Ординатура / Офтальмология / Английские материалы / Ocular Disease Mechanisms and Management_Levin, Albert_2010

Figure 84.1  Mutton fat keratic precipitates from uveitis attributable to sarcoidosis.

Figure 84.2  Multiple small choroidal granulomas in peripheral retina secondary to sarcoidosis.

Box 84.1  Clinical features of ocular sarcoidosis

Anterior inflammation

•White blood cells in anterior chamber

•Keratic precipitates (clumped cells on corneal endothelium)

•Posterior synechiae (adhesions between iris and lens)

Intermediate inflammation

•White blood cells in vitreous cavity, diffuse or clumped

Posterior inflammation

•Choroidal granulomas

•Retinal periphlebitis (taches de bougie)

•Cystoid macular edema

brain granulomas, and skin findings, including erythema nodosum.

Epidemiology

The incidence and prevalence of sarcoidosis vary markedly with geographic locale and patient population. The inci-

Clinical background

dence in African-Americans and in the USA has been estimated at approximately 40–80 per 100 000 person-years, compared with 4–8 per 100 000 person-years in the Caucasian population.1,2 Hispanic individuals appear to be affected more commonly than Caucasians. The disease is also seen in Europe, with an incidence approximately 20 per 100 000 in the UK, and 24 per 100 000 in Sweden.3 There has been a suggestion of female preponderance in some studies, although this has not been observed consistently.

Genetics

While sarcoidosis is not transmitted according to mendelian genetics, there have been suggestions of familial aggregation and racial differences which support the notion that sarcoidosis may occur preferentially in genetically susceptible hosts. For example, siblings of those affected with sarcoid have a modestly increased disease risk with an odds ratio of about 5.4,5 A genome-wide scan performed in German families with sarcoidosis has yielded a possible susceptibility gene on chromosome 6, called BTL2, which is a B7-family costimulatory molecule involved in immune regulation.6,7 Chromosome 5 has also been identified as potentially harboring candidate genes.8,9

Differential diagnosis

The differential diagnosis of sarcoidosis in the eye is broad. It nearly always includes other granulomas and inflammatory conditions such as tuberculosis and syphilis. Other etiologies, including atypical mycobacterial infection, endophthalmitis, herpetic eye disease, and autoimmune conditions such as Vogt–Koyanagi–Harada syndrome, may appear very similar to sarcoidosis clinically.

Diagnostic workup

Definitive diagnosis of sarcoidosis requires pathologic examination of biopsy tissue. The source of this tissue is rarely the eye; frequently, bronchoscopy will be used to generate diagnostic material. Mediastinoscopy may also be used for the biopsy of the hilar lymph nodes. Surface lymphadenopathy may be biopsied transcutaneously. Nondirected conjunctival biopsy has a very low yield in sarcoidosis,10 but biopsy of visible conjunctiva granulomas may be an expeditious way for the ophthalmologist to make this diagnosis. Lacking tissue diagnosis, several laboratory tests may provide supportive (but not definitive) evidence for this diagnosis. Historically, the Kveim–Siltzbach test was used in the diagnosis of sarcoidosis.11 In this test, a standardized extract from the spleen of a patient with sarcoidosis was injected subcutaneously into an individual suspected of having sarcoidosis. Several days later, formation of a granuloma at the site of injection is suggestive of the recipient patient having sarcoidosis. This test is no longer used clinically, but has important implications for the pathophysiology of sarcoidosis (see below). The serum angiotensin-converting enzyme (ACE) level is frequently elevated in patients with sarcoidosis. The positive and negative predictive values of this test for the disease, however, are relatively low, of the order of 83% and 58%, respectively.12 Gallium-67 uptake scanning has been utilized in a number of studies and may be relatively specific

for sarcoidosis, particularly if the “panda sign” is seen. This sign refers to the take-up of gallium by the lacrimose glands, parotid glands, and sinuses, resulting in an image of the face resembling a panda. The combination of elevated ACE level and positive gallium scan is thought to have a positive predictive value in excess of 95%.13,14 Elevated serum calcium and serum lysozyme have also been suggested as markers for systemic sarcoidosis but have low positive and negative predictive values. Definitive diagnosis of sarcoidosis always requires tissue biopsy.

