Ординатура / Офтальмология / Учебные материалы / Uveitis Text and Imaging Text and Imaging Text and Imaging 2009

Figure 11: Anterior segment photograph R/E showing nongranulomatous inflammation with fibrin and exudates in the pupillary area

Figure 12: Ultrasound B scan showed a mass lesion of mixed echogencity with a central hyperdense echo

foamy macrophages (Figure 13), that confirmed the diagnosis of phacoantigenic uveitis due to spontaneous dislocation of the crystalline lens into the vitreous cavity.

Patient underwent pars plana lensectomy and vitrectomy with good outcome (Figure 14).

Case # 4

A 12-year-old boy was seen with complaints of decreased vision in his right eye of 6- month duration. Fundus showed a yellowish-white granuloma over the optic disc with a fibrous band extending from the disc to the retinal periphery (Figure 15).

Figure 13: Diagnostic vitreous specimen showing large foamy macrophages with abundant vacuolated cytoplasm and reniform nuclei, along with a few neutrophils, lymphocytes and RBCs (PAP, x400)

Figure 14: Anterior segment photograph R/E after pars plana vitrectomy showing resolution of inflammation with aphakia

Figure 15: Fundus photograph R/E shows an upper nasal fibrous band from the optic disc

Figure 16: Many eosinophils showing granular eosinophilic cytoplasm and bi-lobed nuclei with occasional macrophages (MGG, x400)

Patient was clinically diagnosed as toxocariasis. Vitreous humour obtained during pars plana vitrectomy showed the presence of eosinophils (Figure 16).

Case # 5

A 12-year-old female child with juvenile rheumatoid arthritis had a visual acuity of hand motions in the right eye with seclusio pupillae and complicated cataract (Figure 17). Ultrasound B scan showed optic disc swelling with no retinal detachment.

Ultrasound biomicroscopy of the same eye showed ciliary body detachment with a tractional cyclitic

Figure 17: Anterior segment photograph right eye showing seclusio pupillae and complicated cataract with patches of iris atrophy

Figure 18: Ultrasound biomicroscopy of the right eye showing ciliary body detachment with a tractional cyclitic membrane (arrow)

membrane (Figure 18). The transverse scan through the ciliary body did not show any atrophy of the ciliary processes.

Patient underwent right eye pars plana lensectomy and vitrectomy followed by posterior subtenon injection of triamcinolone acetonide. Two weeks postoperatively, her visual acuity improved to 20/60 and fundus showed optic disc oedema with hypotonic maculopathy (Figures 19A and B). Her intraocular pressure improved to 12 mm Hg and was maintained over the next 18month follow-up.

Case # 6

A 28-year-old woman was seen with chronic anterior uveitis resulting in bilateral complicated cataract and hypotony. Her visual acuity in the right eye was hand motions close to face with an intraocular pressure of 5 mm Hg. She had complicated cataract with seclusio pupillae in the right eye (Figure 20).

Ultrasound biomicroscopy of the right eye showed cyclitic membrane in less than 180 degree with normal ciliary body in the rest of the eye (Figures 21 A and B). She was on systemic immunosuppressive therapy.

She underwent right eye pars plana lensectomy and vitrectomy with removal of cyclitic membrane. On over 3-year follow up, she maintains a visual acuity

Figure 22: Shows a clear media, well preserved foveal reflex and the optic disc

of 20/80 with intraocular pressure of 12 mm Hg (Figure 22).

KEY POINTS

1.Pars plana vitrectomy in uveitis maybe indicated for diagnostic or therapeutic reasons or both.

2.A clear plan and ready laboratories is the key to positive diagnostic yield.

3.Preoperative ultrasonography and ultrasound biomicroscopy help in prognosticating the outcome of surgery to some extent.

4.Eye having both cataract and cyclitic membrane is better managed with pars plana lensectomy and vitrectomy rather than phacoemulsification.

5.The inflammation should be adequately controlled prior to surgery in eyes undergoing elective therapeutic intervention.

REFERENCES

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2.Margolis R, Brasil OF, Lowder CY, et al. Vitrectomy for the diagnosis and management of Uveitis of unknown cause. Ophthalmology 2007;114:1893-7.

