This is a multisystem disease, with the posterior ocular complications potentially being devastating.
The posterior pole disease should not be treated with corticosteroid alone.
Newer approaches, such as IFN therapy and biologics such as infliximab, have been suggested as being effective for the ocular manifestations, but randomized studies still need to be done.
Retinal vascular involvement is a common finding in many patients with posterior and intermediate uveitis. Behçet’s disease may be the best example of a disorder characterized mainly by its retinal vascular involvement, often with devastating effects on the patient’s eyesight.
Behçet’s disease is a multisystem disorder named after the Turkish dermatologist, Hulusi Behçet (1889–1948), who in 1937 recognized and reported a triad of symptoms: recurrent intraocular inflammatory episodes with oral and mucosal ulcerations. These observations were based on three patients, two of whom had ocular symptoms atypical of the disorder we recognize today. It should be noted that in the 20th century at least two other clinicians reported cases with similar findings earlier than did Behçet: Adamantiades in 1931 (publishing in the French literature) and Shigeta from Japan in 1924. However, their reports did not stimulate the universal interest that Behçet’s did. The disease was known in ancient times, with Hippocrates probably being the first to describe an association between ocular inflammation and oral and genital lesions. Familial occurrence is seen in 8–18% of Turkish patients with the disease, 15% of Koreans, and 13% of Jews, but much less in a Chinese population (2.6%). , In a more recent study reviewing 761 patients in Turkey, almost 57% of patients with an identifiable diagnosis had Behçet’s disease, with 10.4% being juvenile onset. The prevalence has been calculated to be 80–370/100 000. It is interesting to note that the frequency of the disease is 18 times less in Turks living in Germany than in those in Anatolia. In one center in the United States Behçet’s disease constituted 2.5% of uveitis referrals. One report from Iran put at 8.6% the number of patients seen in a uveitis clinic in Teheran having Behçet’s disease, with more cases of ocular toxoplasmosis being seen. The complete form of Behçet’s disease is rare in Northern Italy, with a prevalence calculated at 3.8/100 000 (incidence of 0.24/100 000). The disease has been noted to be especially common in the Far East and in the Mediterranean basin, and is very frequently noted between 30° and 45° north latitude in Asian and European populations. This corresponds to the old Silk Route used for centuries by traders making the dangerous passage from the East to the West ( Fig. 26-1 ). It appears that the disease is changing in character, severity and prevalence. About 40 years ago Japan appeared to have the greatest frequency of this disorder, with an overall prevalence of 70–85 cases/1 000 000 population, as calculated in the late 1970s. In the early 1990s it was estimated that the total number of patients with this disease in Japan was 16 570, with a prevalence of 135 cases/1 000 000 population. However, the northern portions of Japan have a higher incidence than do the southern areas. Of the estimated 15 000 patients in Japan with Behçet’s disease in 1986, 11 000 were under treatment. This diagnosis was applied to more than 20% of the patients with uveitis seen in the uveitis clinic of the University of Tokyo’s Department of Ophthalmology from 1965 through 1977. Other studies have suggested a lower prevalence of 13.5–20/100 000 in Japan and Korea.
This disorder may have devastating consequences for the eyes, and has therefore attracted a great deal of attention. Insight into its mechanisms has led to an improvement in our treatment of this disorder.
The diagnosis of Behçet’s disease is based firmly on the presence of a constellation of clinical findings. Therefore, clinical criteria have been established that help the clinician decide whether a patient has the disease. Numerous sets of clinical criteria have been proposed for the diagnosis of Behçet’s disease. , For our service we have adapted the criteria established by the Behçet’s Disease Research Committee of Japan ( Box 26-1 ). As can be seen, these criteria add an additional major finding to the original three: skin lesions. Further, the presence of ocular inflammatory disease is given greater weight in the diagnosis. It should also be noted that the minor criteria are not considered in this grading system. The Behçet’s Disease Research Committee of Japan recognizes three special cases: intestinal Behçet’s, vasculo-Behçet’s, and neuro-Behçet’s (essentially the minor criteria). It has also specifically included three laboratory tests: a pathergy test (a skin-prick test), HLA testing for HLA-B51, and screening for nonspecific factors indicative of immune system activation, such as an elevated erythrocyte sedimentation rate, positive results for C-reactive protein, and an increase in the number of peripheral blood leukocytes.