Treatment

Ocular sarcoidosis is typically treated with corticosteroids. Anterior disease is often responsive to topical or periocular medication alone. Posterior-segment disease frequently requires oral corticosteroids. As sarcoidosis may be chronic, this may require substitution of steroid-sparing medications for corticosteroids after several weeks. Methotrexate has been used in a number of studies and appears efficacious for this task.15 Additionally, tumor necrosis factor-α inhibitors may have good efficacy for the treatment of sarcoidosis.16,17

Figure 84.3  Hematoxylin and eosin stain of a mediastinal lymph node demonstrating noncaseating granulomas typical of sarcoidosis.

Prognosis

Few data exist on the overall prognosis of patients with ocular sarcoidosis. Most cases are relatively easily treated, but a subset of patients may permanently lose vision from either the sarcoid granulomas themselves (i.e., optic nerve head granulomas or submacular granulomas), or complications secondary to chronic uveitis, such as a cystoid macular edema.18

Pathology

Granulomatous inflammation is a distinctive pattern of chronic inflammatory infiltrate in which the predominant cell type is an activated macrophage. A granuloma is a microscopic focus of inflammation characterized by a collection of modified epithelial-like (epithelioid) macrophages (Figure 84.3). The epithelioid macrophage contains pale pink granular cytoplasm with indistinct cell membranes. Frequently epithelioid macrophages may fuse to form giant cells (40– 50 µm) with multiple nuclei (Figure 84.4). The pathologic diagnosis of sarcoidosis requires the histologic identification of epithelioid granulomas within involved tissue and the exclusion of known causes of granulomatous disease, especially those of infectious etiology. Granulomatous inflammation is encountered in association with a variety of infectious and noninfectious agents, including mycobacterial and some mycotic, bacterial and parasitic infections, berylliosis, some types of vasculitis, and as a reaction to poorly soluble particulate matter. Even after extensive workup many granulomatous lesions remain unclassified.

Although there is no reliable method to distinguish sarcoidal granulomas from those of other disease processes, there are some characteristics of sarcoidal granulomas which may be useful. The granulomas of sarcoidosis are well formed in that the epithelioid and giant cells are compact with sharp circumscription from the surrounding tissue. The granulomas usually exhibit a uniform appearance suggesting

668

Figure 84.4  Multinucleated giant cell in sarcoidosis (arrow).

formation at a single point in time. Early, cellular granulomas become replaced by more fibrotic, hyalinized lesions as the disease progresses. Small central foci of amorphous granular debris (necrosis) may be seen in up to one-third of open lung biopsies in patients with sarcoidosis. Collections of neutrophils (suppuration) and confluent foci of necrosis are usually absent. Abundant necrosis is very unusual for typical sarcoidosis and should alert the clinician to exclude infection. The terms “caseating” and “noncaseating” are often used to describe granulomatous inflammation. Caseation refers to the white, cheesy gross appearance of tissue necrosis most commonly seen in foci of tuberculous infection. Caseation has been used interchangeably with the microscopic description of necrosis and, as described above, should be absent in sarcoidosis.

A variety of nonspecific intracellular inclusions may be seen in the granulomas of sarcoidosis. Schaumann bodies, or conchoidal bodies, consisting of a concentric laminated concretion of calcium salts and iron with a mucopolysac-

Figure 84.5  Schaumann body associated with sarcoid granulomas (arrow).

Figure 84.6  Birefringent calcium oxalate crystals associated with sarcoid granulomas (arrows).

