Ординатура / Офтальмология / Английские материалы / Retinal Vascular Disease_Joussen, Gardner, Kirchhof_2007

tive in a case series and has the advantage over cyclophosphamide of not being gonadotoxic [24]. Our patient responded favorably to this treatment, but about 1 year later, another flare of the nephritis occurred and rituximab was given.

Although a variety of problems could have explained this patient’s visual loss, the precise cause 25 III was never determined with certainty. Several options within the differential diagnosis were excluded by the course and presentation. Hypertension, leukemia, and infection were considered, but these were not consistent with the presentation. The orbital disease was not considered to be clinically significant. It is most likely that this patient had either optic nerve disease and/or choroidal vasculitis. While an angiogram could have helped distinguish among these possibilities, the study was not obtained largely because of the acuteness of the patient’s disease and the need to institute immunosuppression, empiric

therapy for either underlying diagnosis.

In general it is more likely that a patient presenting to an ophthalmologist already has known SLE. In the case of suspicions that eye findings such as microangiopathic retinopathy, retinal vaso-occlusive events or neuropathy might be the first presentation of SLE, a detailed history asking specifically about symptoms such as fatigue, anorexia, fever, weight loss, pleuritic chest pain, skin rash, or arthritis should reveal further evidence for an associated systemic disease suspicious of SLE. Then laboratory investigations can be initiated. An ANA test is the best screening test for SLE, but should not be used unless an acceptable pretest likelihood of a positive result exists (Bayes’ theorem) [35]. An ANA test has a sensitivity of roughly 97 % for systemic lupus, so a negative test is very useful in excluding lupus as a likely diagnostic possibility. A positive ANA can occur in lower levels in normal individuals. This finding increases with age. It is frequently positive in patients with the subset of juvenile arthritis associated with uveitis and among patients with Sjogren’s syndrome. In the case of retinal vaso-occlusive disease especially in younger patients with no previous cardiovascular risk factors, anticardiolipin antibodies and the lupus anticoagulant should be tested as these patients have increased risk for antiphospholipid syndrome [9].

25.2.6Treatment Recommendations, Follow-up and Recommendations for Ophthalmologic Screening of SLE Patients

Essentials

Treatment of microangiopathic changes should be chosen in the context of the systemic disease

Remission is induced with intravenous cyclophosphamide and maintained with other immunosuppressive medications, e.g., azathioprine

Emerging therapies for systemic lupus include mycophenolate mofetil and rituximab

This treatment seems to be effective for SLE related neuropathy as well

Patients with antiphospholipid syndrome are mainly treated with anticoagulation

Ocular findings can be seen as markers for disease activity and a bad prognostic sign [38]. Patients should be referred to a rheumatologist or nephrologist and treated in the context of systemic disease. High dose corticosteroids and intravenous cyclophosphamide in combination therapy are used in severe disease and have been shown to induce remission in a higher percentage of patients with lupus nephritis than prednisone alone [13]. Usually cyclophosphamide is used for up to 6 months to induce remission and then another immunosuppressive medication, e.g., azathioprine, is used to maintain that state. Several recent reports have supported the choice of mycophenolate mofetil orally as an alternative choice for mild or moderate renal disease and intravenous rituximab for severe renal disease [2, 42]. Another treatment under investigation is deoxyspergualin [24]. Systemic treatment also seems to be adequate for SLE related retinopathy. For optic neuropathy, an occlusive vasculopathy should be assessed by checking for antiphospholipid antibodies and the lupus anticoagulant. If the cause is thought to be inflammatory rather than thrombotic, high dose corticosteroids and/or intravenous cyclophosphamide should be administered promptly [11, 20, 34]. In patients with antiphospholipid syndrome without signs of inflammatory activity, anticoagulation alone can be sufficient [36].

