling necessary coagulation treatment of the ischemic retina

Removing vitreous as a scaffold for neovascularizations

Improving retinal metabolism by facilitating diffusion of oxygen, nutrients and growth factors from the vitreous cavity to the retina and vice versa

Since the primary microvascular disease is not addressed by surgery, functional results of surgery in diabetic retinopathy may be limited due to ischemic retinal damage.

19.2.1.2Indications for Surgery in Diabetic Retinopathy: A Practical Approach

19.2.1.2.1 Does the Literature Help?

Many studies have been published on the results of vitreous surgery for complications of diabetic retinopathy. Evidence based medicine differentiates various levels of evidence for a therapeutic procedure. The highest level of evidence is provided by randomized prospective trials. The Vitrectomy for Diabetic Retinopathy Study (VDRS) was such a randomized prospective study comparing “early” vitreous surgery with observation. The DRVS studied two groups: vitreous hemorrhage and severe proliferative diabetic retinopathy with useful vision. For eyes with vitreous hemorrhage this study only showed a benefit for surgery in younger diabetics [10, 12]. For eyes with progressive proliferative diabetic retinopathy a positive effect of surgery was detected for eyes with large active neovascularizations [11]. These results, however, have to be interpreted with caution. Randomized trials usually follow a strict protocol and run a long time before results become available. They are usually not adapted to changing technical developments and improved understanding of the pathophysiology. They may therefore give an answer to a question that is no longer relevant.

Many other non-randomized studies describe retrospectively the outcome of surgery for diabetic reti-

nopathy. Most studies have subdivided the surgical indications into different groups [9, 58 – 60]:

Vitreous hemorrhage

Tractional detachment of the macula Tractional rhegmatogenic retinal detachment Severe, progressive proliferative retinopathy

The individual patient often does not fit so easily into a single category. Patients with a vitreous hemorrhage commonly present with circumscribed tractional detachment or active neovascularization. Definition of macular detachment is not uniform. Some authors include eyes with detachment of the peripheral macula close to the major vascular arcades and a full vision in this group [49, 59], others only eyes with completely detached foveas [19].

Moreover, surgical techniques, instrumentation and understanding of the pathophysiology have considerably improved in recent years. These changes include:

Availability of endolaser [48, 54] Extracapsular instead of intracapsular cataract removal [3, 5]

Wide-angle viewing systems [61] Perfluorocarbon liquids [27]

Peeling of the inner limiting membrane [14] Supplementary drug treatment (e.g., intravitreal triamcinolone) [28]

The results of surgery have therefore improved, complications have become less common and indications for surgery have been extended. Older studies are therefore of limited value for the quantitative estimation of the chances and risks of surgery, but they have helped very much in advancing our indications for surgery, improving our understanding of the pathophysiology, and developing intraoperative strategies.

Many factors have to be considered before an individual decision for or against surgery can be made, including status of the fellow eye, general health status, duration of visual loss, past and expected clinical course of the disease, lens status, extent of macular ischemia and last but not least patient preferences. All these factors are difficult to control in studies of a disease with such a wide variation of clinical features. Thus for a patient with diabetic retinopathy, recommendations for surgery are commonly based more on individual weighing of risks and benefits than on high level evidence based knowledge.

19.2.1.2.2 Vitreous Hemorrhage

The first historic pars plana vitrectomy was performed in an eye with diabetic vitreous hemorrhage [34, 35]. Vitreous hemorrhage is a typical indication

III 19

a

b

c

Fig. 19.2.1.1. a Diffuse vitreous hemorrhage; the position of the optic disk can just barely be suspected. Visual acuity was HM. b Vitreous and subhyaloidal hemorrhage. Extensive fibrovascular membranes can be seen and tractional detachment of the retina is suspected. Vision is HM. c Tractional retinal detachment nasally to the fovea. The membranes are atrophic after scatter laser treatment and the traction does not threaten the fovea. Vision was 20/25 and no further therapy was necessary