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

detect the bacterial genome in vitreous fluid and was found in statistically significant numbers in Eales’ patients [19]. Statistically significant presence of M. tuberculosis DNA in the epiretinal membranes of Eales’ patients was demonstrated, compared to the controls by nested PCR (nPCR) using primers for gene coding for MPB 64 protein of M. tuberculosis

25 III [21, 22]. Conversely the ocular morbidity pattern in 2,010 eyes of patients with active systemic TB was studied prospectively, and was found only in 1.39 %. The commonest finding was bilateral healed focal choroiditis (50 %). Significantly, none of the patients in this series had Eales’ disease [3].

Some studies have drawn attention to the role of oxidative stress, also referred to as free radical induced damage. Biochemical studies show that protein carbonyl group content increases with severity of Eales’ disease. This increase is correlated to decreased antioxidant status [30]. This fact has been corroborated by other studies, including those showing monocyte activation (MC) resulting in oxidant thrust and subsequent tissue damage. More studies need to place in perspective the role of antioxidant supplementation in Eales’. For now the etiology can be considered multifactorial [8].

25.1.10 Management

25.1.10.1 Fundus Fluorescein Angiography

Fundus fluorescein angiography (FFA) is recommended in Eales’ disease to understand the actual extent of involvement, which is often more than the clinical picture. It is advised to examine patients with Eales’ disease with an indirect ophthalmoscope after performing the FA. A good idea is obtained by using high end indirect ophthalmoscopes with blue colored interference filters. Some of these areas are difficult to visualize with a fundus camera. During the active phase of phlebitis, staining of the walls of the vein with dye and some leakage may be observed. Narrowing of the lumen is also noted in some cases. Areas of capillary non-perfusion are seen peripheral to the area of periphlebitis. Fortunately macular ischemia occurs only rarely. Since retinal hemorrhages are often seen in the vicinity of involved vessels, blocked fluorescence may be observed. Collateral channels are often seen. The margin of the perfused and non-perfused areas is usually characterized by the presence of stunted vessels, aneurysms and development of new vessels. The characteristic sea fans typically occur at this junction [24, 36].

25.1.10.2 Medical Treatment

Inflammatory vasculitis is the first step toward a chain of events that progress from vessel closure, to ischemia and subsequent neovascularization. Corticosteroids have been advocated during the phase of inflammation (active periphlebitis) to minimize and reverse the damage. Systemic steroids up to 2 mg/kg of prednisolone have been advocated in the active phase. It is advisable to give some time for the steroids to control the inflammatory component prior to starting retinal laser photocoagulation, where indicated. Needless to say, they have to be used keeping in mind their side effects and ruling out any systemic infection. These can be tapered over 6 – 8 weeks. Subtenon injections of triamcinolone have also been used in a dose of 0.5 – 1 ml (40 mg/ml). This route reduces the risk of systemic toxicity. Use of long-acting depot steroids poses problems in steroid responders and care is needed while administering this injection especially in high myopes. The use of antimetabolites has been reported in one eyed patients and in central disease. Low dose oral methotrexate pulse therapy (at a dose of 12.5 mg/week) for 12 weeks has been reported recently but needs more evaluation [2].

The use of antituberculous drugs in the absence of systemic tuberculosis is one of the controversies in the management of Eales’ disease. A decade ago it was widespread. The treatment recommended is isoniazid (INH) 300 mg and rifampicin (RIF) 450 mg for a period of 9 months. Its indication for use today is restricted to patients with extensive exudative sheathing, nodule formation or a strongly positive Mantoux test (with induration and ulceration) in the presence of Eales’ disease [10].

25.1.10.3 Role of Laser Treatment

The rationale for retinal laser is that regression of existing neovascularization can be achieved by scatter treatment of the ischemic retina. Prophylactic laser treatment to severely ischemic areas documented on FFA can prevent the development of new vessels [18]. Since photocoagulation has to be performed in the far periphery, delivery systems other than the slit lamp like the laser indirect ophthalmoscope are a useful option. In patients where some amount of hemorrhage obscures the view, transscleral diopexy or anterior retinal cryopexy can be used [29]. Laser treatment may be performed focally in areas of ischemia where the disease is localized (Fig. 25.1.13a–c). Panretinal photocoagulation may be performed in the presence of NVD or when extensive areas of ischemia exist (Fig. 25.1.14a, b). Retinal laser has also been used to perform “anchoring treat-

Fig. 25.1.13. a Spider shaped NVE just outside the superotemporal arcades. b FA showing leakage from the NVE. c Retinal laser treatment of the involved area (1 month post-treatment)

ment” (Fig. 25.1.15a, b). This is done by placing a barrage of laser at the base of the fibrovascular traction band. This helps to prevent the development of a combined retinal detachment should the band contract causing a retinal tear. It is important to do anchoring treatment prior to doing a scatter in such eyes, as regression is often associated with contraction of the fibrovascular bands [29]. Six monthly fol- low-up is advised to the patient as retinal non-perfu- sion may be progressive in this condition; hence new areas of neovascularization may develop which will require supplemental treatment. The patient is advised to report earlier if any new visual symptoms are noted.

