Exudative Retinal Detachment

Exudative retinal detachment develops when fluid collects in the subretinal space.
The subretinal space between the photoreceptors and the retinal pigment epithelium is the remnant of the embryonic optic vesicle.
In the developed eye the subretinal space is of minimal size, but it can reopen under pathological conditions that disrupt the integrity of blood-retinal barrier.
Inflammatory, infectious, infiltrative, neoplastic, vascular, and degenerative conditions may be associated with blood-retinal barrier breakdown and the sequential development of exudative retinal detachment.
This elaborate on the pathogenesis and the differential diagnosis of exudative retinal detachment and specifically discuss the spectrum of diseases associated with exudative retinal detachment in uveitis clinics.

1. Exudative Retinal Detachment Dr R S Walpitagamage Registrar in Ophthalmology TH Kandy

2. Introduction Exudative retinal detachment develops when fluid collects in the subretinal space. The subretinal space between the photoreceptors and the retinal pigment epithelium is the remnant of the embryonic optic vesicle. In the developed eye the subretinal space is of minimal size, but it can reopen under pathological conditions that disrupt the integrity of blood-retinal barrier. Inflammatory, infectious, infiltrative, neoplastic, vascular, and degenerative conditions may be associated with blood-retinal barrier breakdown and the sequential development of exudative retinal detachment. This elaborate on the pathogenesis and the differential diagnosis of exudative retinal detachment and specifically discuss the spectrum of diseases associated with exudative retinal detachment in uveitis clinics.

3. Epidemiology No data are available to suggest the incidence or prevalence of ERD. Every pathological condition (inflammatory, infectious, vascular, neoplastic, and degenerative) is potentially capable of violating the integrity of the BRB and results in the development of ERD. The spectrum of associated diseases is wide, ranging from isolated ocular conditions to multisystemic diseases.

4. Pathogenesis ERD develops when fluid collects in the subretinal space as a result of disruption of the integrity of the BRB. The BRB plays an important role in the homeostatic regulation of the retinal microenvironment by controlling fluid and molecular movement between the ocular vascular beds and the retinal tissues and prevents leakage into the retina of macromolecules and other potentially harmful agents. The BRB consists of inner and outer components. The inner BRB ( iBRB ) is formed by the tight junctions (TJs) between neighboring capillary endothelial cells that rest on a basal lamina covered by the foot processes of astrocytes and Muller cells. Pericytes, separated from the endothelial cells by the basal lamina, are the third cell type of relevance to the iBRB . Astrocytes, Müller cells, and pericytes are thought to contribute to the proper functioning of the iBRB .

5. The outer BRB (OBRB) is formed by TJ between cells of RPE. The RPE resting upon the underlying Bruch membrane separates the neural retina from the fenestrated choriocapillaris and plays an important role in transporting nutrients from the blood to the outer retina. The apical surface of the RPE shows long projecting processes (villi) that partially envelop the outer segments of the photoreceptors. These villi are involved in the phagocytosis of outer segment disks. The metabolic interaction between these apical villi and the photoreceptors, for example, exchange of metabolites such as vitamin A and amino acids, is considered to be critical for the maintenance of visual function.

6. There are no structural attachments between the RPE and the outer retina, but neural cell adhesion molecules expressed on the apical surface of the RPE cells create adhesion between the retina and RPE although functional factors may be more important. Although inter-RPE cell TJs are important in the control of paracellular movement of fluids and molecules between the choroid and retina, the polarized distribution of membrane proteins in the RPE is also important. As the integrity of the BRB is dependent on the normal functioning of the cells that determine its structure, hypoxia-ischemia secondary to inflammatory, infectious, infiltrative, neoplastic, vascular, and degenerative conditions may be associated with BRB breakdown. RPE SRF PED

7. Diagnosis Symptoms Depending on cause Usually no photopsia- no traction Floaters – if vitritis VF defect may develop suddenly and progress rapidly Detailed systemic history to find the etiology Examination Physical findings depending on the cause Fundus – RD convex configuration, surface smooth not corrugated Detached retina is very mobile and exhibits the phenomenon “shifting fluid” Other findings depending on cause History Investigations OCT B scan UBM FFA ICGA Ophthalmic imaging Hematological and serological tests Imaging XR CT MRI Microbiological tests and pathological tests