Box 84.2  Key pathologic features of sarcoidosis

•Granulomatous inflammation featuring epithelioid histiocytes

•Inflammation is noncaseating (i.e., not necrotic)

•Multinucleated giant cells

•Schaumann bodies (concretions of calcium salts, iron, and mucopolysaccharides)

•Birefringent calcium oxalate crystals

•Disease progression is associated with fibrosis

charide matrix, occur in up to 70% of cases (Figure 84.5 and Box 84.2). Birefringent calcium oxalate crystals are seen within giant cells almost as frequently (60%) (Figure 84.6). Less frequently seen is the star-shaped densely eosinophilic asteroid body. Hamazaki–Wesenberg bodies are yellowbrown oval or spindle-shaped structures which are believed to represent large lysosomes. They are often found in the subcapsular sinuses of lymph nodes involved with sarcoidosis. These various inclusions can be very prominent and are important to recognize in order not to mistake them for causative foreign material or infection.

Because pulmonary involvement is almost universal, the histologic diagnosis of sarcoidosis is often rendered on material obtained by lung or bronchial biopsy. In lung tissue, granulomatous inflammation may be found in the bronchial or bronchiolar submucosa accounting for the over 90% diagnostic yield of bronchoscopic biopsy. Studies of bronchoalveolar lavage and bronchoscopic biopsy material in patients with sarcoidosis have demonstrated a predominance of CD4+ T cells, which is helpful in diagnosis. The combination of a CD4-to-CD8 ratio greater than 4 : 1, a lymphocyte percentage greater than 16%, and a biopsy demonstrating granulomas is associated with a 100% positive predictive value for distinguishing sarcoidosis from other interstitial lung diseases, and an 81% positive predictive value for distinguishing sarcoidosis from all other diseases.19

The early sarcoid granuloma consists predominately of CD4+ T cells and monocytes. The monocytes mature into macrophages and occasional multinucleated giant cells. It is generally assumed that sarcoidal granulomas are initiated when macrophages phagocytose an inciting antigen in a classic major histocompatibility complex (MHC) II restricted pathway. The antigen-presenting cells stimulate the proliferation of the CD4+ T cells and macrophages which in turn secrete inflammatory mediators such as interferon-γ, tumor necrosis factor-α and interleukin-2, believed to be important for granuloma formation.

Factors altering the immune response influence the development of sarcoidosis and help to define the immunologic features required for granulomas to form. In studies of human immunodeficiency virus (HIV)-infected patients, sarcoidal granulomas disappear when patient’s T-cell counts drop below 200/µl.20 Implementation of effective antiviral therapy can result in sarcoid recrudescence. Cytokine therapy used for cancer or HIV treatment has also been associated with the clinical development of sarcoidosis.21 Interferon-α used in the treatment of hepatitis C can trigger or exacerbate sarcoidosis.22 Sarcoidosis is also known to occur in association with a variety of autoimmune diseases.

Etiology

A number of environmental risk factors have been identified for sarcoidosis. In the Isle of Man study, the predominant risk factor for sarcoidosis was living within 100 meters of another individual with sarcoidosis, suggesting some transmissible agent.23,24 Older literature suggested that nurses have a sevenfold higher lifetime risk of sarcoidosis than the average population.25 Certain environmental triggers have been suggested in outbreaks of sarcoidosis. Most recently, it is suspected that the dust fallout from the twin towers collapse in 2001 led to a small epidemic of new sarcoidosis cases in the ensuing several years in New York city.1

Transplant studies also suggest a transmissible agent. These are based mostly on small case studies. In one study,

an individual with a known history of sarcoidosis served as a bone marrow donor for his brother, who did not have disease at time of engraftment. Despite aggressive immunomodulation postimplantation, the sibling developed sarcoidosis within several weeks of the transplant.26 Similar transmission from affected donor to naïve host has been associated with cardiac transplantation.27 Conversely, sar- coid-positive recipients typically redeveloped disease in naïve organs. The estimated rate of redevelopment of pulmonary sarcoidosis in lung transplantation is close to 80%.