25.1.10.4 Vitreoretinal Surgery

Pars plana vitrectomy has an important role to play in the presence of media opacities or abnormal vitre-

a

c

oretinal relationships. Surgical anatomy of the vitreoretinal interface in Eales’ disease has been studied [1]. Fibrous and fibrovascular proliferations have multiple areas of adhesions to the posterior vitreous cortex. The presence of type II collagen in

b

the ERM indicates a possible vitreous collagen component to the double layered membranes (vitreoschisis). Recognition of this double layered membranes aids in relief of traction during surgery by delamination. Also noteworthy of this condition is the fact that the hemorrhages are predominantly intragel.

Indications for surgery are the same as in other conditions: non-resolving vitreous hemorrhage, traction retinal detachment threatening the macula and combined retinal detachment. The recommended waiting period for the vitreous hemorrhage to clear spontaneously has reduced from 6 months previously to 6 – 8 weeks today. This is attributed to the higher safety margin of the vitrectomy procedure and to the fact that delay in dealing with the neovascularization causes progressive worsening.

Vitrectomy permits vitreous clearance, removal of the vitreous scaffolding and traction, and an

opportunity to perform endolaser. Often, a large part of the inferior retina is otherwise not amenable to laser treatment, due to residual vitreous hemorrhage. Most vitrectomies except in long-standing disease are of a lower relative degree of difficulty. Wide angle fundus viewing systems permit a complete vitreous clearance with excellent visualization of the periphery – an asset in these cases. Endolaser is mandatory for these vitrectomies as vitreous rebleeds may not permit laser treatment postoperatively (Fig. 25.1.16a–d). Opinions on the use of encirclage routinely for vitrectomies in Eales’ disease are divided. Care of the lens during vitreous surgery is especially important while performing any surgical maneuvers in the periphery. Vitrectomy for combined retinal detachment requires meticulous membrane peeling to relieve vitreoretinal traction and tamponade with gas or silicone oil (Figs. 25.1.17a, b, 25.1.18a, b). Delay in performing vitrectomy (repeated vitreous hemorrhages with only percep-

Fig. 25.1.16. b Post-PPV the next day. Note the fresh 500 u endolaser marks. c Post-PPV after 1 month showing complete regression of the NVD. VA 6/12. d Post-PPV after 1 week

tion of light vision) is an important cause of poorer postoperative visual recovery [17, 28]. According to Shanmugham et al., visual acuities for individual cases were quite stable at the 60 month follow-up, with 50 eyes (78.5 %) either maintaining or improving upon their 2 month postoperative visual acuity [33]. Response to surgical treatment is good opposed to conditions like sickle cell retinopathy. Visual results are good as the macula is usually unaffected.

a

d

b

25 III

a

c

Fig. 25.1.18. a Combined retinal detachment after retinal laser due to contraction of fibrovascular traction band. b A close-up of the retinal tear and the offending fibrovascular tissue. c Reattached retina after PPV + MP + endolaser + C3F8

References

1.Badrinath SS, Gopal L, Sharma T et al (1999) Vitreoschisis in Eales’ disease: pathogenic role and significance in surgery. Retina 19:51 – 54

2.Bali T, Saxena S, Kumar D (2005) Response time and safety profile of pulsed oral methotrexate therapy in idiopathic retinal periphlebitis. Eur J Ophthalmol 15:374 – 378

3.Biswas J, Badrinath SS (1995/1996) Ocular morbidity in patients with active systemic tuberculosis. Int Ophthalmol 19:293 – 298

4.Biswas J, Rao NA (1990) Epiretinal membrane in Eales’ disease and other vascular retinopathies. Invest Ophthalmol Vis Sci 31 [Suppl]:369

5.Biswas J, Narain S, Roy S, Madhavan HN (1997) Evaluation of lymphocyte proliferation assay to purified protein derivative, enzyme-linked immunosorbent assay and tuberculin hypersensitivity in Eales’ disease. India J Ophthalmol 45: 93 – 97