8. Diagnosis It is imperative to keep in mind that ERD may develop in association with a protean number of pathological conditions, ranging from isolated ocular to generalized systemic conditions. Diagnosis thus necessitates a road-map pathway through which information is collected by means of ocular and medical history, physical and ocular examination, and ancillary tests. On one hand, thorough medical and ocular history may help to reveal a possible link to an underlying systemic disease or on the other hand, ERD may be the presenting manifestation leading to the unfolding of the underlying etiology ( e.g , choroidal metastasis). Physical examination is essential to assess the extent and severity of systemic involvement (neurologic, cardio-respiratory, intestinal, genitourinary, articular, and cutaneous). A complete ophthalmic examination is the key step that allows the ophthalmologist to precisely document the ocular findings. Tailored work-up is then performed to confirm or rule-out possible diagnoses (e.g., serpiginous choroiditis, choroidal hemangioma, and so on). Ancillary ophthalmic imaging tests such as FA, Indocyaninegreen angiography, OCT, and echography may be selectively performed to better illustrate the involved structure and the extent of involvement and to monitor disease course. Systemic investigations (blood tests, X-rays, CT scan, and magnetic resonance imaging) are selectively performed. Ultimately, the collective information (by revealing specific as-sociations) leads to ascertaining the definitive diagnosis

9. Etiology of ERD Uveitic entities associated with ERD Non Uveitic entities associated with ERD Inflammatory conditions Infectious conditions Choroidal pathologies Retinal pathologies Miscellaneous Vogt- Koyangi -Harada Sympathetic ophthalmia Posterior scleritis Serpiginous choroiditis Behcet’s disease Relapsing polychondritis Intermediate uveitis Tuberculosis Syphilis Dengue Lyme disease CMV retinitis Nematode infestation Fungal infection Choroidal melanoma Choroidal osteoma Choroidal hemangioma Choroidal lymphoma Choroidal metastases Hematological malignancies Coat’s disease Vasoproliferative tumours Retinal astrocytic hamartoma Vitreoretinal lymphoma Familial exudative vitreoretinopathy Retinal vein occlusion Diabetic macular oedema Preeclampsia/eclampsia/HELLP HUS and TTP Idiopathic macular telengectasia Wet ARMD CSCR Uveal effusion syndrome Cavitatary optic disc anomalies Bilateral diffuse uveal melanocytic proliferation Acute paraneoplastic polymorpous vitelliform maculopathy

10. Etiology of ERD Uveitic entities associated with ERD Non Uveitic entities associated with ERD Infectious conditions Choroidal pathologies Retinal pathologies Miscellaneous Tuberculosis Syphilis Dengue Lyme disease CMV retinitis Nematode infestation Fungal infection Choroidal melanoma Choroidal osteoma Choroidal hemangioma Choroidal lymphoma Choroidal metastases Hematological malignancies Coat’s disease Vasoproliferative tumours Retinal astrocytic hamartoma Vitreoretinal lymphoma Familial exudative vitreoretinopathy Retinal vein occlusion Diabetic macular oedema Preeclampsia/eclampsia/HELLP HUS and TTP Idiopathic macular telengectasia Wet ARMD CSCR Uveal effusion syndrome Cavitatary optic disc anomalies Bilateral diffuse uveal melanocytic proliferation Acute paraneoplastic polymorpous vitelliform maculopathy Inflammatory conditions Vogt- Koyangi -Harada Sympathetic ophthalmia Posterior scleritis Serpiginous choroiditis Behcet’s disease Relapsing polychondritis Intermediate uveitis

11. Vogt- Koyangi -Harada ( VKH) Idiopathic multisystem autoimmune disease Predominantly affects females in their second to fifth decades of life and ethnic groups with more heavily pigmented skin. Severe bilateral granulomatous posterior or pan uveitis associated with ERD, disk edema, and vitritis , with eventual development of a sunset glow fundus. Multiple ERDs with diffuse choroiditis typically presenting as early manifestations. Marked choroidal thickening and delayed choriocapillaris filling with subsequent break down of RPE barrier integrity, leading to accumulation of serous material and finally to ERD.

