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

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Fig. 25.4.2. Chronic venous sclerosis of the vena temporalis superior with a linear white opacity (arrows) in a patient with MS-associated uveitis with narrowing and irregularity of vein caliber. There is also optic atrophy due to recurrent retrobulbar neuritis

Fig. 25.4.3. Fluorescein angiography of active periphlebitis demonstrates delayed filling, persistence of dye, staining, and leakage from affected vessels, which indicates breakdown of the blood-retinal barrier

Activity of periphlebitis in MS is not correlated with optic neuritis, systemic exacerbations, or severity of disease. Schmidt et al. showed that MS patients with concomitant intraocular inflammation are not distinct from “classic” MS with regard to the clinical course of disease, disability, and neuroimaging features [32].

Fluorescein angiography of active periphlebitis demonstrates delayed filling, persistence of dye,

Fig. 25.4.4. Occlusive periphlebitis with branch vein occlusion indicated by intraretinal hemorrhage

Fig. 25.4.5. Retinal neovascularization in patient with occlusive MS-associated vasculitis shown by fluorescein angiography

staining, and leakage from affected vessels, which indicates breakdown of the blood-retinal barrier [40] (Fig. 25.4.3). Some vessels show staining of leakage in areas without clinically detectable periphlebitis. Venous sclerosis may show either late staining or normal appearance on angiography.

Complications of intermediate uveitis include cataract formation, CME, epiretinal membrane formation, glaucoma, retinal detachment, and occlusive vasculitis (Fig. 25.4.4) with subsequent neovascularization (Fig. 25.4.5) with and without vitreous hemorrhage. There seems to be no difference in the rate of complications in patients with primary or other secondary forms of intermediate uveitis.

Table 25.4.1 summarizes the characteristic findings of intraocular inflammation in patients with MS.

Table 25.4.1. Characteristic features of uveitis in multiple sclerosis

Bilateral, intermediate uveitis with or without optic neuritis in the past

„Granulomatous” changes in the anterior segment

Linear periphlebitis

Cystoid macular edema

Occlusive vasculitis with subsequent formation of retinal neovascularization

Table 25.4.2. Differential diagnosis of MS-associated uveitis

25.4.5 Differential Diagnosis

Inflammatory systemic diseases that produce encephalomyelopathy, optic neuritis, extraocular muscle disturbances, intermediate uveitis with retinal vasculitis, and may mimic MS-associated uveitis include the diseases shown in Table 25.4.2.

25.4.6 Therapeutic Options

25.4.6.1Corticosteroids and Immunosuppression

For patients with primary or non-infectious secondary forms of intermediate uveitis, systemic corticosteroids (initial dosage 1 mg/kg body weight) are still the mainstay of initial treatment. If the inflammatory activity (density of cells in the vitreous or anterior chamber) can be reduced by systemic corticosteroids and there is no relapse of disease above the Cushing threshold (about 7.5 mg prednisone equivalent per day) but a relapse after complete cessation, a lowdose prednisone scheme should be attempted. If the relapse is above the Cushing threshold, the use of corticosteroid-sparing drugs (like methotrexate or mycophenolate mofetil) should be used. The use of inhibitors of tumor necrosis factor (TNF) in patients with MS-associated uveitis is contraindicated due to the possibility of induction of MS. However, it should

be considered in patients with severe primary or secondary (other than MS) intermediate uveitis and vasculitis; infliximab seems to provide a stronger anti-inflammatory potency than etanercept.

25.4.6.2Immunomodulatory Therapy with Interferon for Cystoid Macular Edema

Interferon (IFN) has been shown to have beneficial effects in patients with MS [27, 28] and/or ON [10]. Jacobs et al. showed that initiating treatment with IFN-1a at the time of the first demyelinating event, like optic neuritis, is beneficial for patients with brain lesions on MRI that indicate a high risk of clinically definite multiple sclerosis [16].