Ophthalmologic examinations should be performed at regular intervals to monitor efficacy of treatment in patients with known retinopathy. These patients generally have a favorable outcome in terms of visual acuity [38]. Screening of all SLE patients

ophthalmologically does not seem warranted as vision threatening ocular manifestations are rare. AAO recommendations for ophthalmologic routine examinations for each age group are appropriate. The subgroup of SLE patients with antiphospholipid syndrome might benefit from regular fundus examinations. The finding of minor vascular occlusion might be a rationale for anticoagulation therapy or aspirin, but there are no studies confirming a benefit of this approach. Patients receiving chloroquine or hydroxychloroquine treatment should have a baseline examination and follow-up depending on the dose and duration of the drug [26]. Additional risk factors such as renal disease might prompt more frequent monitoring for antimalarial toxicity. The typical “bull’s-eye maculopathy” is the clinical hallmark of retinal toxicity (Fig. 25.2.3). Unfortunately this can progress sometimes even after the treatment has been stopped [25].

References

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3.Arevalo JF, Lowder CY, Muci-Mendoza R (2002) Ocular manifestations of systemic lupus erythematosus. Curr Opin Ophthalmol 13:404 – 410

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5.Asherson RA, Merry P, Acheson JF, Harris EN, Hughes GR (1989) Antiphospholipid antibodies: a risk factor for occlusive ocular vascular disease in systemic lupus erythematosus and the ’primary’ antiphospholipid syndrome. Ann Rheum Dis 48:358 – 361

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8.Boumpas DT, Fessler BJ, Austin HA 3rd, Balow JE, Klippel JH, Lockshin MD (1995b) Systemic lupus erythematosus: emerging concepts. Part 2: Dermatologic and joint disease, the antiphospholipid antibody syndrome, pregnancy and hormonal therapy, morbidity and mortality, and pathogenesis. Ann Intern Med 123:42 – 53

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11.Galindo-Rodriguez G, Avina-Zubieta JA, Pizarro S, Diaz de Leon V, Saucedo N, Fuentes M, Lavalle C (1999) Cyclophosphamide pulse therapy in optic neuritis due to systemic lupus erythematosus: an open trial. Am J Med 106:65 – 69

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13.Gourley MF, Austin HA 3rd, Scott D, Yarboro CH, Vaughan EM, Muir J, Boumpas DT, Klippel JH, Balow JE, Steinberg AD (1996) Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial. Ann Intern Med 125:549 – 557

14.Graham EM, Spalton DJ, Barnard RO, Garner A, Russel RWR (1985) Cerebral and retinal vascular changes in systemic lupus erythematosus. Ophthalmology 92: 44 – 448

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Ingelmo M (1999) Association of antiphospholipid antibodies with retinal vascular disease in systemic lupus erythematosus. Semin Arthritis Rheum 28:326 – 332

29.Nag TC, Wadhwa S (2005) Histopathological changes in the eyes in systemic lupus erythematosus: an electron microscope and immunohistochemical study. Histol Histopathol 20:373 – 382

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33.Rosenbaum JT, Robertson JE Jr, Watzke RC (1991) Retinal vasculitis – a primer. West J Med 154:182 – 185

34.Rosenbaum JT, Simpson J, Neuwelt CM (1997) Successful treatment of optic neuritis in association with systemic lupus erythematosus using intravenous cyclophosphamide. Br J Ophthalmol 81:130 – 132

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Core Messages

Behcet’s¸ disease is a systemic vasculitis, with a prevalence of 0.12 – 370/100,000 inhabitants Diagnosis is made according to the following criteria: recurrent oral aphthous ulcers in combination with two of the following lesions: eye lesions, genital ulcers, skin lesion, pathergy testing

Immune mediated disorder (T, B, NK and neutrophilic cells), leading to inflammation and endothelial dysfunction

HLA-B51 is the most important genetic marker Treatment is with systemic immunosuppression: corticosteroids, cyclosporin A, most recently successful biologicals such as interferon- and tumor necrosis factor (TNF)- antagonists

25.3.1Epidemiology and Definition of Behcet’s¸ Disease

25.3.1.1 Definition

Beh¸cet’s disease (BD) is a systemic vasculitis [86, 94]; thus, almost any organ system can be affected. The diagnosis of BD is usually based on the criteria of the International Study Group from 1990 (Table 25.3.1) [39].