Recurrent aphthous ulcers of oral mucosa
Erythema nodosum, acne, cutaneous hypersensitivity thrombophlebitis
Ocular inflammatory disease
Recurrent anterior and posterior
Obliteration, occlusion, aneurysm
Four major symptoms simultaneously or at different times
Three major symptoms simultaneously or at different times
Typical recurrent ocular disease with one other major criterion
Two major symptoms, excluding ocular
One main symptom
Another system that the reader should be familiar with is the one suggested by the International Study Group for Behçet’s Disease, , which requires the presence of oral aphthous ulcers for the diagnosis in all patients ( Box 26-2 ). These investigators emphasize the importance of oral aphthous ulcers as a sign of this disease on the basis of data collection from a large number of patients and control subjects, in which they found that 97% of patients with Behçet’s disease had oral aphthae.
RECURRENT ORAL ULCERATION
Minor or major aphthous lesions or herpetiform-like lesions need to have been observed by the physician or patient at least three times within a 12-month period.
PRESENCE OF TWO OTHER CRITERIA
Recurrent genital ulceration
Observation by the physician or patient of the aphthous ulceration or scar is required.
The ocular disease can include anterior and/or posterior uveitis, cells in the vitreous, or the presence of a retinal vasculitis.
These changes, noted by the physician or patient, include erythema nodosum, pseudofolliculitis, and papulopustular lesions. In addition, lesions would include an acneiform nodule in postadolescent patients not receiving corticosteroid therapy.
Positive pathergy test result
Read by physician at 24–48 hours.
Other systems have used the minor criteria by equating two of those to one major criterion. Others have tried to introduce a standardized scoring system for all parts of the disease. There is no question that some degree of uncertainty is built into any system, because the various criteria may manifest at different times during the clinical course. Until we have a better way to diagnose this disease, we have favored a strict adherence to the Japanese criteria, as the patients in whom we have diagnosed Behçet’s disease have fairly homogeneous clinical findings.
In a 1991 survey of 3316 patients with Behçet’s disease in Japan, oral aphtha was the most frequently seen major criterion, occurring in 97.7%. Other commonly seen problems were skin lesions (90.4%), with genital ulcers and ocular attacks having a similar incidence (79.8% and 78.6%, respectively) ( Table 26-1 ). Oral aphthae are by far the most common major criterion at presentation ( Table 26-2 ). After the oral aphthae, the order of appearance of the major criteria is skin lesions, ocular symptoms (25.4% in males), genital ulceration in males, and ocular lesions in females (8.6%). Of the minor criteria the most frequently seen in Japan was arthritis (see Table 26-1 ). The ratio of males to females with this disease in Japan was 1.2 : 1 in 1972, whereas in 1981 it had changed to 0.77 : 1. A study involving 25 eye centers and 14 countries identified 1465 patients with ocular lesions. In those patients 94.5% had oral ulcers, with skin lesions and genital ulcers found in over 60%. Differences over 20 years have been noted in the various aspects of the disease and their presence in men and women ( Table 26-3 ). In Israel, Krause and colleagues evaluated 100 patients with Behçet’s disease, 66 of whom were Jewish (with origins from Iran, Turkey, and North Africa) and 34 of whom were Arab. The expression of the disease seemed to be the same, but the patients of Arab ethnicity appeared to have more serious eye disease. In Turkey, however, the male-to-female ratio is 3.3 : 1. More males have the complete form of the disease than do females. Although it is a disease with onset during early adulthood, childhood onset has been reported to occur in rare cases. , Laghmari and associates studied 13 patients with childhood Behçet’s disease and found that familial Behçet’s disease as well as articular and digestive manifestations were more commonly seen in younger children, whereas neurologic and vascular involvement, including panuveitis, seemed to occur more frequently in the older children. Ando and colleagues compared patients seen in a Tokyo eye clinic from 1974 to 1983 with those seen from 1984 to 1993. The number of women presenting with the disease increased to about one-quarter of the patients. Initially 70% of patients manifested ocular symptoms (in the third and fourth decades), and by 1993 almost two-thirds of the patients seen had the incomplete form of the disease. What was striking was the observation that the patients seen between 1984 and 1993 had a much better visual course, ascribed by the authors to better therapy (see below). In one study of 520 patients with Behçet’s disease in North Africa, 83% were male and patients had a mean age of 20 years, which is very young based on our experience. Eighty percent of the patients had ophthalmic involvement, with one-quarter being blind because of their disease. Being male, presenting initially with poor visual acuity to the eye clinic, and posterior or panuveitis were all associated with a poor visual outcome. , Being female and having the disease at a young age were associated with nonrecurrence of ocular inolvement.