The biological effects of IFNs have been known since the early 1970s. Type I IFNs (IFN- and -) share about 30 % homology in their amino acid sequence and use the same receptor (there is also an additional IFN- receptor). Therefore, the therapeutic effects of type I IFNs are quite similar. Type II IFNs (IFN-) have different amino acid structures.

Several studies show that IFNtreatment shifts the balance of cytokines in favor of a net anti-inflam- matory response, by either suppressing Th1 or by increasing Th2 cytokine production or both [12, 39]. IFN- also suppresses the IFN--mediated expression of major histocompatibility complex (MHC) class II on astrocytes and microglia in vitro and reduces the antigen-presenting capacity of these cells [18, 31].

In the nomenclature of interferons, a “1” indicates a closely related protein within the -family; “a” indicates that the synthetic product has the same primary structure as the natural substance. Minagar showed in a recent study that IFN-1a and IFN-1b blocked the IFN--induced disintegration of endothelial junction integrity and therefore protected endothelial barriers. They also showed that the protective effects of IFN- on occludin and VE-cadherin stability appear to represent molecular mechanisms for the therapeutic effects of the IFN- on bloodbrain barrier in MS [22]. Interestingly, the reduction of vascular leakage and hence reduction of edema of the posterior pole and increase in visual acuity seems to be an important effect of IFN in the treatment of patients with uveitis associated with MS in one of our recent studies [6]. Because of the different mode of action of IFNs (“immunomodulatory” rather than “immunosuppressive”), it is thought that IFNs need an unsuppressed immune system. Therefore, it is recommended to use additional corticosteroids only

in low doses. The concurrent use of immunosuppressives should be avoided during IFN treatment.

The current approach to treating patients with optic neuritis has been modified by the results of the Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS). Patients with an initial clinical episode of demyelination (optic neuri-

25 III tis, incomplete transverse myelitis, or brain-stem/ cerebellar syndrome) and at least two characteristic demyelinating lesions within the brain were randomized to receive interferon 1a or placebo after initial treatment with intravenous corticosteroids. At a 3-year follow-up, patients treated with IFN-1a showed a 50 % reduced risk of progression to clinically definite MS (CDMS) [5, 10, 13]. The results of this study have set the standard of treatment for patients with a first bout of demyelinating optic neuritis.

25.4.6.3 Laser Photocoagulation

In cases of severe neovascularization, argon laser treatment might be an option if the disease is unresponsive to immunosuppressive drugs or treatment with IFN. Sectorial panretinal photocoagulation is the treatment of choice (Fig. 25.4.6). IFN- has been shown to lead to regression of inflammatory retinal neovascularization in patients with occlusive periphlebitis associated with Beh¸cet’s disease [34]. In our experience, prophylactic treatment of occlusive periphlebitis in patients with MS-associated uveitis seems to shrink the total area of non-perfusion, inhibit the formation of retinal neovascularization and reduce the amount of vascular leakage (Figs. 25.4.7, 25.4.8).

Fig. 25.4.7. Occlusive retinal vasculitis before treatment with interferon- in a patient with MS-associated uveitis

Fig. 25.4.6. Regression of neovascularization in the same patient of Fig. 25.4.5 after sectorial photocoagulation shown by fluorescein angiography

Fig. 25.4.8. Occlusive retinal vasculitis after treatment with interferon- in the same patient as Fig. 7: regression of areas of non-perfusion, no formation of retinal neovascularization, reduction of vascular leakage

25.4.6.4 Treatment Strategy

Multiple factors influence the decision on how to treat patients with MS-associated uveitis. Table 25.4.3 delineates the personal treatment strategy of the authors. Due to the chronic course of MS-associ- ated uveitis, patients should be on a regular followup according to clinical activity. In cases of mild inflammatory activity we recommend 3-monthly intervals of ophthalmologic examinations.