12. Sympathetic ophthalmia Previously reported predominantly in males with biphasic peaks in children and the elderly because of the greater incidence of accidental trauma and ocular surgery, respectively. Nowadays, the incidence is increasing after surgery in females and in elderly patients. Bilateral granulomatous panuveitis consequent to ocular surgery or penetrating injuries. Multilobular ERD associated with yellow-white midperipheral sub-RPE nodules (Dalen-Fuchs nodules)

13. Bahcet’s disease Behcet's disease is a chronic, relapsing, multisystem, idiopathic inflammatory disorder characterized by a triad of oral ulcers, genital ulcers, and ocular lesions. However, the spectrum of disease is even wider with the involvement of articular, intestinal, vascular, urogenital, and neurologic systems, besides the mucocutaneous and ocular finding. Primarily affects young males , in the third or fourth decade of life. Strongly associated with HLA B 51 Diffuse vitritis , retinal infiltrates , sheathing of predominantly retinal veins, and occlusive vasculitis. ERD is a rare manifestation, reported in association with severe and hemorrhagic retinal vasculitis.

14. Serpiginous choroiditis Predominantly young to middle-aged males. HLA B7 ERD is rarely reported. Usually bilateral. Gray-yellow choroidal lesions in peripapillary/macular area with centrifugal extension. Progressive choroiditis leading to loss of choriocapillaris and atrophy of the overlying RPE with scarring.

15. Relapsing polychondritis Predominantly seen in middle-aged Caucasians, with no gender predilection. ERD is seen in association with posterior scleritis. Proptosis, eyelid edema, extraocular muscle palsy, episcleritis/scleritis, conjunctivitis, corneal infiltrates , peripheral ulcerative keratitis, corneal thinning and perforation, iridocyclitis, sclero uveitis, retinopathy, optic neuritis, and ERD. Chronic posterior scleritis causing multiple RPE defects and oBRB compromise.

16. Posterior scleritis Predominantly young to middle aged females Choroidal folds, optic disk edema, macular edema, annular ciliochoroidal detachment. ERD is frequent manifestation. Choroidal thickening, choroidal perfusion delay with resultant leakage points through the RPE.

17. Etiology of ERD Uveitic entities associated with ERD Non Uveitic entities associated with ERD Inflammatory conditions Infectious conditions Choroidal pathologies Retinal pathologies Miscellaneous Vogt- Koyangi -Harada Sympathetic ophthalmia Posterior scleritis Serpiginous choroiditis Behcet’s disease Relapsing polychondritis Intermediate uveitis Tuberculosis Syphilis Dengue Lyme disease CMV retinitis Nematode infestation Fungal infection Choroidal melanoma Choroidal osteoma Choroidal hemangioma Choroidal lymphoma Choroidal metastases Hematological malignancies Coat’s disease Vasoproliferative tumours Retinal astrocytic hamartoma Vitreoretinal lymphoma Familial exudative vitreoretinopathy Retinal vein occlusion Diabetic macular oedema Preeclampsia/eclampsia/HELLP HUS and TTP Idiopathic macular telengectasia Wet ARMD CSCR Uveal effusion syndrome Cavitatary optic disc anomalies Bilateral diffuse uveal melanocytic proliferation Acute paraneoplastic polymorpous vitelliform maculopathy

18. Tuberculosis Primarily an airborne infection that spreads from one person to another when a person with pulmonary or laryngeal tuberculosis coughs or sneezes, expelling droplets that contain Mycobacterium tuberculosis. Chalazion-like nodules, orbital granulomas, anterior, intermediate, posterior uveitis, and endophthalmitis. ERD-Usually in association with choroidal tubercles, tuberculomas, retinal vasculitis, or as part of paradoxical TB-associated immune reconstitution inflammatory syndrome. Treatment-Systemic steroids combined with anti tuberculous therapy.

19. Syphilis May be transmitted trans placentally to the fetus or acquired postnatally by sexual contact. Anterior, intermediate, posterior, or panuveitis , neuroretinitis , episcleritis/scleritis, keratitis. Described in association with punctate inner retinitis, chorioretinitis, panuveitis . Treatment-Parenteral penicillin is the drug of choice for ocular syphilis. Oral corticosteroids can be used to treat inflammatory complications.