3.Ausburger J. Invasive diagnostic techniques for uveitis and simulating conditions. Trans Am Ophthalmol Soc 1990; 88:89-104.

4.Forster R, Abbott R, Gelender H. Management of infectious endophthalmitis. Ophthalmology 1980;87:313-9.

5.Verbraeken H. Diagnostic vitrectomy and chronic uveitis. Graefes Arch Clin Exp Ophthalmol 1996;234(S):2-7.

6.Bovey EH, Herbort CP. Vitrectomy in the management of uveitis. Ocul Immunol Inflamm 2000;8:285-91.

7.Savitri S, Subhadra J, Muralidhar V, et al. Sensitivity and predictability of vitreous cytology, biopsy and membrane filter culture in endophthalmitis. Retina 1996;16:525-9.

8.Davis JL, Solomon D, Nussenblatt RB, et al. Immunocytochemical staining of vitreous cells. Indications, techniques and results. Ophthalmology 1992;99:250-6.

9.Chevez-Barrios P. Immunohistochemistry in ophthalmic pathologic diagnosis. Adv Clin Ophthalmol 1994;1:141-78.

10.Witmer R. Clinical implications of aqueous humor studies in uveitis. Am J Ophthalmol 1978;86:39-44.

11.de Boer JH, Verhagen C, Bruinenberg M, et al. Serologic and polymerase chain reaction analysis of intraocular fluids in the diagnosis of infectious uveitis. Am J Ophthalmol 1996;121:650-8.

12.Hirakata A, Inami T, Saito M, et al. Diagnostic value of interleukin-10 and interleukin-6 in the vitreous of intraocular malignant lymphoma patients. Nippon Ganka Gakkai Zasshi 2004;108:359-67.

13.Becker M, Davis J. Vitrectomy in the treatment of uveitis. Am J Ophthalmol 2005;140:1096-105.

14.Wiechens B, Nolle B, Reichelt JA. Pars plana vitrectomy in cystoid macular edema associated with intermediate uveitis. Grafes Arch Clin Exp Ophthalmol 2001;239:47481.

15.Stavrou P, Baltatzis S, Letko E, et al. Pars plana vitrectomy in patients with intermediate uveitis. Ocul Immunol Inflamm 2001;9:141-51.

16.Tranos P, Scott R, Zambarakji H, et al. The effect of pars plana vitrectomy on cystoid macular oedema associated with chronic uveitis: a randomized, controlled pilot study. Br J Ophthalmol 2006;90:1107-10.

17.Ieki Y, Kiryu J, Kita M, et al. Pars plana vitrectomy for vitreous opacity associated with ocular sarcoidosis resistant to medical treatment. Ocular Immunol Inflamm 2004;12:35-43.

18.Kiryu J, Kita M, Tanabe T, et al. Pars plana vitrectomy for epiretinal membrane associated with sarcoidosis. Jpn J Ophthalmol 2003;47:479-83.

19.Dev S, Mieler WF, Pulido JS, Mitra RA. Visual outcomes after pars plana vitrectomy for epiretinal membranes associated with pars planitis. Ophthalmol 1999;106:108690.

20.Heiligenhaus A, Bornfeld N, Wessing A. long-term results of pars plana vitrectomy in the management of intermediate uveitis. Curr Opin Ophthalmol 1996;7:77-9.

21.Androudi S, Ahmed M, Fiore T, et al. Combined pars plana vitrectomy and phacoemulsification to restore visual acuity in patients with chronic uveitis. J Cataract Refract Surg 2005;31:472-8.

22.O’Connell SR, Majji AB, Humayun MS, deJuan E Jr. The surgical management of hypotony. Ophthalmology 2000; 107:318-23.

23.deSmet MD, Gunning F, Feenstra R. The surgical management of chronic hypotony due to uveitis. Eye 2005;19:60- 4.

24.Yu EN, Paredes I, Foster CS Surgery for hypotony in patients with juvenile idiopathic arthritis-associated uveitis. Ocular Immunol Inflamm 2007;15:11-7.

INTRODUCTION

Choroidal neovascularization (CNV) is one of the many causes of visual impairment in patients with uveitis. Many diseases, disrupting the homeostasis between the retinal pigment epithelium (RPE) and Bruch’s membrane, can create the conditions for the choroidal neo-angiogenesis. Both non-infectious and infectious uveitis can have CNV as a possible complication.