Table 25.4.3. The personal treatment strategy of the authors

References

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Core Messages

Sarcoidosis is a multisystem granulomatous disease

Ocular manifestations may precede or coexist with systemic disease

Most common ocular features are dry eyes and uveitis

Posterior segment disease may involve retinal vessels, retina and/or choroid

Retinal vasculitis is a cardinal feature of posterior segment disease

Retinal neovascularization may be due to inflammation and/or ischemia

25.5.1 Epidemiology

Sarcoidosis is a multisystem granulomatous disease with protean clinical manifestations and occurs worldwide. It affects all age groups, with two-thirds of patients being less than 40 years old at the time of diagnosis [43]. The clinical manifestations and severity of the disease vary widely and are strongly associated with racial and ethnic factors: acute and more severe disease is typical of black patients, whereas asymptomatic and chronic disease is more frequent in whites [35, 62]. Among the white patients, it is more prevalent among Scandinavians [55]. The disease also tends to affect certain organs in certain populations. For example, ocular and cardiac sarcoidosis appears to be more common in Japanese while erythema nodosum occurs more often in people of north European descent [32, 49].

25.5.2 Etiology

The etiology of sarcoidosis is unknown. Current theories suggest an abnormal immune response directed against one or more possible antigens in a susceptible individual [70]. Proposed antigens fall into three categories that include infectious, environmental, and autoantigens [44]. The most common infectious agents implicated are Mycobacterium tuberculosis, Propionobacterium acne and herpes virus 8 [16]. Specific HLA associations have also been connected with disease susceptibility and outcome [54]. Genetic polymorphisms of the ACE [24] and vitamin D receptor genes [45] may also be of potential relevance in the expression and outcome of the disease.

In addition, a promoter polymorphism of the TNF- gene (TNF-308) has been associated with Löfgren’s syndrome [63].

25.5.3 Molecular Mechanisms

Unknown antigen(s) or abnormal defense mechanisms triggered by various insults may be responsible for T cell activation in a genetically predisposed host. The compartmentalization of the T cells occurs as a result of cellular distribution from peripheral blood or in situ proliferation [15]. The CD4+ cells and macrophages are increased in areas of granuloma formation. Therefore, in areas of disease activity, the CD4:CD8 ratio is high while the CD4+ cells in the blood decrease, resulting in a reduced or inverted CD4:CD8 ratio [29]. B-cell activation also occurs, increasing the production of immunoglobulin. Increased serum vascular endothelial growth factor (VEGF) has also been observed in sarcoidosis and may be a useful prognostic indicator [56].

25.5.4 Pathology

The characteristic histopathologic findings are multiple non-caseating epithelioid granulomas. The center of the granulomas consists of histiocytes, epithelioid cells and multinucleated giant cells that may contain intracytoplasmic inclusions such as asteroid bodies and Schaumann bodies. The epithelioid cells are derived from monocytes and secrete several cytokines. They are surrounded by lymphocytes, plasma cells and fibroblasts. These granulomas secrete glucuronidase, collagenase, calcitriol and

angiotensin-converting enzyme (ACE). The granulomas may resolve spontaneously or with treatment.

25.5.5 Special Pathological Findings

25.5.5.2 Ocular Sarcoidosis

Ocular involvement is the third commonest manifestation of sarcoidosis, preceded by pulmonary disease and hilar adenopathy [39]. It may precede or coexist

Organ Common manifestations

with systemic disease. Ocular disease may be the presenting feature in 9 % of cases. Twenty-five to 40 % of patients with systemic sarcoidosis will at some point in the disease course show ocular involvement [46]. Sarcoidosis can present with a variety of ocular involvement. There are two peaks in age incidence for ocular sarcoid: 20 – 30 years and 50 – 60 years [52]. The most common manifestations are dry eyes and uveitis.