20. Etiology of ERD Uveitic entities associated with ERD Non Uveitic entities associated with ERD Inflammatory conditions Infectious conditions Retinal pathologies Miscellaneous Vogt- Koyangi -Harada Sympathetic ophthalmia Posterior scleritis Serpiginous choroiditis Behcet’s disease Relapsing polychondritis Intermediate uveitis Tuberculosis Syphilis Dengue Lyme disease CMV retinitis Nematode infestation Fungal infection Coat’s disease Vasoproliferative tumours Retinal astrocytic hamartoma Vitreoretinal lymphoma Familial exudative vitreoretinopathy Retinal vein occlusion Diabetic macular oedema Preeclampsia/eclampsia/HELLP HUS and TTP Idiopathic macular telengectasia Wet ARMD CSCR Uveal effusion syndrome Cavitatary optic disc anomalies Bilateral diffuse uveal melanocytic proliferation Acute paraneoplastic polymorpous vitelliform maculopathy Choroidal melanoma Choroidal osteoma Choroidal hemangioma Choroidal lymphoma Choroidal metastases Hematological malignancies Choroidal pathologies

21. Choroidal melanoma Usually seen in Caucasians, in the sixth decade. Pigmented dome-shaped mass with median basal dimension of 11mm and thickness of 4.5mm Clinically detected in 75% of the iBRB and oBRB eyes, however, all eyes have microscopic SRF. ERD is a risk factor for tumor growth, metastasis, and tumor related death. ERD is due to increase permeability of both iBRB and oBRB . Proton beam radiotherapy, plaque brachytherapy, and stereotactic radiation therapy among others. Surgical drainage of SRF at time of irradiation was applied, also intravitreal TA and IVB.

22. Choroidal osteoma More in young female patients in their early twenties. Juxtapapillary , yellow-white to orange-red lesions. ERD due to multiple pinpoint leakage sites over the osteoma with gradual atrophy of the overlying RPE and Bruch's membrane, resulting in degenerated oBRB . ERD carries poor visual prognosis, more as a result of CNV. Treatment-IVB, FLT, spontaneous resolution of SRF also reported.

23. Choroidal hemangioma Circumscribed hemangioma presents at a mean age of 47 years. Diffuse hemangioma (part of Sturge-Weber syndrome) presents at a mean age of 8 years. Circumscribed tumors are discrete, round, orange-red, posterior to the equator near or temporal to optic disk with a pigmented rim. Diffuse tumors appear as diffuse red ("tomato-catsup) fundus appearance with choroidal thickening and increased tortuosity of retinal vessels. SRF was reported to occur in 81% of patients with circumscribed tumors. RPE alterations develop indicating degenerative changes with a resultant imbalance between accumulation and removal of SRF. PDT, laser, anti-VEGF therapy may be used for primary management of localized tumor. For patients with extensive ERD, they can be treated using radiotherapeutic modalities . For the diffuse tumor, EBR, proton beam therapy, brachytherapy, PDT, and anti-VEGF therapy.

24. Etiology of ERD Uveitic entities associated with ERD Non Uveitic entities associated with ERD Inflammatory conditions Infectious conditions Choroidal pathologies Retinal pathologies Miscellaneous Vogt- Koyangi -Harada Sympathetic ophthalmia Posterior scleritis Serpiginous choroiditis Behcet’s disease Relapsing polychondritis Intermediate uveitis Tuberculosis Syphilis Dengue Lyme disease CMV retinitis Nematode infestation Fungal infection Choroidal melanoma Choroidal osteoma Choroidal hemangioma Choroidal lymphoma Choroidal metastases Hematological malignancies Coat’s disease Vasoproliferative tumours Retinal astrocytic hamartoma Vitreoretinal lymphoma Familial exudative vitreoretinopathy Retinal vein occlusion Diabetic macular oedema Preeclampsia/eclampsia/HELLP HUS and TTP Idiopathic macular telengectasia Wet ARMD CSCR Uveal effusion syndrome Cavitatary optic disc anomalies Bilateral diffuse uveal melanocytic proliferation Acute paraneoplastic polymorpous vitelliform maculopathy

25. Coat’s disease Coats' disease is retinal telangiectasia within the macula and periphery vessels and secondary resulting in subretinal accumulations of exudates, forming yellow white mounds with superficial crystalline deposits if long standing, commonly occurs in temporal macula and mid periphery. Male predominance with a mean age at diagnosis of 5 years ERD is due to chronic low level of leakage from the telangiectatic retinal vessels. ERD extent increases as the vascular and exudative components of the disorder proceed, until a total ERD overlying a yellow-green subretinal mass results. Treatment – Observation, Laser, cryotherapy, Surgery if RD.