Infectious uveitis is provoked by infective agents that directly affect the choroid and/or the retina whereas non infectious uveitis (endogenous uveitis) is a group of diseases where the cause is likely to be autoimmune with no evidence of a direct infectious origin. Toxoplasmosis,1 Toxocara canis,2 Tuberculosis,3 viral retinopathies,4 presumed ocular histoplasmosis syndrome, a choroiditis associated with a positive histoplasmin skin test and thought to be caused by Histoplasma capsulatum, as well as other infectious uveitides have been described as possible triggers for the choroidal neoangiogenesis.

Several non-infectious uveitis have been associated with CNV including punctate inner choroidopathy (PIC), multifocal choroidits (MFC), acute posterior multifocal placoid pigment epitheliopathy (APMPPE) and Vogt-Koyanagi-Harada disease presenting CNV as a possible severe complication. The probable common denominator predisposing these cases to the development of CNV is the formation of chorioretinal scars.

ANATOMOPHYSIOLOGY

The choroid5 is the vascular compartment situated between the retina internally and the shell of the eye, the sclera externally.

The choroid can be divided into following different layers:

1.Haller’s layer: Outer layer composed by large vessels

2.Sattler’s layer, situated more internally and providing the distribution of the blood into the choriocapillaris over the extent of the choroid. Together these two layers form what is clinically called the choroidal stroma

3.The choriocapillaris is the capillary system of the choroid (Figure 1) and is composed of tightly packed capillaris with large fenestrations through which large sized molecules and fluid leak freely creating a quasi lake of extravascular fluid. The main role of the choriocapillaris is to provide oxygen, micronutrients, ions and water to the pigment epithelium and the outer retina. In case of choriocapillaris non perfusion the RPE and the outer retina are suffering metabolic stress and hypoxemia with mild to severe consequences on visual function. If the ischemia of the outer retina is widespread and confluent, compensatory permeability increase of retinal vessels of the inner retina causes leakage and sometimes massive intraretinal pooling such as in APMPPE seen on fluorescein angiography.

Figure 1: Schematic representation of chroidal vessels: note the tight structure of the choroid and the connections with arteries and veins

Figure 2: Thickness variation between the posterior pole and the ora serrata: the choroid has a maximal thickness in the posterior pole, where it is 0,22 mm thick, and it becomes thinner anteriorly, down to 0,1 mm thick

The thickness of the choroid is variable depending on location, being maximal (0.22 mm) in the posterior pole, with thickness reduced to 0.1 mm at the ora serata (Figure 2).

The architecture of the choriocapillaris also depends on the topography (Figure 2): In the posterior

pole vessels are arranged in anatomical units called lobules. Arterial blood reaches the lobule in the centre and then circulates centripetally towards the edge of the lobule with drainage from there into the venous system.

In the periphery the bundles of capillaries become less tight and their arrangement takes a radial pattern.

The physiologic particularity of the choroid is its hemodynamic characteristics, being the vascular structure with the highest blood flow in the body. Therefore the venous blood is only slightly less saturated in oxygen than the arterial PO2.

Connective tissue, melanocytes and cells of the immune system are interspersed between the vessels of the choroidal stroma.

The distribution of cells belonging to the immune system in the choroidal spaces may be a factor contributing to the pathophysiology of CNV. Several cells act to disrupt the immunological homeostasis in the retina during the neovascular process. Moreover, in recent years the role of immunology has increasingly been recognised as playing an important role in abnormal angiogenesis including neoangiogenesis in age related macular degeneration (AMD).

PATHOPHYSIOLOGY OF CHOROIDAL NEOVASCULARIZATION

HISTORY

Angiogenesis is a crucial event in several situations including tissue repair, tumors and inflammation. It can be beneficial such as in tissue repair, but it can also be detrimental such as in inflammation

The so-called “X-factor” is the miliary stone of CNV pathophysiology. Between 1948 and 1957, both Michaelson6 as well as Ashton and Wise theorised the existence of a molecule with proangiogenic and propermebility properties.