25.5.5.2.1 Anterior Segment Involvement

Eyelids can be involved as part of cutaneous or ocular sarcoidosis and it usually presents as painless skin or subcutaneous nodules [27]. Lacrimal gland involvement varies from 7 % to 69 % and is more common in black patients. It may manifest as bilateral or unilateral painless lacrimal gland enlargement with or without parotid gland involvement (Fig. 25.5.1). Lacrimal gland enlargement is usually asymptomatic, though it may lead to keratoconjunctivitis sicca or diplopia [14]. Orbital inflammatory syndrome can also occur in less than 1 % of patients [11]. Orbital pseudotumor like reaction may manifest as the initial presentation of sarcoidosis with painful ophthalmoplegia and occasionally decreased vision [22]. The inflammation may also involve the extraocular muscles directly, resembling Graves’ ophthalmopathy, or it may present as an orbital granuloma (Fig. 25.5.2).

Conjunctival involvement has been reported in up to 40 % of patients with ocular sarcoidosis [46]. Mul-

Fig. 25.5.1. Lacrimal gland enlargement in sarcoid

Fig. 25.5.2. Orbital granuloma

tiple, translucent, pale conjunctival granulomas have frequently been described as the first clinical sign of sarcoidosis and they can be easily biopsied. Conjunctival biopsy is technically simple, cost-effective and gives a good positive yield when the granulomas are seen [18]. These granulomas usually respond well to topical steroid treatment. Chronic inflammation may lead to dry eyes, symblepharon, cicatricial conjunctivitis and even entropion [25]. Corneal involvement is extremely rare. Corneal band degeneration may develop as a consequence of long-standing anterior uveitis.

Scleritis is uncommon in sarcoidosis though a recent report suggests that sarcoidosis can present with scleritis [21].

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Fig. 25.5.3. Mutton fat keratic precipitates

Uveitis occurs in 30 – 70 % of patients, with more than 80 % presenting within 1 year of onset of systemic disease [30]. Sarcoidosis is the most frequently reported systemic disease associated with non-infec- tious uveitis in the Western world with a reported incidence of about 7 %. The most common type of uveitis in sarcoidosis is anterior uveitis in black patients compared to posterior uveitis in elderly white females. If left untreated, the uveitis may cause severe visual loss due to cystoid macular edema, severe vitritis, cataract, secondary glaucoma and vitreous hemorrhage secondary to retinal neovascularization.

Sarcoid related uveitis may occur in five ways:

Acute anterior uveitis

Chronic anterior uveitis

Intermediate uveitis

Posterior uveitis

Panuveitis

Acute anterior uveitis presents especially in Löfgren’s syndrome, associated with erythema nodosum and bilateral hilar lymphadenopathy. This responds well to topical steroids but occasionally periocular steroids are also required. The prognosis for vision is good. Chronic uveitis is usually bilateral, with mutton fat keratic precipitates (Fig. 25.5.3) and granulomatous nodules in the iris or anterior chamber angle (Fig. 25.5.4). The iris nodules may be Koeppe’ nodules and/or Busacca’s nodules. Half of these patients have chronic and recurrent episodes with associated complications of iris bomb´e, cataract, glaucoma and

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Fig. 25.5.4. Iris nodules

cystoid macular edema. Vitritis may result from a spill over from anterior uveitis, intermediate uveitis or it may accompany posterior segment involvement. Intermediate uveitis may present as a fine cellular reaction or run a more chronic course with snowball opacities that accumulate in the inferior vitreous and/or snowbank formation.

Posterior subcapsular lenticular opacities are a well-recognized complication of uveitis and both systemic and topical steroid therapy. Akova and Foster studied cataract extraction in patients with ocular sarcoidosis and found that posterior chamber lens implantation in patients with sarcoidosis-asso- ciated uveitis is well tolerated when absolute control of the inflammation is achieved. Preexisting retinal pathology and glaucoma as a result of uncontrolled inflammation resulting in permanent ocular structural damage were found to be the most important factors for determining the postoperative final visual acuity [1].