|Japan *||Israel †|
|Criteria||n = 139||n = 70||n = 209||n = 54|
|No. Male||No. Female||Gender||Ratio|
|With ocular disease||403/230||750/402||1.75||1.87|
|Without ocular disease||172/298||300/725||0.58||0.41|
|With genital ulcers||260/352||338/806||0.74||0.42|
|Without genital ulcers||315/176||712/321||1.79||2.22|
|With both ocular and genital||88/54||73/104||1.63||0.7|
|Ocular without genital||315/176||674/298||1.79||2.26|
|Genital without ocular||172/298||300/725||0.58||0.41|
The majority of our patients with Behçet’s disease are male. We recently reviewed 120 Behçet’s disease patients seen at the National Eye Institute and compared those we have seen over several decades (late 1960s to the early 2000s). Over the three decades the majority (68%) were Caucasian, and the median age at diagnosis was remarkably similar over the three decades ( Table 26-4 ); 95% of the patients had bilateral disease. All the patients presented with oral ulcers, with genital and skin lesions being next most common. Over the three decades 8–22% of patients had central nervous system disease ( Table 26-5 ). The reader can compare these extraocular findings with the frequency of clinical findings and onset of manifestations reported in 661 Turkish patients ( Table 26-6 ). Table 26-7 compares the therapies used over the three decades. We have seen a marked improvment in the initial visual acuity in those patients treated in the 1990s and 2000s as compared to earlier groups. The mean inflammation score decreased as well.
|Total, n (%)||45 (38)||26 (21)||49 (41)||120 (100)|
|Sex, n (%)|
|Female||19 (42)||10 (38)||24 (49)||53 (44)|
|Male||26 (58)||16 (62)||25 (51)||67 (56)|
|Race, n (%)|
|Caucasian||35 (78)||19 (73)||28 (57)||82 (68)|
|African-American||4 (9)||1 (4)||6 (12)||11 (9)|
|Hispanic||2 (4)||2 (8)||2 (4)||6 (5)|
|Asian||2 (4)||1 (8)||4 (8)||8 (7)|
|American-Indian||1 (2)||1 (4)||3 (6)||5 (4)|
|Other/unknown||1 (2)||1 (4)||6 (12)||8 (7)|
|Age at diagnosis, median (yrs) (range)||28 (13–50)||28 (15–46)||30.5 (6–59)||28 (6–59)|
|Missing age at diagnosis, n||4||3||3||10|
|Follow-up, median (yrs) (range)||0.5 (0–9.3)||2.9 (0–16.8)||1.8 (0–13.1)||1.7 (0–16.8)|
|Period between ocular onset and first visit (yrs)||3.8||3.4||4.0||3.8|
|Manifestation||1960s, n (%)||1980s, n (%)||1990s, n (%)||Total, n (%)|
|Total patients||45 (38)||26 (21)||49 (41)||120 (100)|
|Oral ulcers||45 (100)||26 (100)||49 (100)||120 (100)|
|Genital ulcers||32 (71)||16 (62)||35 (71)||83 (69)|
|Skin lesions||26 (58)||17 (65)||27 (55)||70 (58)|
|Arthritis||13 (29)||12 (46)||20 (41)||45 (38)|
|Central nervous system||10 (22)||5 (19)||4 (8)||19 (16)|
|Vascular lesions||3 (7)||–||3 (6)||6 (5)|
|Epididymitis||2 (4)||1 (4)||2 (4)||5 (4)|
|Clinical Features||Patients (n = 661)||%|
|Skin pathergy reaction||250||37.8|
|Simultaneous occurrence of the symptoms (n = 79)|
|Oral and genital ulcer||65||9.8|
|Oral ulcer and erythema nodosum||21||3.1|
|Oral ulcer and ocular involvement||15||2.2|
|Oral ulcer, genital ulcer and erythema nodosum||16||2.4|
|Oral ulcer, genital ulcer and ocular involvement||11||1.6|