In 1971, Folkman put forward the concept that in tumor angiogenesis, the neoplasm constantly produced what he called a “tumor angiogenesis factor”.7

Ten years later, Dvorak8 proved the secretion by tumors of a propermeability factor that he named: “vascular permeability factor (VEP)”. The name of vascular endothelium growth factor (VEGF) was introduced by Leung in 19869 and Napoleone Ferrara identified and cloned this molecule.10

This name, “Vascular endothelial growth factor (VEGF)” is now universally accepted and recognized to identify the most important proangiogenic agent in neovascular process. VEGF is a potent neoangiogenesis inducer and, probably, the most effective agent on vascular permeability10 VEGF has naturally also physiological properties being essential for normal fetal growth. It is also considered a survival factor in certain emergencies, such as in stroke and other vasculopathies.

The pathways involved in the neoangiogenesis are still imperfectly known but thought to be due to an imbalance of the local cell biology.

NEOVASCULARIZATION: GENERAL CONCEPTS

The balance between physiological and pathological pro-angiogenic factors is determined by the equibrium of inhibitory and stimulating agents of cell proliferation.

Neoangiogenesis is thought to be the result of an imbalance between inhibitory11 and stimulatory activities12 of different chemical messengers produced in vivo by the RPE, leading to a “vicious circle”.13

Inflammatory factors are assuming a pivotal role for the pathophysiology of CNV not only for inflammation derived neovessels but also for the neovascular process in AMD and the so-called idiopathic neovessels.13

In the group of CNV related to inflammatory intraocular diseases, neoangiogenesis can occur in absence of evident inflammatory activity or can be the late complication of chronic low-grade inflammation. This concept has been proven in animal models, including posterior experimental uveitis (PEU) which features CNV as a late sequela.14

Moreover, the inflammation can be subtle and choroidal lesions can be often not detectable15,16 (Figure 3).

Surgically removed (inflammatory) CNVs have shown on histological examination the presence of inflammatory cells, such as macrophages and lymphocytes in a higher proportion as seen in AMD.17

Unfortunately, there is lack of histological studies on inflammatory CNV in humans as surgical removal is becoming less frequent with the development of efficient non surgical treatments of CNV. The use of animal models contributed however some information

Figure 3: Chroidal neovascularization (black arrow), generating close to the edge of an active granuloma (white arrow)

on the role of cells and biological mediators in CNV pathogenesis. They showed that the macrophage recruitment to the choroid seems to be central in CNV pathogenesis: Espinosa-Heidmann et al18 conducted a study to determine whether treatment with clodronate liposomes (CL2MDP-lip), which cause depletion of blood monocytes and lymph node macrophages, diminishes the severity of neovascularization in a mouse model of laser-induced CNV. Recently, Joust et al19 proved the crucial role of plasminogen activator inhibitor-1 (PAI-1) in the neoangiogenesis: the authors stated that an adequate balance between serine proteases and their PAI-1 is critical for pathological angiogenesis. Anyway, the large number of pathways involved in the CNV pathogenesis and the peculiarity of the immune system of the eye, make this process difficult to be understood.

CHOROIDAL NEOVASCULARISATION: PATHOLOGY

As new choroidal blood vessels grow, they may extend into the sub-RPE space (Figure 4A, Gass type 1) or into the subretinal space (Figure 4B, Gass type 2).20 The location, growth pattern, and type (1 or 2) of CNV depend on the patient’s age and the underlying disease. Bleeding and exudation occur with further growth, accounting for the visual symptoms.

The CNV occurring in patients with inflammatory diseases are generally classified as Type 2 neovascular membranes, which will determine the type of

Figure 4: Schematic representation of Gass type 1 choroidal new vessels (A), and Gass type 2 choroidal new vessels (B)

therapeutic approach best suited as discussed in the following paragraphs of this chapter.

INFECTIOUS UVEITIS

BACTERIA

Choroidal neovascularization can be a rare sequela of bacterial infectious choroiditis. Few cases have been reported indicating that focal choroiditis can lead to a local disruption of the blood retinal barrier, inducing the release of proangiogenic mediators triggering neoangiogenesis.

Several conditions can induce a bacterial metastasis, such as endocarditis, aortic valve infection, renal and bone abscess and intravenous drug abuse.