A major prognostic factor for visual morbidity in ocular sarcoidosis is the presence of secondary glaucoma. The main causes of secondary glaucoma include secondary open angle glaucoma due to inflammation, pupillary block, peripheral anterior synechiae, trabeculitis and neovascular glaucoma. Rubeosis may result from chronic inflammation but more commonly occurs due to ischemia from extensive retinal vascular closure. Anterior segment inflammation usually responds to topical steroids, but in some patients the intraocular pressure (IOP) rises on treatment with steroids (steroid response) and may require treatment to lower the IOP. Abnormalities noted in the endothelium of Schlemm canal suggest that Schlemm canalitis resembling microangiopathy seen in skin and lung biopsies of sarcoidosis may be another cause of secondary glaucoma [28].

Posterior segment involvement may be the only manifestation of ocular sarcoidosis [51]. Posterior segment manifestations also show demographic variations. American black patients have a higher incidence of posterior segment involvement compared to European black patients suggesting that genetic and environmental differences between populations may vary.

The inflammatory process may involve the retinal vessels, retina and/or choroid. Retinal vasculitis constitutes one of the cardinal features of posterior segment inflammation. It is typically characterized by perivenous sheathing in the equatorial retina, which is usually segmental (Fig. 25.5.5). The cuffing of the affected veins is due to the collection of infiltrating cells at sites of disruption of the inner blood-retinal barrier. The condition may remain asymptomatic at this stage and is often an incidental finding. It is nonspecific and non-diagnostic as it may occur in many types of uveitis.

However, vasculitis may also result in leakage or occlusion of the lumen of the veins resulting in more severe signs and symptoms. Leakage leads to retinal swelling, exudation and edema. Franceschetti and Babel described the perivenous exudation as tache de bougie (candle wax drippings) [23]. Though described as typical of sarcoid vasculitis, it is not a common finding (Fig. 25.5.6).

Retinal vasculitis can also lead to vascular occlusion resulting in intraretinal hemorrhage, cottonwool spots and capillary non-perfusion.

Neovascularization occurs in approximately 11 % of patients with posterior segment disease and is thought to be induced by a variety of angiogenic factors. Neovascularization may develop as a result of

Fig. 25.5.5. Retinal vascular sheathing

two mechanisms: (a) severe ocular inflammation and (b) retinal vascular occlusion and ischemia [20]. Neovascularization may involve the optic disk or peripheral retina (Fig. 25.5.7). A higher rate of vitreous hemorrhage has been noted in younger patients with periphlebitis than their older counterparts. The neovascularization usually responds to anti-inflam- matory agents when the drive is inflammatory but laser photocoagulation may be required if there is any retinal ischemia present.

Fluorescein angiography is an important investigation for the assessment of the integrity of the vessels and the degree of ischemia. Vessel staining and leakage may indicate active vasculitis or retinal ischemia. Diffuse fern-like vascular leakage may be seen on angiography (Fig. 25.5.8). The areas of capillary closure are best delineated by fluorescein angiography. Likewise, macular edema may often be more evident angiographically than clinically.

Cystoid macular edema (CME) is a major cause of visual loss in ocular sarcoidosis. Females and older patients have a higher rate of CME and worse visual

acuity [65]. CME usually responds to treatment with steroids but may require the use of additional immunosuppressive agents.

Multifocal chorioretinitis in sarcoidosis may be central, peripheral or both. It is often associated with CME (Fig. 25.5.9) [38]. Subfoveal choroidal neovascularization has also been reported in sarcoidosis secondary to multifocal choroiditis [31]. Peripapillary choroidal neovascularization that responds to systemic steroids has also been observed [10].

Retinal macroaneurysms are associated with multifocal choroiditis in women and are associated with severe cardiovascular disease. Elderly patients with multiple retinal macroaneurysms, uveitis, disk staining, and peripheral chorioretinitis should be thoroughly investigated for sarcoidosis [53].

Acute multifocal posterior placoid epitheliopathy (AMPPE) and bird shot chorioretinopathy like picture have also been associated with sarcoidosis [17, 37]. Extensive posterior pole choroiditis may resemble serpiginous choroiditis. Plaque-like yellowish