|Complication||1960s, n (%)||1980s, n (%)||1990s, n (%)||Total, n (%)|
|Total patients||45 (38)||26 (21)||49 (41)||120 (100)|
|Cataract||19 (42)||11 (42)||15 (31)||45 (38)|
|Macular edema||13 (29)||9 (35)||16 (32)||38 (32)|
|Optic atrophy||13 (29)||8 (31)||9 (18)||30 (25)|
|Epiretinal membrane||8 (18)||5 (19)||8 (16)||21 (18)|
|Glaucoma||7 (16)||5 (19)||6 (12)||18 (15)|
|Papillitis||13 (29)||8 (31)||2 (4)||23 (19)|
|Intra/subretinal hemorrhage||10 (22)||5 (19)||3 (6)||18 (15)|
|Intravitreal hemorrhage||5 (11)||6 (23)||3 (6)||14 (12)|
|Branch retinal vein occlusion||9 (20)||3 (12)||3 (6)||15 (13)|
|Maculopathy||5 (11)||2 (8)||3 (6)||10 (8)|
|Retinal detachment||2 (4)||2 (8)||3 (6)||7 (6)|
|Disc/retinal neovascularization||1 (2)||3 (12)||1 (2)||5 (4)|
|Phthisis bulbi||2 (4)||1 (4)||–||3 (2.5)|
|Corneal ulcer||2 (4)||–||–||2 (2)|
|Macular hole||–||1 (4)||1 (2)||2 (2)|
Barra and colleagues from Brazil reviewed 49 patients with Behçet’s disease, representing 2% of the total number of patients with uveitis they saw over a 16-year period. Of their patients 71% were male, and more than three-quarters of all patients were white; in 34.5% the ocular attack was the first symptom of their disease, whereas on the whole it took a little more than 3 years for the ocular symptoms to appear after the first manifestation of disease. In a review of 31 French patients, an ocular manifestation was the first symptom in 29%.
How similar is the presentation of the ocular complications of Behçet’s disease in various parts of the world? It would appear that there are more similarities than differences. Muhaya and colleagues compared 19 patients with the disease seen at Moorfields Hospital in London with 35 patients seen at the Kurume University Eye Clinic in southern Japan over the same period. The Japanese patients were older (43 years) than those seen in London (35 years). No significant differences were noted in extraocular findings. More of the Japanese patients had acute uveitis and posterior pole disease and received treatment with topical steroids. Those in London were more often treated with systemic steroids.
Oral aphthous ulcers
An almost universal finding in Behçet’s disease is the amount of discomfort the oral lesions can cause. The number of patients with oral aphthae in the general population is quite high. However, in our experience the lesions in patients with Behçet’s disease can occur in clusters and may be found not only on the gums but also on the lips, posterior pharynx, uvula, palate, and tongue. They can be small but painful, and they recur ( Fig. 26-2 ). They usually heal in 7–10 days without scarring, but scarring occurs when a particularly large ulcer heals. It has been suggested that in contrast to the regular flat borders of the aphthae seen in this disorder, the lesions in the Stevens–Johnson syndrome tend to be irregular, whereas in Reiter’s syndrome they can have heaped-up edges. Some patients can provoke the appearance of these lesions by eating certain foods, whereas Wray and colleagues have shown that trauma to the oral mucosa can cause them to appear, strikingly reminiscent of the prick test.