6.Biswas J, Mukesh BN, Narain S, Roy S, Madhavan HN (1998) Profiling of human leukocyte antigen in Eales’ disease. Int Ophthalmol 21:277 – 281

b

7.Biswas J, Raghavendran R et al (2001) Presumed Eales disease with neurologic involvement: report of three cases. Retina 21:141 – 145

8.Biswas J, Sharma T, Gopal L, Madhavan HN, Sulochana KN, Ramakrishnan S (2002) Eales disease – an update. Surv Ophthalmol 47:197 – 214

9.Charmis J (1965) On the classification and management of the evolutionary course of Eales’ disease. Trans Ophthalmol Soc UK 85:187

10.Das T, Biswas J, Kumar A, Nagpal PN, Namperumalsamy P et al (1994) Eales’ disease. Indian J Ophthalmol 42:3 – 18

11.Das TP, Namperumalsamy P (1987) Combined photocoagulation and cryotherapy in treatment of Eales’ retinopathy. Proc All Ind Ophthalmol Soc 45:108

12.Das TP, Namperumalsamy P (1990) Photocoagulation in Eales’ disease. Results of prospective randomised clinical study. Presented in XXVI Int Cong Ophthalmol, Singapore

13.Duke-Elder S, Dobree JH (1967) System of ophthalmology, vol X. Kimpton, London

14.Eales H (1880) Retinal haemorrhages associated with epistaxis and constipation. Brim Med Rev 9:262

15.Eales H (1882) Primary retinal haemorrhage in young men. Ophthalmic Rev 1:41

16.Elliot AJ (1975) Thirty years observation of patients with Eales’ disease. Am J Ophthalmol 80:404

17.Gadkari SS, Kamdar P, Jehangir RP (1992) Pars plana Vitrectomy in Vitreous haemorrhage due to Eales’ disease. Ind J Ophthalmol 40:35 – 37

18.Gopal L, Abraham C (1985) Efficacy of photocoagulation in Eales’ disease. Trans Asia-pacific. Acad Ophthalmol 10:689

19.Gunisha P, Madhavan HN, Jayanthi U, Therese KL (2000) Polymerase chain reaction using IS6110 primer to detect Mycobacterium tuberculosis in clinical samples. Indian J Path Microbiol 43:395 – 402

20.Kalsi R, Patnaik B (1979) The developing features of phlebitis retinae (a vertical study). Ind J Ophthalmol 27:87

21.Madhavan, HN. Therese KL, Gunisha P, Jayanthi U, Biswas J (2000) Polymerase chain reaction for detection of Mycobacterium tuberculosis in epiretinal membrane in Eales’ disease. Invest Ophthalmol Vis Sci 41:822 – 825

22.Madhavan HN, Therese KL, Dora Swamy K (2002) Further investigations on two association of Mycobacterium Tuberculosis with Eales disease. Ind J Ophthalmol 50:35 – 39

23.Majji AB, Vemuganti GK, Shah VA et al (2006) A compara-

J.T. Rosenbaum, F. Mackensen

25 III

Core Messages

Sicca is the most common ocular manifestation of systemic lupus erythematosus (SLE)

While sicca is commonly associated with many rheumatic diseases, cotton-wool spots and intraretinal hemorrhages are present in 7 – 8 % of patients with SLE and are not commonly found in other rheumatic diseases

SLE related retinopathy is an activity marker and a prognostic factor for poor outcome

25.2.1Epidemiology and Disease Criteria for SLE

Essentials

Reported prevalence of systemic lupus erythematosus (SLE) ranges from 15 to 124 cases per 100,000 per year

Mainly women of childbearing age are affected

Socioeconomic factors influence course and outcome of SLE

Four of 11 ACR (American College of Rheumatology) criteria must be fulfilled to make a certain diagnosis of SLE

The prevalence of SLE in the United States ranges from 15 to 124 cases per 100,000 per year [16, 18]. In Europe comparable prevalence rates have been reported in Sweden and Italy [6, 39]. The disease had been thought to be more common and more severe in blacks than in whites, but patients of Hispanic and Asian origin are also severely affected [17, 31]. In later studies socioeconomic and environmental factors have been shown to influence the course and outcome of SLE, which might have biased previous epidemiological studies assessing the contribution of race to disease severity [22, 30]. About 90 % of affect-

All ocular disease in patients with lupus is not due to inflammation related to SLE: infections, thrombosis related to antiphospholipid antibodies, and medication toxicities need to be considered

Screening of all SLE patients for ophthalmic disease does not seem warranted; they should be seen as is recommended for their age group Patients with known SLE retinopathy or hydroxychloroquine treatment should be observed more closely

ed persons are women, usually of child bearing age [17]. For men the incidence increases after the 7th decade of life.

