Ophthalmologic Manifestations of Behcet Disease Clinical Presentation

Ocular involvement in Behçet disease

Ocular involvement is seen in about 70% of patients who have Behçet disease.

In most cases, the ocular symptoms follow the oral and genital ulcers by 3-4 years, although ocular disease is the initial manifestation in about 20% of cases.

Behçet disease is characterized by severe recurrent attacks of intraocular inflammation. In one series, anterior uveitis was present in 59% of cases; posterior uveitis was present in 76% of cases; and panuveitis was present in 88.1% of cases. ^[4]

Symptoms include periorbital pain, redness, photophobia, and blurred vision.

Oral aphthous ulcers in Behçet disease

Recurrent painful oral aphthous ulcers are the most common lesions associated with Behçet disease and occur in 99.3% of cases. ^[5]

Skin involvement in Behçet disease

Cutaneous hypersensitivity is relatively common, occurring in 81.8% of cases. Acnelike lesions or folliculitis occurs frequently. Migratory thrombophlebitis also can develop.

Genital ulcers in Behçet disease

Recurrent painful genital ulcers occur in 62.8% of cases.

Initial ocular involvement may be unilateral in Behçet disease, but it progresses to bilateral disease in at least two thirds of cases.

In a large retrospective study of Behçet disease, the mean age at onset of uveitis was 28.5 years in male patients and 30 years in female patients. Ocular involvement was bilateral in 78.1% of patients and unilateral in 21.9% of patients. Panuveitis was the most common form in both sexes. Fundus lesions and sight-threatening complications were more common in male patients than in female patients. At the beginning of follow-up, potential visual acuity was 0.1 or less in 30.9% of eyes in male patients and 24.2% of eyes in female patients. The Kaplan-Meier survival analysis estimated the risks of losing useful vision (P >.10) at 5 and 10 years in male patients and female patients, with results of 21% versus 10% and 30% versus 17%, respectively. ^[6]

Ocular involvement in Behçet disease

This is described in 75% of patients, either anterior segment iridocyclitis or posterior segment involvement. Panuveitis and posterior uveitis/retinitis occur more frequently in males than in females (28.9% vs 11.5% and 57.9% vs 36.1%, respectively; P< .05).

The classic finding of Behçet disease, iridocyclitis with hypopyon, is present in about one third of cases. Gonioscopy may reveal an occult hypopyon in many cases. One characteristic feature of the hypopyon in Behçet disease is that it may change position with head movement, and it may form and disappear rapidly without sequelae. Recurrent attacks may result in posterior synechiae, peripheral anterior synechiae, iris atrophy, and secondary glaucoma.

Retinal disease is the most serious complication of Behçet disease. The classic fundus finding is retinal vasculitis, which affects both arteries and veins in the posterior pole.

Ophthalmoscopy shows venous engorgement, retinal hemorrhages, yellow-white exudates deep in the retina, white focal retinal infiltrates, retinal edema, and optic disc edema with hyperemia.

Severe vasculitis may lead to thrombosis of vessels and secondary ischemic retinal changes. Optic disc edema may be secondary to inflammation and may be seen during the acute phase in at least one fourth of cases.

Vitreous cellular infiltration almost always is present during the acute phase.

Retinal neovascularization, secondary to either retinal vein occlusion or chronic inflammation, may result in retinal or vitreous hemorrhage.

Neovascular glaucoma occurs in as many as 6% of patients and often results in phthisis bulbi.

Repeated episodes of posterior segment inflammation cause sheathing of retinal vessels, chorioretinal scars, and retinal and optic nerve atrophy.

Oral aphthous ulcers in Behçet disease

Recurrent aphthous ulceration of the oral mucosa is the most common nonocular manifestation of Behçet disease. They are the first symptoms in 50-70% of patients and develop in as many as 98% of patients. The lesions are located on the gingiva, lips, tongue, buccal mucosa, hard palate, uvula, and posterior pharynx.

A nationwide study in Japan revealed that 97.7% of patients who have Behçet disease have recurrent aphthous ulcers. Ulcers tend to develop in crops, which recur at various frequencies.

White or yellowish pseudomembrane usually covers the surface of the ulcer.

They usually heal within 7-10 days with no scarring.

However, fusion of several small ulcers may produce a large ulcer that leads to scar formation.

Skin involvement in Behçet disease

Skin involvement appears in 70% of patients. Behçet disease may produce a variety of skin lesions in affected individuals.

Erythema nodosum, acneiform lesions, thrombophlebitis, and cutaneous hypersensitivity are most common.

Erythema nodosum lesions, which occur in more than two thirds of patients with Behçet disease, usually are found on the anterior surface of the legs but also may be seen on the face, arms, and buttocks. These lesions appear as slightly raised, red nodules with subcutaneous induration and tenderness. They tend to involute in 10-14 days without ulceration.

Acneiform lesions occur in almost 60% of patients and may occur in patients who receive corticosteroid treatment; therefore, their presence is of questionable diagnostic usefulness.

A peculiar feature of Behçet disease is cutaneous hypersensitivity, which results in small pustules that form on skin after it has been scratched, shaved, or pricked with a needle.

Genital ulcers in Behçet disease

Genital ulcers occur in 80% of patients. They are painful punched-out lesions similar to those that occur in mouth and usually are located in the scrotum or vulva.

These genital ulcers may be deep and, in many cases, result in scarring. These scars are indicators of old disease and may help in diagnosis.