Erythema nodosum-like lesions are frequently noted on the anterior surface of the legs ( Fig. 26-3 ) but can be seen on the face, neck, buttocks, and elsewhere. These lesions involute without ulceration after several weeks.
Acne-like lesions or folliculitis are also common dermatologic lesions. They can appear on the back and face and are histologically identical to those of the ‘typical’ disorder. Thrombophlebitis is found usually in the extremities. This finding surely denotes a more general vascular disease that can be life-threatening (discussed later). The thrombophlebitis in the extremities can be migratory and can also follow an injection or the taking of a blood sample.
Cutaneous hypersensitivity is a characteristic feature of Behçet’s disease. Dermatographs can be observed in one-third to one-half of patients. Scratching the skin with a needle or taking a blood sample often results in a pustule at that site. This phenomenon – pathergy – has become the basis for the ‘prick’ test, with some researchers believing that this is an important criterion that can be used in diagnosing the disease (discussed later), as first suggested by Curth. In our experience this phenomenon seems to be less common in patients with Behçet’s disease.
In males the lesions may appear on the scrotum and penis and are therefore quite evident, sending the patient for professional help early in the disease. Females usually have their lesions on the vulva or on the vaginal mucosae. Other lesions may be perianal. Kobayashi and colleagues reported that lesions on the vulva occur in the premenstrual portion of the month. It has been suggested that the genital lesions in males are more painful, but this has not been our experience. We have seen female patients with particularly painful and distressing genital lesions, frequently diagnosed initially as being herpetic in origin.
The genital lesions can be deep and therefore leave scars. Thus an examination of the genital region in a patient with suspected Behçet’s disease can be useful as signs of old disease may be present.
The ocular manifestations in Behçet’s disease have serious implications for the patient. Mamo estimated that vision was lost 3.36 years after the onset of ocular symptoms. The ominous clinical course makes us especially careful in our evaluation of these patients. This has led us to be highly cautious in our use of the diagnosis, and the presence of ‘ocular inflammation’ associated with other symptoms does not equate in our minds to the diagnosis of Behçet’s disease.
The disease can affect both the anterior and posterior portions of the globe, but certain characteristic signs can and should be looked for. Statistically ocular disease manifests some 2–3 years after the initial symptoms are noted. The disease is bilateral, with unilateral cases occurring rarely (see Case 26-1 ). One important aspect is the recurrent, explosive nature of the ocular disease. Patients do not have ‘chronic’ ocular inflammatory disease, that is, a lingering inflammatory episode that can be chronically noted. Rather, the disease will appear and be floridly active for a set period (2–4 weeks) and then disappear, with the patient’s ocular disease being quiescent for some time, whether one treats or not. Therefore, therapeutic strategies and their evaluation must be undertaken with this in mind (see later discussion).
An anterior uveitis or iridocyclitis is seen frequently, with an associated hypopyon in about one-third of patients ( Fig. 26-4 ). Although a typical occurrence, it is not pathognomonic for the disease. The hypopyon may not be visible to the naked eye but seen only with the slit lamp. On occasion a small hypopyon can be seen cradled in the angle when gonioscopic examination is performed. The inflammatory disease has a nongranulomatous appearance. The cells will move easily and slide over the corneal endothelium if the patient’s head is tilted in the right direction. Using confocal microscopy, Mocan and colleagues identified that the KPs in Behçet’s disease are made up of small round cells, one of five types identified in ocular inflammatory disease. When the disease is particularly severe and long-standing, cyclitic membranes can form, putting these eyes at risk of developing phacoanaphylaxis. Posterior synechiae can obscure the view of the posterior pole. In our experience an isolated vitreous reaction is not characteristic of this disorder. We have observed this when a patient is receiving therapy that is insufficient to completely prevent the ocular inflammation, and then a smoldering response ensues. Smoldering disease or impending reactivation remain significant problems. Although one does not measure acute activity by the flare in the anterior segment in patients who have had chronic or repeated attacks, Tugal-Tutkan et al., using the laser cell flare meter and examing a large number of Behçet patients, felt that those eyes with flare measured at >6 photons/s had a higher possibility of recurrence.