As noted above, it is not thought that sarcoidosis is a genetic disease per se. However, there are diseases that are nearly identical in clinical appearances to sarcoidosis that clearly have a genetic basis. Blau syndrome is also a multi- organ-system granulomatous inflammation, typically affecting children. It is transmitted as an autosomal-recessive trait. The disease is due to mutations in the NOD2/CARD15 gene.28 This gene has been implicated in Toll-like receptor (TLR) signaling, suggesting that aberrant innate immunity to bacterial pathogens may underlie sarcoidosis. Similarly, linkage has been reported between TLR polymorphisms and sarcoidosis.29 Human leukocyte antigen (HLA) DRB1*1101 has also been associated with sarcoidosis.30

Pathophysiology

The data suggesting a transmissible agent as a trigger for sarcoidosis have led to many studies examining pathology specimens for the presence of possible microbial infection. Among the earlier hypotheses for this pathogen was “L- form” mycobacteria. These are thought to be mycobacterial species that lack cell walls, and are therefore not amenable to staining with standard reagents. Molecular biologic studies have suggested a high rate of detection of mycobacterial DNA in the lymph nodes of patients with sarcoidosis.31 Although some studies have suggested a high rate of human herpesvirus-8 infection in sarcoid lymph nodes, this result has not been replicated across multiple populations.32,33

Research groups in Japan have found a high rate of propionibacteria in lymph nodes of patients with sarcoidosis.34 In particular, Propionibacterium acnes has been identified in bronchoalveolar lavage washings of a high proportion (~70%) of sarcoid patients.35 The same bacteria have also been identified in vitreous samples from patients with sarcoidosis.36 Animal studies have suggested that Propionibacterium is able to prime the host in the development of sarcoid-like pulmonary granulomatosis in mice.37,38 However, the finding of propionibacteria in granulomas of non-Asian sarcoidosis patients has been limited to date.

The Kveim–Siltzbach reagent was an obvious place to look for a microbial pathogen in sarcoidosis. However,

detailed examination of this reagent for bacterial DNA by polymerase chain reaction yielded no evidence of infection.39 Kveim–Siltzbach reagent has long been noted to be resistant to protease treatment. Song and colleagues digested the reagent with a cocktail of proteases, and separated the resulting degraded proteins on one-dimensional gel electrophoresis. They then probed this protein by Western blot using sera from patients with and without sarcoidosis. This analysis revealed a single band of protein that was both protease-resistant and an antigenic target in patients affected with sarcoidosis. Mass spectroscopy analysis of this band revealed that it was the catalase gene of Mycobacterium tuberculosis.40 Subsequent work challenging T cells of patients with sarcoidosis with peptides derived from bacterial catalase has revealed that a high proportion of sarcoidosis patients do indeed have reactivity to mycobacterial antigens.41 Interestingly, the majority of these patients do not show skin responses to purified protein derivative (PPD), suggesting that either this represents a variant of M. tuberculosis that does not feature reactivity to the antigens found in the PPD reagent, or that sarcoidosis may be due to a related mycobacterial species with a very similar catalase gene.

Summary

Sarcoidosis is a multisystem granulomatous inflammatory disease of unknown etiology. It frequently affects the eyes, typically causing intraocular inflammation. Recent work has suggested a coherent model for the genesis of sarcoidosis. Disseminated infection with a relatively indolent bacterial species such as a nontuberculous mycobacterium or Propionibacterium results in a mild inflammatory response. The bacterium is cleared by the innate and adaptive immune systems, but protease-resistant antigens cannot be effectively processed. These antigens than become a nidus for chronic inflammatory disease, particularly in genetically susceptible individuals (i.e., those with impaired innate immune responses as the result of specific polymorphisms). Thus, the pathology of sarcoidosis resembles conditions of inflammation due to other nonclearable antigens, such as silicosis or berylliosis.

These insights into pathophysiology portend the possibility of improved diagnostic tests for sarcoidosis; if a small subset of bacterial pathogens are found to incite sarcoidosis, T-cell reactivity to the specific protease-resistant antigens may provide very specific and rapid noninvasive diagnostic tests. At present it is unclear how specific intervention could be engineered for clearance of protease-resistant antigens, as is suggested by this model. Thus, we will likely be treating ocular sarcoidosis with general immunomodulatory treatments for the foreseeable future.