The diagnosis of SLE is based on clinical and laboratory criteria proposed by the American College of Rheumatology (ACR) [40]. If 4 out of 11 criteria are present, a diagnosis of SLE can be made with 98 % specificity and 97 % sensitivity. Ocular disease is not included among the criteria. These criteria are to classify SLE for published studies and, thus, the criteria are stricter than what is sometimes used in practice. The main screening laboratory marker is the ANA (antinuclear antibody), but further findings must support the diagnosis. Systemic symptoms are usually prominent and include fatigue, fever, anorexia and arthralgia. Activity of SLE is measured by different clinical and laboratory criteria. Activity scores that are used, for example, include the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) or the European Consensus Lupus Activity Measurement (ECLAM) [15]. Only the former includes retinal changes as a criterion for activity.

25.2.2Frequency and Prognostic Value of Ocular Findings in SLE

Essentials

Ocular involvement in SLE is common in the form of dryness

Retinal pathologies can be found in 7.5 % of patients with SLE, mostly microangiopathic changes with cotton-wool spots

Cotton-wool spots and retinal hemorrhages correlate with disease activity and are a negative prognostic sign

SLE patients with antiphospholipid syndrome have an increased risk for retinal vaso-occlusive disease

A summary is given in Table 25.2.1. There are few prospective epidemiologic studies for ocular involvement in SLE. Generally vision threatening ocular manifestations of SLE are rare, perhaps thanks in part to the earlier diagnosis and better treatment the patients receive. Suspected uveitis in patients with SLE has been reported anecdotally, but not frequently [12]. Orbital disease is also rare [3]. Episcleritis and scleritis are slightly more frequent. In a case series of patients with scleritis, 1 % had SLE [41]. Ocular involvement is correlated to the severity of disease and subtype of SLE [12, 38]. A study by Soo et al. on 52 randomly chosen patients from Malaysia with inactive SLE (SLEDAI score 4) and no ocular symptoms found pathologic Schirmer testing in 31 % as the only abnormal ocular finding. Fifty

age matched controls had normal Schirmer tests [37]. Stafford-Brady and colleagues examined 550 patients with SLE of varying activity prospectively for retinopathy over a period of 16 years. They found retinal pathologies in 41 (7.5 %) patients, most of which consisted of microangiopathic changes with cotton-wool spots and hemorrhages. Only 2 of the 41

patients presented with ischemic optic neuropathy, 2 III 25 more with retinal vaso-occlusive disease, and only

one with choroidal vasculitis complicated by serous retinal detachment. These 41 patients had a reduced survival curve compared to the SLE patients without retinopathy. Of the patients with retinopathy, 88 % had active systemic disease, with active central nervous system lupus in 73 %, renal disease in 63.5 % and detectable lupus anticoagulant in 38 %. Many of the patients in this valuable series were evaluated during an era when anticardiolipin or antiphospholipid antibodies were not routinely measured. Twen- ty-seven percent of the patients with retinopathy also had mild to moderate hypertension. No data are given at all about the presence of ocular symptoms. Equally not mentioned is the severity of disease in the remaining 474 patients [38]. In patients with raised anticardiolipin antibodies (antiphospholipid syndrome) a higher prevalence of retinal vaso-occlu- sive disease was seen with 8 % of 84 patients in one series [5] as well as retinopathy in general with 33 % vs. 6 % [28].

25.2.3Special Pathological Features and Molecular Mechanisms

Essentials

The pathogenetic mechanisms of SLE are complex and only partially understood

25 III A triggering event such as an infection might lead to activation of autoreactive T and B cells

Retinal vasculitis is a misunderstood term and is reserved by internists generally for histological diagnosis

There are few case reports about postmortem findings of the eyes of SLE patients. These are of note mainly for thrombosis of retinal arterioles

The variety of autoantibodies found in patients with SLE strongly suggests that it is an autoimmune disease. Although the mechanisms are not yet completely understood, a coincidence of several events such as an infection as a stimulus in a genetically susceptible organism and a subsequent activation and expansion of autoreactive T and B cells are a potential explanation for the loss of tolerance to autoantigens in SLE. Research in mice and humans has shown involvement of multiple cellular and humoral components of the immune system (summarized by [32]). Tissue damage has been shown to occur through immunecomplex deposits or a direct effect of autoantibodies. A number of clinically different syndromes fulfill the ACR criteria for SLE, which makes it also likely that several pathogenetic mechanisms exist. SLE can affect nearly all organs including skin, kidney, brain, heart, lung and also the eyes [7, 8].