Musculoskeletal involvement in Behçet disease

Painful swelling with redness of joints occurs in as many as 50% of patients.

Transient, recurrent, nondestructive, and nonmigratory arthritis commonly affects large joints such as the knee, ankle, elbow, and wrist. The knee joint is most commonly affected.

Gastrointestinal involvement in Behçet disease

At least 50% of patients who have Behçet disease develop gastrointestinal symptoms.

Intestinal erosions and ulcers may cause abdominal pain, melena, and perforation.

This constellation of intestinal signs and symptoms may simulate Crohn disease and other inflammatory bowel disorders.

Vascular involvement in Behçet disease

Thrombophlebitis is found in 15% of these patients.

Obliterating thrombophlebitis, arterial occlusion, and aneurysm may occur in vessels of all sizes.

Neurologic involvement in Behçet disease

Multiple neurologic disorders that involve pyramidal and extrapyramidal tracts, the cerebellum, the cranial nerves, and, rarely, the peripheral nerves occur more commonly in male patients and in 5-30% of cases.

Both the central nervous system and the peripheral nervous system can be involved. Central nervous system manifestations can be divided into 2 main groups: (1) parenchymal involvement, which includes brainstem involvement, hemispheric manifestations, spinal cord lesions, and meningoencephalitic presentations; and (2) nonparenchymal involvement, including dural sinus thrombosis, arterial occlusion, and/or aneurysms. Peripheral neuropathy and myopathy are relatively rare.

The etiology and the pathogenesis of Behçet disease are not clear but are presumed to be multifactorial, involving genetic, infectious, and immunological factors. Increasing evidence suggests that antigens derived from infectious agents (eg, Streptococcus sanguis, herpes simplex virus, heat shock proteins) are implicated in the pathogenesis of the disease, and it has also become increasingly apparent that these events, once triggered, may be influenced by numerous interdependent and independent genetic regions.

Despite 20 years of intense efforts to identify other associated genetic regions in chromosome 6 and elsewhere, human leukocyte antigen B51 (HLA-B51) remains foremost among candidate risk factors for the disease. MICA alleles in the major histocompatibility complex (MHC) have also been implicated, but their close linkage with HLA-B51 has made their independent contribution to the disease less easy to define. ^[3] A recent review of related genetic studies is available. ^[7]

In 2009, a known association of ACE gene and eNOS gene polymorphisms with Behçet disease in a group of Turkish patients with or without ocular involvement was been investigated. ACE gene polymorphism was found to not play a role in the pathogenesis of Behçet disease. The findings related to the eNOS gene polymorphisms confirmed the significant association with Behçet disease and even more in patients with ocular involvement. ^[8]

Since Behçet disease is characterized by a vasculitis, the underlying mechanism is believed to be an autoimmune process.

Human leukocyte antigen B5

Although familial occurrences have been reported, no consistent inheritance pattern has been established; however, human leukocyte antigen B5 (HLA-B5) is associated with Behçet disease and poor visual prognosis.

Considerable evidence now points toward a more specific association with HLA-B51, a split antigen of HLA-B5.

The frequency of HLA-B51 is 57% in Japanese patients with Behçet disease, compared with only 14% in the control group, which equates to a relative risk of 7.9 for this marker.

Meta-analysis has shown that HLA-B51/B5 carriage predominates in males and is associated with moderately higher prevalences of genital ulcers, ocular and skin manifestations, and a decreased prevalence of gastrointestinal involvement. ^[9]

Restriction fragment link polymorphism studies show linkage disequilibrium between the HLA-B51 locus and the gene for tumor necrosis factor-beta (TNF-beta). This finding may imply that lower levels of TNF-beta may contribute to activation of the inflammatory cascade in persons with Behçet disease.

In Japan, an association has been found between human leukocyte antigen A26 (HLA-A26) and Behçet disease.

The disease occurs more frequently in temperate, northern parts of Japan than in subtropical, southern parts, a distribution that suggests environmental factors influence the prevalence of disease.

With regard to the immunology of Behçet disease, several data suggest a direct role of Th1 lymphocytes in the pathogenesis of the disease lesions. Th1 cytokines, including interleukin 2 (IL-2), TNF-alpha, interferon gamma (IFN-gamma), interleukin 12 (IL-12), and interleukin 18 (IL-18), are elevated and probably contribute to neutrophil and endothelial cell activation. ^[3]

Other diagnostic considerations in Behçet disease

It is important to consider other forms of uveitis in the differential diagnosis, especially in those patients who have a mild or atypical presentation of Behçet disease.

Human leukocyte antigen B27 (HLA-B27)-related anterior uveitis also may cause recurrent iridocyclitis with hypopyon, but it is typically unilateral.

Since Behçet disease is a bilateral panuveitis, other inflammatory processes that affect both eyes must be considered. Syphilis causes a retinitis with vitreitis rather than a strict vasculitis. The diagnosis for syphilis is confirmed by serology.

Sarcoidosis, another bilateral inflammatory process, may have posterior pole findings similar to those in Behçet disease but is generally more indolent, in contrast to the explosive recurrent attacks of Behçet disease. Furthermore, the vasculitis seen in sarcoidosis usually is not occlusive in nature and typically involves only veins, compared with the involvement of both arteries and veins in Behçet disease.

Other conditions that may mimic the ocular changes of Behçet disease include collagen vascular diseases and viral retinitis.