2.Prezant DJ, Dhala A, Goldstein A, et al. The incidence, prevalence, and severity of sarcoidosis in New York City firefighters. Chest 1999;116:1183–1193.

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3.Hosoda Y, Yamaguchi M, Hiraga Y. Global epidemiology of sarcoidosis. What story do prevalence and incidence tell us? Clin Chest Med 1997;18:681–694.

4.Rybicki BA, Sinha R, Iyengar S, et al. Genetic linkage analysis of sarcoidosis phenotypes: the sarcoidosis genetic analysis (SAGA) study. Genes Immun 2007;8:379–386.

10.Dios E, Saornil MA, Herreras JM. Conjunctival biopsy in the diagnosis of ocular sarcoidosis. Ocul Immunol Inflamm 2001;9:59–64.

18.Edelsten C, Pearson A, Joynes E, et al. The ocular and systemic

prognosis of patients presenting with sarcoid uveitis. Eye 1999;13:748– 753.

23.Hills SE, Parkes SA, Baker SB. Epidemiology of sarcoidosis in the Isle of Man – 2: evidence for space-time clustering. Thorax 1987;42:427–430.

26.Heyll A, Meckenstock G, Aul C, et al. Possible transmission of sarcoidosis via allogeneic bone marrow transplantation. Bone Marrow Transplant 1994;14:161– 164.

Key references

28.Miceli-Richard C, Lesage S, Rybojad M, et al. CARD15 mutations in Blau syndrome. Nat Genet 2001;29:19–20.

40.Song Z, Marzilli L, Greenlee BM, et al. Mycobacterial catalase-peroxidase

is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis. J Exp Med 2001;201:755– 767.

Bowman membrane dystrophies, 23–25, 32 Bowman’s layer

corneal pannus and, 74–75 FECD and, 37

loss, 44, 44 “Bowtie” atrophy, 338 Brachytherapy

plaque, 390, 391 retinoblastoma and, 369 vs enucleation, 392

Bragg scattering, 1 Brain imaging, 449, 450

Brain-derived neurotrophic factor (BDNF), 207

Brainstem control, 290–291, 290, 291 Brainstem smooth pursuit circuits, 292–293,

293

Branch retinal artery occlusion (BRAO), 486, 488, 490

Branch retinal vein occlusion (BRVO), 490–494

treatment, 496

Branch Vein Occlusion Study Group, 497 Brimonidine, 321

Buried drusen, 337

C

Café-au-lait spots, 408, 409 Calcification, dystrophic, 422, 422 Cancer stem cells (CSCs), 413 Cancer-associated retinopathy (CAR)

syndrome, 599, 600, 602–603, 605–606

Candida, 45, 49, 101

Candida albicans, 51, 53–54, 54

Capillaries damage, 530

nonperfusion/degeneration, 509–511, 511 permeability, 511–512

Capsulotomy, yttrium aluminium garnet (YAG), 238

Carbonic anhydrase inhibitors (CAIs), 299,

299

Carboxyethylpyrrole (CEP), 501–502 Cardiovascular events, 318

Caspase activation, 211 Cataracts

age-related see Age-related cataract, biochemical mechanisms

diabetes mellitus (DM) see Diabetes mellitus (DM)-associated cataracts

secondary see Posterior capsule opacification (PCO)

steroid-induced see Steroid-induced cataracts

surgery, 276, 319 “Cat-scratch fever”, 658–659

Cell adhesion, 172, 174, 175–176 Cell death

programmed, 589 RPE, 503–504

see also Retinal ganglion cell (RGC) death, glaucoma

Cell proliferation, 615–616

Cell surface-associated mucins, 138 Cell-based therapy, 534

Cellular mechanics, 161

Cellular replacement see Retina, cellular repopulation

Central corneal thickness (CCT), 180 Central nervous system (CNS)

axonal injury and, 322, 327–329 cellular repopulation, 607–609 optic neuritis and, 251–252 retinoic acids (RAs) and, 301