Retinal disease is the most disquieting aspect of Behçet’s disease and can ultimately lead to blindness. These recurrent retinal vasoocclusive episodes ultimately cause irreversible alterations. Macular ischemia, even bilateral, has been reported, , leading to a severe depression in visual acuity with a guarded possibility for a return in vision. Bilateral central retinal vein thrombosis has been described. A funduscopic examination during the acute attack will, in addition, reveal areas of retinal hemorrhage and edema, accompanied by an inflammatory response in the vitreous. The retinitis often has the appearance of a virally induced lesion, and the decision as to what has caused the lesion usually is based on the overall context in which it is being observed ( Fig. 26-5 ). Indeed, the disease can readily mimic acute retinal necrosis. The sequelae of the retinal vasoocclusive episodes can be best seen with fluorescein angiography, and we follow disease activity using this tool ( Fig. 26-6 ). Some of the changes can be extensive, far more so than imagined on clinical examination alone. Areas of capillary dropout and vascular-tree rearrangement are not uncommon. The loss of a clearly defined capillary-free zone is commonly seen but is not unique to this type of intraocular inflammation. In addition, the angiogram may show diffuse retinal vascular leakage, late staining of the vasculature, leakage from the disc, and neovascularization. It is most important when evaluating a Behçet patient to consider performing a fluorescein angiogram, as although the clinical examination may not demonstrate dramatic changes, angiography may show extensive changes ( Fig. 26-7 ). It has been thought that the posterior pole disease is essentially retinal disease. However, one can see evidence of choroidal, outer retinal, or retinal pigment epithelial involvement, raising the question that in some patients choroidal involvement is probably of some importance. An example of this is seen in Figure 26-8 . This patient with Behçet’s disease had fluorescein angiographic evidence of a central serous retinopathy associated with retinal edema, further suggesting an occlusion of the choriocapillaris. Indocyanine green (ICG) angiographic evaluation of the disease has been used and reported. In one study, Bozzoni-Pantaleoni and associates noted several patterns of dye accumulation. In 50% of eyes, poorly defined areas of intermediate and late hyperfluorescence were seen. Atmaca et al. reported choroidal areas of hyper- and hypofluorescence in 53 of 69 (76.8%) of the eyes they studied. Therefore, subretinal alterations are not a rare event. However, it still appears that the retinal alterations are the most damaging. In most studies, the presence on the ICG angiogram of hyperfluorescent areas up to the late phase was related to disease duration.
Other ocular manifestations include episcleritis, filamentary keratitis, conjunctivitis, and subconjunctival hemorrhages. Extraocular muscle paralysis may be a result of neuro-Behçet’s disease.
The complications of repeated inflammatory bouts are of major concern and depend somewhat on where the inflammation is located. Anterior segment inflammation can lead to glaucoma, particularly angle-closure glaucoma. Iris atrophy may be seen as well. Cataract formation is not unusual, due to either the inflammation or the medications added to treat the condition. Iris neovascularization and secondary glaucoma are ominous findings and can accompany recurrent posterior globe inflammatory episodes. The visual prognosis for a patient with anterior segment uveitis only in Behçet’s disease is thought to be good. More women than men in the Japanese experience have this type of disease, and therefore their visual prognosis is less guarded than that for men. We have not seen this subgroup of patients – that is, those with only anterior segment disease. In our experience the disease most frequently involves both segments of the eye. This was the opinion of the late Dr David Ben Ezra in Israel as well (personal communication, 1987). The reader can see that the ocular complications we have seen over three decades has been relatively similar in percentage distribution ( Table 26-8 ).