CNVs occurring in bacterial choroiditis generally are classic membranes which grow close to the primary chorioretinal lesion, or in neighbouring area of an old atrophic scar.

Infective embolic choroidopathy can be associated with the occurrence of CNV such as Staphylococcus aureus endocarditis of the aortic valve;21 renal abscess22 and intravenous drug use23 can be another possible via to the choroid for metastasis of septic emboli. One of the most ubiquitous bacteria is mycobacterium tuberculosis. It is often misdiagnosed and under-

estimated24-28 and its miliary form especially can be associated with CNV.29, 30

Fluorescein angiography (FA) can be useful in detecting and in evaluating the bacterial originated CNV activity, but no particular pattern has ben established. So far no indocyanine green angiography (ICGA) studies and optical coherence tomography (OCT) descriptions are available.

The treatment is based on the association of systemic drugs and other techniques, such as argon laser photocoagulation, photodynamic treatment (PDT), surgical removal and intravitreal anti-VEGF drugs; no trials and/or case series are available in the literature, and the clinical rationale only should be followed.

VIRUSES

CNV has been reported as an infrequent complication of viral retinopathies. Viral diseases as any condition that affects the RPE, Bruch’s membrane, or the choroid may be the trigger of choroidal neoangiogenesis. Viruses, such as rubella or West Nile virus can have CNV mostly as a late complication.

Rubella has been the first reported viral infection associated with CNV (Figures 5A-D). The first description in 1978, by Frank and Purnell,31 reported two patients affected by congenital rubella retinopathy with congenital deafness, which developed unilateral subretinal neovascularisation, hemorrhage, and scarring. Other reports described the same pattern few years later.32-35

Another virus, recently associated with CNV, is the West Nile virus. In 2006, Khairallah et al36 reported, for the first time, the case of a 60-year-old man with diabetes mellitus, who had a sudden decrease in vision in his right eye; 3 weeks after, West Nile virus infection was confirmed. Dense retinal haemorrhages and retinal arterial sheathing in the macula of the right eye were observed. FA proved an extensive ischemic capillaropathy in the macula and few months later a choroidal neovascularization developed near a chorioretinal scar. One year later, in 2007, Seth et al37 described the case of a 86-year-old man who, 5 years later, developed a CNV, that was successfully treated with intravitreal injection of bevacizumab.

PROTOZOA

Although several protozoa can affect the retina, such as Trypanosoma cruzi,38 Trypanosoma evansi,39 Leishmania,40 Pneumocystis carinii,41 Toxoplasma gondii1 is the protozoan that most commonly affects the eye and is the only one that has been associated with CNV.

Toxoplasma gondii belongs to the genus Toxoplasma and is an endocellular parasite in humans. The diffusion of the parasite is cosmopolitan. Ocular toxoplasmosis is the most common posterior uveitis

in the World42-43 and in some areas its prevalence in patients with posterior uveitis can be around 80 percent.44

Congenitally acquired toxoplasmosis was until recently thought to make up for the majority of toxoplasmic retinochoroiditis. It is however now accepted that in most cases toxoplasmic retinochoroidits results from acquired disease.45-46

Association between toxoplasmic retinochoroiditis and CNV is frequent and very well known.1 CNV is typically growing close to the border of an old atrophic

Figure 6: Color picture showing an active choroidal neovascular membrane surrounded by fresh blood (white arrow) growing close to the edge of an old atrophic scar (white arrowhead). The patient had positive serum IgG titres for toxoplasmosis

scar (Figure 6) although CNV and active toxoplasmic retinochoroiditis can occasionally be synchronous (Figure 7).The prevalence of CNV in ocular toxoplasmosis is estimated between 0.3 percent and 19 percent.48-50 It represents a severe complication of ocular toxoplasmosis potentially causing sudden loss of vision as it occurs often in the macular area.

The patient complains of a decrease in visual acuity, of metamorphopsia and of a grey scotoma the intensity of which depends on the amount of fluid and on the haemorrhagic component. The haemorrhage generally tends to surround the CNV (Figure 8).

Fluorescein angiography is useful for the diagnosis of CNV, especially to distinguish it from reactivation of retinochoroiditis. In the latter situation the lesion is first hypofluorescent and becomes progressively hyperfluorescent through leakage and pooling in the