Table 25.3.1. Criteria of the International Study Group 1990 [39]

Plus 2 of the following:

Recurrent Aphthous ulcerations or scarring genital ulcers

25.3.1.2 Epidemiology

Essentials

Most common along the Silk Route from the Mediterranean to eastern Asian countries

Incidence: 0.8/100,000 inhabitants in Japan

Prevalence: 0.12 (USA)–370 (Turkey)/ 100,000 inhabitants

Gender ratio: previously male:female 3:1; today probably 1:1

Beh¸cet’s disease has been reported from many countries all over the world. Especially along the ancient Silk Route from the Mediterranean to the eastern Asian countries, BD patients are endemic [44]. The disease is most common between the latitudes 30° and 45°N in Asian and European populations [113]. These geographic data and the fact that certain ethnic groups are affected hint at the transfer of genetic material and/or of an exogenous agent, which may have been responsible for the spread of the disease [117].

The prevalence of the disease (Table 25.3.2) varies around the world and seems to be strongly dependent on geographic area [44, 113, 117]. Single or small numbers of cases have been reported from all continents, but the highest prevalence has been described in Turks living in Anatolia (northwestern Turkey), with 370 patients per 100,000 inhabitants [112, 117]. The overall prevalence in Asia varies between 18 and 110 patients [44, 75, 112]. The preva-

Table 25.3.2. Prevalence of Beh¸cet’s disease in different popula-

lence in southern Europe, especially in the Mediterranean countries, is 1.53 – 7.50 patients per 100,000 inhabitants; in northern Europe and in the USA the highest prevalence was recorded in the Swedish population with 1.18 patients per 100,000 inhabitants. Interestingly, the data from Germany exhibited a prevalence of 20.75 per 100,000 inhabitants in patients of Turkish origin compared to only 0.42 per 100,000 inhabitants in patients of German origin [118].

Data on the incidence of BD are available for only a few countries [113, 117]. From Japan, a country with well organized registration of patients with BD, it was reported that in the year 1990 0.8 new cases per 100,000 inhabitants were diagnosed with BD [73].

Average age of onset is recorded at 25 – 35 years worldwide and it seems to be independent of the origin of the patients and their gender [113, 117]. Variations in many studies may be based on different definitions. Most authors consider the onset of the disease to be the age at which the patient met the diagnostic criteria of the disease, while for others BD onset should be associated with the first symptom [113, 117].

Concerning the gender distribution of BD patients, Japanese and Turkish reports have found a predominance of males to females [68, 113, 117] of 3 to 1, but current epidemiological studies have registered an approximately equal rate [31, 73, 117].

25.3.2 Special Pathological Features

Essentials

Immune mediated disorder with participation of T, B, NK and neutrophilic cells

Hyperactive neutrophils can lead to increased chemotaxis, phagocytosis and superoxide generation

Increase in gamma/delta T cells has been demonstrated

Endothelial dysfunction with abnormalities of coagulation and fibrinolytic pathway may lead to venous and arterial occlusion Several microbial antigens have been shown to stimulate T cells of BD patients

BD is, at least in part, an immune mediated disorder, in which multiple cells are major and minor components. This includes cells of the innate immune system (neutrophils, NK cells), but also of the specific immune system, especially the T cells.

Hyperactive neutrophils, with a high expression of CD10, CD11a and CD14, infiltrate BD lesions, leading also to an increase in CD64+ neutrophils in the serum [103], and they seem to initiate an increased chemotaxis, phagocytosis and superoxide generation [11, 84]. Stimulation seems to be initiated by T cells which secret tumor necrosis factor (TNF)- , interleukin (IL)-8 and granulocyte-macrophage colony-stimulating factor (GM-CSF) [74]. T cells in BD patients seem to be, at least in part, apoptosis resistant, e.g., due to NF-kappaB [100], and with a high expression of Fas ligand [107].