In some patients with SLE perivascular sheathing can be seen with the ophthalmoscope. This finding is usually termed retinal vasculitis. Sheathing is a nonspecific sign of blood-retinal-barrier disruption and can have many causes. The term “vasculitis” should be reserved for histopathologically diagnosed cases, but this is a standard that is impossible to achieve with tissue that is not readily accessible to biopsy. As a clinical description microangiopathic retinopathy or retinal vaso-occlusive disease seem more apt [19, 33]. From animal studies we also know that leukocytes leave the vessel and enter the perivascular tissue if an intraocular inflammation exists, without the vessel wall itself being damaged. Ischemia can also produce secondary inflammatory changes.

In systemic vasculitis the diagnosis is commonly based on the Chapel Hill Consensus Conference relying mainly on the size of the affected vessels [21]. For the histological diagnosis infiltration of the vessel wall

by inflammatory cells must be present and a destruction of the wall with necrosis and/or fibrinous exudates should be in evidence. Patients with SLE can evolve a secondary vasculitis which is mainly thought to be due to immune-complex deposits [27]. This is rare. More frequent systemic vascular involvement consists of thrombosis and/or endothelial damage and atherosclerotic changes [7, 8]. An additional vasodestructive influence of hypertension due to renal disease has to be taken into account. In mice with lupuslike syndrome, immune-complex deposits were found to produce non-inflammatory vascular lesions [1].

Histopathologic studies of affected eyes are rare due to the obvious difficulty of biopsies and most information stems from postmortem exams. Less than ten published cases report thrombosed retinal arterioles, but active vasculitis or foci of inflammatory cells have not been demonstrated. However, some authors describe choroidal cell infiltrates and choroidal vasculitis [10, 14] and others also detected immune-complex deposits in the choroidal vessels [4, 23, 29]. This is similar to changes detected in brain biopsies of SLE patients [14].

25.2.4Retinopathy in SLE patients: Clinical Picture and Course of Disease

Case Report

An 18-year-old female presents to the Emergency Department with a history of recent, sudden bilateral vision loss left more than right. Systemically she reports having fever of 5 weeks duration of unknown origin, oral ulcers and multiple swollen lymph glands. A lymph gland biopsy shows non-specific inflammation. She has a history of pancytopenia. EBV reactivation has been suspected. Her only medication is roxithromycin. Visual acuity is 20/30 and 20/60. Intraocular pressure is normal. The slit lamp examination is unremarkable; fundus examination shows a single cotton-wool spot at the left optic disk with an intraretinal hemorrhage. Blood pressure is 140/85. MRI of the brain and orbits is normal except for enhancement in the orbital fat tissue. Fluorescence angiography was not performed.

25.2.5 Differential Diagnosis

Essentials

Hypertensive retinopathy

SLE related retinopathy

Leukemic retinopathy

Infection secondary to immunosuppression Bilateral optic neuropathy

Choroidal vasculitis

Orbital inflammatory disease

The patient was transferred to the Rheumatology Department with a suspected diagnosis of SLE, which was supported by ANA levels of 1:20,000, positive ds (double stranded) DNA antibodies and reduced complement levels. Proteinuria was detected and a renal biopsy showed active glomerulonephritis. With oral ulcers, nephritis, pancytopenia, positive dsDNA and an elevated ANA titer, she fulfilled 5 of the 11 ACR criteria for the classification of systemic lupus. Treatment with high dose corticosteroids and intravenous cyclophosphamide was initiated. Ocular symptoms responded quickly and visual acuity recovered. Three weeks after onset of therapy, visual acuity was 20/20 in both eyes. The left eye now showed some cotton-wool spots and small

intraretinal hemorrhages; the right eye demonstrated only a few small cotton-wool spots. Three months after onset of therapy, visual acuity was 20/20 in both eyes and the retinal changes were slowly disappearing, but still showed cotton-wool spots and a dissolving retinal hemorrhage, sometimes termed a “Roth” spot (Fig. 25.2.1). The last pictures (Fig. 25.2.2) were

taken 5 months after first presentation. Visual acuity III 25 was 20/20 and the fundus findings had nearly completely resolved. Further follow-up examina-

tions were performed in 3 monthly intervals by the local ophthalmologist and the Rheumatology Department. Even though no further eye symptoms occurred, proteinuria increased again after azathioprine was substituted for cyclophosphamide, so that treatment with 15-deoxyspergualin was initiated. Deoxyspergualin (NKT-01) shows both in vitro and in vivo immunosuppressive activity affecting B-lym- phocyte, T-lymphocyte and macrophage/monocyte function and is currently being tested in an openlabel, multicenter Phase I/II pilot study for patients with SLE nephritis. It has been reported to be effec-