26. Vasoproliferative tumors Primary VPTs more in females, with a mean age of 44 years at presentation. Secondary VPTs have a younger mean age at presentation. Yellow-red, often ill-defined retinal-based mass, far-peripheral, inferotemporal location with exudates and ERD. Primary VPTs tend to be solitary, small, and between the globe equator and oraserrata . Secondary VPTs are more often multifocal and bilateral. ERD- similar to coat’s disease.

27. Retinal astrocytic hamartoma Classically seen in association with tuberoussclerosis complex (50% of cases) Small, sessile noncalcified lesion in the nerve fiber layer, or a multinodular yellow white calcified lesion, or as a combination of 2. Initially iBRB is involved however with progressive growth and retinal destruction also oBRB may be damaged. ERD consists of yellow, lipoproteinaceous exudation in the sensory retina and subretinal space, with spontaneous resolution of SRF usually within 4 weeks. If ERD persists more than 6 weeks , treatment should be considered. Laser, PDT, IVB

28. Diabetic macular oedema Risk factors for developing DME glycemic blood pressure control, duration of DM, lipid metabolism, presence of nephropathy, obesity, genetic factors, nutrition, and pregnancy. Thickening and cystoid oedema of the macula often with hard exudates. ERD has been described in15%-30% of patients with DME. ERD occurs due to transient migration of fluid from the cystoid spaces in the retina to the subretinal space, another theory is that it occurs subsequent to failure of the RPE pump mechanism. Treatment- FLT, Anti VEGF

29. Retinal vein occlusion Associated with increasing age, high blood pressure, diabetes, glaucoma and various disorders of the blood. Engorgement and dilatation of the retinal veins, commonly associated with intraretinal hemorrhage ,retinal oedema , CWS, exudates and ME. ERD was described in association with all types of RVO and was found to correlate with the extent of retinal non perfusion. Extensive leakage from capillaries affected by RVO may migrate to the subretinal space, resulting in ERD. IV steroid and anti VEGF, Laser.

30. ARMD It is the leading cause of irreversible blindness in adults over 50 years of age. The hallmark of neovascular AMD is the development of CNV characterized by fluid exudation, RPE detachment, hemorrhage and scarring. ERD has been reported in70%-85% of patients, described in association with all lesion types. ERD due to RPE damage and oBRB dysfunction, with subsequent disruption of the ELM-photoreceptor complex by invasion and proliferation of the CNV. Treatment- IV anti VEGF

31. Vitreoretinal lymphoma Familial exudative vitreoretinopathy Preeclampsia/eclampsia/HELLP HUS and TTP

32. Central serous chorioretinopathy CSCR primary affects men in their 3 rd and 4 th decades ERD and or RPE detachment , changes most often confined to the macula. Hyperpermeable choroidal vessels are thought to produce increased tissue hydrostatic pressure , which promotes the formation of RPE detachment (PEDs), overwhelms the barrier function of the RPE and leads to areas of fluid accumulation between the retina and RPE. FLT and low fluence PDT Epilerenone - a mineralocorticoid receptor antagonist is being investigated

33. Treatment Medical treatments Interventional therapy Corticosteroids and immunomodulatory therapy Biologic therapy IV Anti VEGF Other FLT Cryotherapy Low dose plaque radiotherapy PDT

34. Corticosteroids and immune modulatory therapy The most commonly used approach for the treatment of ERD in noninfectious uveitis such as in VKH syndrome is high-dose systemic corticosteroids (IV 1 g/day or prednisone 1 mg/kg/day) followed by oral steroids in tapered doses. Slow steroid taper is important because treatment of less than 6-month duration is associated with recurrences of ERD. ERD may rarely recur despite prolonged therapy or may be unresponsive to treatment in some cases. Different immunosuppressive and biological agents have been used in these refractory cases and also as steroid-sparing due to long-term steroid use These agents included cyclosporine A, azathioprine, methotrexate, mycophenolate, nofetil , and infliximab. Andrade and colleagues successfully used intravitreal triamcinolone acetonide in the treatment of the acute phase of VKH with marked decrease in the extent of ERD in the first week after the injection and subsequent return to normal retinal thickness in all eyes.

35. Biologic therapy The main groups of biologic agents include TNF alpha inhibitors(etanercept, infliximab, and adalimumab), interferon alpha-2,interferon-beta, specific cell inhibitors (rituximab and daclizu-mab ), receptors antagonists (anakinra and efalizumab).Infliximab, a chimeric (immunoglobulin G1-1gG1) mono-clonal antibody containing human and murine portions targeting TNF-a, has been shown to be an effective immunosuppressant for the treatment of refractory non infectious uveitis in adults and children There is a growing body of evidence indicating that infliximab may be a successful alternative especially for cases of refractory VKH unresponsive to conventional therapy.