T-cell-mediated immune reactions seem to play a major role in BD, but how is not well understood. There is a strong TH1 response with expression of high amounts of IL-2, IFN- [24] and IL-18 [70, 80]. Excessive expression of Txk, a member of the Tec family of tyrosine kinases, seems to contribute to excessive Th1 cytokine production of T cells of BD patients [72]. A reduced CD4/CD8 ratio has been found, but there are indications for a defect of the CD8 suppressor cells [85]. Several microbial antigens have been shown to stimulate T cells in BD patients, e.g., staphylococcal antigens, streptococcal antigens [40, 57, 59], E. coli derived peptides, Chlamydia pneumoniae [6], and especially important heatshock proteins (hsp) of various microbes [58]. Subcutaneous injection of hsp peptides (with adjuvant), but also oral and nasal administration (without adjuvant), can induce experimental autoimmune uveitis in rats [35]. The finding of cytotoxic T cells may show some evidence for a role of virus, e.g., HSV or others, in the pathogenesis of BD. Also unclear is the role of -T cells, which are elevated in BD patients. In correlation to activity, a subset of these cells has a proliferative response to four mycobacterial hsp-derived peptides. This suggests a regulatory role of the -T cells [33]. On the other hand, Vgamma9 Vdelta2 T cells have been isolated from eyes of BD patients, recognizing non-peptide prenyl pyrophosphate antigens [106].

The role of natural killer cells also remains unclear at the moment [114]. BD patients also show

an increased concentration of antibodies against phosphatidylserine and ribosomal phosphoproteins, which may stress the role of NK cells in BD [9]. Recently, an abnormal KIR (killer inhibitory receptor) expression on NK cells of BD patients was found [98]. Kinectin [60] and alpha-tropomyosin [61] have also recently been suggested as important autoantigens in BD.

Vascular involvement is a major feature of BD, leading to venous or arterial occlusion. Additionally to the immunological reaction, it seems that endothelial dysfunction and abnormalities of the coagulation and fibrinolytic pathway facilitate BD. Endothelial dysfunction [53] in BD patients has been reported. Endothelial cells are characterized by a reduced flow-mediated dilation of arteries [15], impaired synthesis of endothelial cell-derived prostaglandins [45], increased levels of endotheliumderived antiaggregant PGF1 , and platelet-derived proaggregant TXB2 [34]. Additionally, antibodies against endothelial cells have been detected in up to 50 % of BD patients, directed especially against microvascular cell antigens [7, 12, 21, 55], at least in part directed against alpha-enolase [54]. In most studies the incidence of anti-endothelial cells correlates with BD activity. An increase of soluble E-selec- tin in BD patients may be caused by activated endothelial cells and may serve as a control parameter in BD vasculitis [91].

Besides endothelial dysfunction, abnormalities of the coagulation and the fibrinolytic system have been detected. An elevation of the thrombin-anti-

thrombin III complex, of thrombin activatable fibrinolysis inhibitor (TAFI) [22] and of prothrombin 1 and 2, but also of plasma plasminogen activator inhibitor-1 (PAI-1) antigens and PAI-1 activities [81], may cause intravascular thrombin formation. Further, also defects in protein C, protein S and factor V Leiden have been demonstrated in patients

with BD after thrombosis, when they carry the factor III 25 V Leiden and prothrombin gene [13, 64, 89, 93]. Also

mutations which increase the risk of thrombosis have been located in BD patients [27, 29, 62, 105]. The relevance of elevated anticardiolipin antibodies (25 % in BD patients) [101], especially in the active state [69], remains unclear at present. All findings support an imbalance toward a prothrombotic state: endothelial dysfunction may facilitate immunemediated vasculitis, leading to profound tissue damage.