Central nervous system (CNS), glaucoma and, 200–205, 207

central visual changes, 202–204, 204 clinical background, 200, 201 clinical implications, 204–205, 205 etiology, 200–201, 201

LGN, transsynaptic degeneration, 201–204, 202–204

retinal pathology, 200, 201 visual cortex changes, 203, 204

Central retinal artery (CRA), 317, 320 Central retinal artery occlusion (CRAO),

486

arteritic, 486–487

clinical background, 488–490, 489, 490 nonarteritic, 486, 487

Central retinal vein occlusion (CRVO), 490 diagnostic workup, 495

non-ischemic, cilioretinal artery occlusion associated, 494–495, 494

pathogenesis, 487, 493–494 prognosis, 497

risk factors, 490–492, 491

site of occlusion, 492–493, 493 treatment, 495–496

Central Retinal Vein Occlusion Group, 496 Central serous retinopathy (CSR), 554 Central Vein Occlusion Study Group, 495 Cerebellar smooth pursuit circuits, 292, 293 Cerebellum, 292

Cerebral cortical control, 291, 291 Cerebral gaze paralysis, 290, 291, 291 Cerebral smooth pursuit circuits, 292–293,

293

Cerebral venous sinus pressure, 304 Cerebrospinal fluid (CSF), 299–302

movement model, 300 pressure, 182

Cerebrospinal fluid (CSF) outflow models, 302–305, 305

arachnoid villi, 304

cerebral venous sinus pressure, 304 human, 302–304, 305 structure/function, 302–303, 304

Cerebrovascular events, 318 Chalazia, 131, 136

Chédiak–Higashi syndrome, 467, 467, 470 Chemical/thermal injury, 87, 87

Chemokines, 16, 214–219, 218 GCA and, 310–311

uveitis, 623, 624

Chemotherapy, retinoblastoma and, 371, 373 Chiasm, albinism and, 350, 352 Cholesterol, 251, 252

Chondroitin sulfate, 175

Chondroitin sulfate proteoglycan (CSPG), 609–610

Chondroitinase ABC, 609

Choroidal capillaries, oxidative damage, 530 Choroidal circulation, 573

Choroidal effusion, 197–198 Choroidal melanoma, 389–394

future directions, 393, 393 large, 392–393, 392, 393 medium, 390–392, 391, 392 overview, 389, 390

small, 389–390, 390, 391

Choroidal neovascularization (CNV), 424 AMD and, 536, 538–540 angiogenesis and, 544, 547, 550

Choroidal new vessels (CNVs), 527, 529, 530

complement pathway and, 530–531, 531 Ciclosporin A, 144

Ciliary body, 197, 267 Ciliary muscle, 266

Ciliary neurotrophic factor (CNTF), 594, 596

Ciliary Neutrotrophic Factor (CNTF) study, 534

Cilioretinal artery occlusion, 486, 488, 494–495, 494

Cilioretinal artery sparing, 488 Citicoline, 321

Classification of Eye Movement Abnormalities and Strabismus (CEMAS), 344

Clinically significant macular edema (CSME), 519

Coagulase-negative staphylococci, 136 Coating theory, Twersky’s hard-core, 2 Cogan’s microcystic dystrophy, 23, 24, 32 Colagenases, 16

Coleman’s caternary theory, 268, 268 Collaborative Corneal Transplantation Studies

(CCTS) (USA), 57

Collaborative Longitudinal Evaluation of Keratoconus (CLEK), 45

Collaborative Normal Tension Glaucoma

Study, 178, 179, 225, 225

Collaborative Ocular Melanoma Study (COMS), 383–384, 384, 385–386, 386, 387

Collagen cross-linking, 43

fibrils, 1–4, 2, 14, 67 IV, 36, 550

VIII, 37

Color vision defects, 478–485 acquired, 480–481, 480, 483 diagnostic workup, 480