36. Intravitreal anti vascular endothelial growth factor Anti-VEGF therapy, owing to its anti angiogenic and anti permeability properties, has been used in the management of conditions characterized by associated SRF exudation. For example, IVB, a recombinant humanized monoclonal anti-VEGF antibody, has been reported to be effective in CSC patients with duration over 3 months. In acute CSC of 3 months of symptom duration, IVB may not be of therapeutic benefits compared with observation because of the spontaneous resolution. In DME, ARMD, CRVO the benefit of anti VEGF to reduce SRF is proven with many studies.

37. Eplerenone Eplerenone - a mineralocorticoid receptor antagonist, has been explared as a treatment option for chronic CSC given the increasing evidence of overstimulation of the mineralocorticoid- receptor in choroidal endothelial cells, inducing vasodilatation, hyperpermeability, and accumulation of SRF. Bousquet and colleagues and Singh and colleagues reported that-following therapy, there was a significant reduction in SRF and improved VA thus suggest in have a role in selected cases with unresolved CSC. Cakir and colleagues reported in the largest treated with eplerenone that 29 % of patients with chronic CSC demonstrated complete resolution of SRF with oral administration of eplerenone. Improvement in VA was more likely among patients with subtle RPE changes and an intact ellipsoid zone than those with chronic atrophic CSC and widespread RPE atrophy at baseline.

38. Treatment Medical treatments Interventional therapy Corticosteroids and immunomodulatory therapy Biologic therapy IV Anti VEGF Other FLT Cryotherapy Low dose plaque radiotherapy PDT

39. Focal laser photocoagulation(FLT) Focal laser photocoagulation(FLT) for example, delivered to the leakage site is one of the treatment options in CSC. This treatment attempts to produce a "sealing" of the RPE defect as identified through FA. An additional effect is promoting the pump function of the RPE through stimulation of adjacent RPE cells. Although patients receiving laser treatment showed a faster flattening of the ERD, laser treatment appeared less effective in achieving improvement in VA or reducing new episodes of active CSC. Laser application in a subthreshold setting (micro pulse diode laser photocoagulation [810 nm]) was also explored in acute and chronic CSC.

40. Cryotherapy and low-dose plaque radiotherapy Cryotherapy and low-dose plaque radiotherapy were used in the treatment of peripheral retinal elevations in parsplanitis associated with telangiectatic vessel leakage. Regression of the former peripheral pathologies and absorption of the hard exudates with resolution of the retinal elevation was reported in 4 of 5 eyes by Pollack and colleague .

41. PDT PDT with verteporfin in the treatment of CSC is believed to act on the pathogenic mechanism leading to choroidal vascular hyperpermeability. PDT is suggested to have a possible direct action on the choriocapillaris endothelium leading to choriocapillaris occlusion, achieving both blood flow stasis and reduction of vascular permeability. Promising results were reported in several publications.

42. Prognosis As ERD is associated with a wide spectrum of underlying pathologies, its prognosis is determined by the prognosis of that specific condition. Illnesses that are generally self-limited such as ERD in preeclampsia and pregnancy-associated CSC have excellent visual prognosis, whereas conditions leading to irreversible loss of tissue, such as CMV retinitis or Behcet uveitis, may have dismal visual outcomes.

43. Conclusions ERD may develop as a consequence to any pathological condition that violates the integrity-of the inner or the outer BRB. It is therefore encountered in the setting of conditions that affect the retinal vasculature and conditions which primarily affect the choriocapillaris, RPE, outer retinal complex. Insight into the pathogenesis of each of those pathological conditions may allow better understanding of the cellular and molecular mechanisms involved and may thus enable ophthalmologists to implement local and systemic therapies that modulate the course of those sight-threatening diseases. Prompt diagnosis and institution of appropriate therapy is indispensable for reducing the risk of ophthalmic complications. Future research in regenerative medicine may attempt to change the course and outcome of chronic diseases through the possibilities of engineering damaged tissues via stimulating the body's own repair mechanisms or by growing tissues in the laboratory and safely implanting them when the body cannot heal itself. This may hold promise for limiting potential visual morbidity in pathological conditions associated with ocular blood barrier functional and structural deficits.

44. Thank you!