As the genetic contribution to the pathogenesis of BD is estimated at only 20 – 30 % [30], infectious agents, heat shock proteins, abnormalities in the innate immune system such as neutrophil hyperfunction or an increase in gamma delta T-cells together with pro-coagulatory factors play a major role. The present hypothesis for the pathogenesis of BD is depicted in Fig. 25.3.1.

Fig. 25.3.1. Hypothesis for the pathogenesis of MB: (1) genetic factors, e.g., HLA-B*51, induce a general hyperactivity of the immune system (TH1 response, granulocytes). (2) Bacterial or viral infection stimulates the expression of HSP60 (self) and MICA on different cells (e.g., endothelial cells), upregulation of adhesion molecules, activation of coagulation, stimulation of T cells (especiallyand NK cells), continuing elevation of the cytokine production; and finally (3) tissue damage (vasculitis). Additionally, molecular mimicry with HLA-B*51 may play a role. In parallel, B cells will be stimulated polyclonally (not shown on the figure) and may produce more antibody (e.g., against HSP)

Molecular

Mimicry

Self-HSP 60

25.3.3Genetics and Molecular Mechanisms

Essentials

The genetic contribution to the pathogenesis of BD is estimated to be 20 – 30 %

25 III HLA-B51 is the most important genetic marker for BD

Analysis of multicase families suggests a complex genetic inheritance model

The most important allele for BD seems to be B*5101, while at least in Japanese B*5201 seems protective

Other genes are in linkage disequilibrium with HLA-B51, like MICA

The critical region for susceptibility antigens, coding for BD, lies between the HLA-B locus, the TNF locus and the locus for MICA, or possibly at the telomeric end of chromosome 6pi

Despite the fact that cause and pathogenesis of BD are still to a large extent unclear, important factors for the pathogenesis have been identified in the last approximately 30 years. With a strong genetic predisposition, primary or secondary abnormalities of the immune system, probably following a still unknown infection, seem to initiate BD.

It seems that HLA-B51, with HLA-B52 one of the split antigens of HLA-B5, is a very important genetic marker for this disease. HLA-B5 is present in 40 – 80 % of all BD cases [67], while in the respective healthy population the prevalence is between 8 % (northern Europe) and 24 % (Turkey, Middle East) [104]. Table 25.3.3 shows the prevalence of HLA-B51 in different studies. This strong association has been confirmed in patients of different ethnic origin. The analysis of multicase families suggests a complex genetic inheritance model [29]. Hence, familial cases of BD are only rarely reported. This high association only exists with HLA-B51, but not HLA-B52. BD has not been reported yet from countries with an extremely low prevalence of HLA-B51.

Table 25.3.3. Prevalence of HLA-B*51 in patient groups, healthy controls and general population, relative risk for BD. (Modified from [104] and [116])

Empty fields: no data available a Southern Spain

The B51 antigen comprises 29 alleles at the amino acid level, B*5101-B*5124 [23]. The distribution of these alleles has been shown to be very different in ethnic groups. While B*5108 and B*5101 were found to be relatively high in patients from Greece, Iran, Italy and Saudi Arabia, this allele is unknown in Japan, where there is a dominance of 58.3 % BD patients who are B*5101 positive. The fact that in Japanese patients B*5201 (13.2 % of BD patients) seems protective for BD, in contrast to B*5101, has provoked the following hypothesis: B*5101 and B*5201 differ only by two amino acid substitutions at position 63 and 67. In B*5101 (also in B*5102 and B*5108) position 63 has asparagine, and position 67 has phenylalanine [66]. Both positions seem to be an important part of the pocket of the HLA groove. The difference in the allelic distribution between the Japanese patients and patients from the more Western located countries around the Silk Route may be due to different methods of distribution. It appears likely that BD spread among the various populations together with its associated HLA- B*51 allele prior to divergence into suballeles. Recently it has been shown for Japanese patients that HLA- A*2602 and B*3901 might also have some secondary influence on the onset of BD [41]. The analysis of sister chromatid exchange (SCE) has demonstrated a higher SCE frequency in HLA-B51 positive patients than in HLA-B51 negative ones, pointing to a higher rate of DNA damage in HLA-B51+ patients [37].

Besides the association with HLA-B51, the contribution of other genes has been investigated. Most research focuses on chromosome number 6, which also contains the genes for the major histocompatibility complex (MHC), in the human HLA system. Besides others, polymorphisms for the alleles encoding the intercellular adhesion molecule (ICAM-1) [10], the CTLA-4 gene [87] and the VEGF gene [90] have been found also for the endothelial nitric oxidase synthase [88], for IL-18 [42], and for IL-1 [46]. Recently it has been suggested that the gene responsible for the familial Mediterranean fever (MEFV) may also be involved in the pathogenesis of BD [38]. Some other protein alleles seemed to be associated with BD, like MICA [36], but were finally found to be in linkage disequilibrium with HLA-B*51. An additional susceptibility locus was mapped to 12p12 – 13 and 6p22 – 24, which is well beyond the strong linkage disequilibrium region [30, 47]. The TNF- gene polymorphisms are unlikely to play an important role in the pathogenesis and severity of BD [4, 56] in contrast to the MBL2 gene (mannose-binding lectin gene-2), in which the HYPA haplotype seems to play a role in MBL levels and increases the susceptibility to MB [83], and also the endothelial nitric oxide synthase gene [49]. Identification of other susceptibility genes is under investigation.

Hence, at present HLA-B51 is the only major disease susceptibility antigen which is directly associated with BD. The critical region in which susceptibility antigens for BD are coded probably lies between the HLA-B locus, the TNF locus and the locus for MICA (MHC Class I chain related A), or possibly at the telo-

meric end of chromosome 6pi.

III 25

25.3.4 Course of the Disease

25.3.4.1 Extraocular Manifestations

Essentials

BD is a multisystem vasculitis, affecting nearly all organ systems

Common manifestations can be distinguished from rarer ones

Predilection sites are mucous membranes with oral aphthous ulcers as the main feature

Young and male patients may have shortened life expectancy due to more severe courses of the disease

Although BD as a multisystem vasculitis may affect nearly all organ systems, mucous membranes, the skin and the eye are preferred sites [86, 94]. Table 25.3.4 presents an overview of the extraocular manifestations and their frequency in patients with BD.

The main features of BD are oral aphthous ulcers, which affect nearly all patients. In contrast to habitual aphthosis, ulcerations in BD occur in uncommon locations (e.g., sublingually, hard and soft palate, epipharynx, pharynx and larynx), last a long time (2 weeks), relapse frequently and are very painful.

Genital ulcerations and skin lesions are also frequent manifestations of BD. The latter may present,

Table 25.3.4. Extraocular manifestations and their frequency in Beh¸cet’s disease

e.g., as papulopustules, acneiform pseudofolliculitis, erythema nodosa or superficial thrombophlebitis. Cutaneous hypersensitivity is demonstrated by the so-called pathergy phenomenon: 24 – 48 h after an intracutaneous stick with a sterile 21G needle a sterile papulopustule occurs [20, 26]. If the skeletal system is involved, arthritis is mostly oligoarticular

25 III (less than five joints affected), asymmetrical, affects the lower extremities and is non-erosive (thus usually not being visible on X-rays). Gastrointestinal, neurological and vascular (thromboses and arterial aneurysms) are less frequent but potentially very serious manifestations of BD. Cardiac (e.g., pericarditis), urogenital (mostly epididymitis) and renal manifestations rarely occur. Life expectancy may be shortened especially in young and male patients tending to more severe courses of BD. Involvement of the CNS, arterial aneurysms and gastrointestinal involvement are the most life threatening manifestations [109].

25.3.4.2 Ocular Manifestations

Essentials

In 10 – 20 % of patients intraocular inflammation may be the initial manifestation of BD

Anterior uveitis (iritis with hypopyon), posterior or panuveitis with occlusive retinal vasculitis and cystoid macular edema are typical findings in ocular BD

Ocular disease is mostly bilateral, running a chronic relapsing and progressive course

Ocular involvement in BD, often termed as “ocular BD,” is usually characterized by the occurrence of a non-granulomatous inflammation, especially as diffuse uveitis with retinal vasculitis, and is found in 60 – 80 % of patients [5, 16, 97, 99, 113]. The reported frequency of ocular manifestations is 83 – 95 % in males and 67 – 73 % in females, and several studies indicate that the disease is more severe in men [51, 97, 113].

The first signs of uveitis are reported on average 4 years after disease onset, but it could also be the initial BD symptom in 10 – 20 % of patients [16, 97, 113].

Ocular BD demonstrates a chronic relapsing course and progress by successive attacks. As the healing of lesions is very slow, a new attack will occur before the healing is completed. As a result, lesions will accumulate from one attack to another, progressing gradually toward severe loss of vision [17].

The primary eye lesions in 50 – 87 % of patients may be unilateral and may occur most often as an

Fig. 25.3.2. Iritis with hypopyon

anterior uveitis, but later on, in 75 % of cases bilateral panuveitis with a chronic relapsing course is reported [97, 115] – so an anterior segment type and a panuveitis type of inflammation is reported [65].

Less than 20 % of patients present only with anterior uveitis [1, 65, 113]. The occurrence of hypopyon (Fig. 25.3.2), found in 16 – 39 % of cases, is not necessarily a distinctive feature of the ocular manifestation in BD [1, 65]. The explanation for this phenomenon could be that nowadays, due to early and aggressive treatment, the inflammation will be dampened [97, 115].

Slit lamp examination will reveal conjunctival and ciliary injection, keratic precipitates, cells and flare in the anterior chamber, and vitreous opacity.

Interestingly, the acute inflammation of the anterior chamber may resolve spontaneously over 2 – 3 weeks even without therapeutic intervention. So, the visual prognosis for the anterior segment type is more favorable than for the panuveitis type.

Complications of recurrent anterior uveitis could be iris atrophy, and posterior and peripheral anterior synechiae, resulting in development of secondary glaucoma and secondary cataract formation [97, 113, 115].

Rarely described anterior segment manifestations in BD are conjunctivitis with or without subconjunctival hemorrhage, episcleritis or scleritis, keratitis, and, seldomly, extraocular muscle paralysis [16, 97, 115].

Inflammatory changes in the panuveitis type include vitritis, whereas an isolated vitreous inflammation is not characteristic of ocular BD. The most frequent finding is retinal vasculitis, resulting in intensive retinal edema, yellowish-white exudates and hemorrhages (Figs. 25.3.3, 25.3.4). This retinal vasculitis shows an occlusive course and ocular histopathology during the attack is characterized by severe angiitis with intensive infiltration of neutrophil leukocytes largely in the uveal tract and the retina; the latter is severely affected and loss of visual cells and other neural elements results [65].

In most patients retinal vasculitis occurs mainly affecting the retinal veins, which is pathognomonic for BD as it is the only systemic vasculitis affecting

Fig. 25.3.3. Acute infiltration of the central retina

small and medium sized arteries and veins. So, perivascular sheathing has been observed frequently, whereas sheathing of the veins often precedes sheathing of the arteries [97, 115]. A typical complication is retinal vein branch occlusion, mentioned in a study by Özdal et al. [78] in about 6 % of affected eyes.

Severe retinal vasculitis may lead to ischemic III 25 alterations due to the vascular occlusion (Fig. 25.3.5),

which will cause tissue hypoxia and, subsequently, retinal neovascularizations due to stimulating growth factors. These neovascularizations, which could occur all over the retina, especially at the optic disk, have a high risk of bleeding in the vitreous capacity, which may induce membrane formation, causing retinal holes with secondary retinal detachment [97, 113, 115].

Also the optic nerve can be affected due to ischemic lesions and results in optic disk paleness in about 7 % of cases [78], but more often, in at least