History
In 1990, the International Study Group (ISG) for Behçet's Disease clarified criteria for the diagnosis of Behçet disease. [3] The ISG compared the clinical findings of 914 patients with a history of aphthous ulcers with those of controls. Initial criteria for diagnosis require the occurrence of at least three episodes of oral herpetiform or aphthous ulcerations within a 12-month period observed directly by a physician or reported by the patient. To confirm the diagnosis, at least two of the following must also be demonstrated:
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Recurrent painful genital ulcers that heal with scarring
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Ophthalmic lesions, including anterior or posterior uveitis, hypopyon, or retinal vasculitis
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Skin lesions, including erythema nodosum–like lesions, pseudofolliculitis, or papulopustular or acneiform lesions
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Positive results from pathergy skin testing, defined as the formation of a sterile erythematous papule 2 mm in diameter or larger that appears 48 hours following a skin prick with a sharp sterile needle (22-24 gauge [a dull needle may be used as a control])
See the Behcet's Syndrome International Study Group Criteria calculator.
Considering the above diagnostic criteria, case presentation often includes the following characteristics:
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Multiorgan system involvement, often beginning with mucocutaneous involvement and usually sparing the liver, kidneys, and heart
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Age of 25-35 years at onset
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Organ-specific manifestations characterized by exacerbations and a relapsing/remitting course
In 2014, the International Team for the Revision of the International Criteria for Behçet's Disease (ICBD) proposed a set of diagnostic criteria including vascular and neurologic involvement (see the table below). The ICBD has considerably higher sensitivity than the ISG criteria (94.8% versus 85.0%, respectively) but somewhat lower specificity (90.5% versus 96.0%, respectively). [44]
Table. International Criteria for Behçet's Disease (Open Table in a new window)
Sign/Symptom |
Points |
Genital aphthosis |
2 |
Oral aphthosis |
2 |
Skin lesions |
2 |
Neurologic manifestations |
1 |
Vascular manifestations |
1 |
Positive pathergy test (optional) |
1 |
Patients with an ICBD score of 4 or higher are classified as having Behçet disease. [44]
Skin and mucous membrane manifestations
Painful oral lesions (aphthous or herpetiform) are one of the criteria for diagnosis and may be the first manifestation (70% of cases). See the image below.
Oral lesions are commonly found in keratinized areas of the oropharynx, often excluding the nonkeratinized surfaces of the dorsal tongue, gums, and hard palate. The lesions are usually not distinguishable from those due to other causes but often have a high recurrence rate (often more than five times per year, despite only three times per year specified in ISG criteria) and appear as multiple lesions or crops (often more than six simultaneous lesions at a given time).
Skin lesions often occur in the genital region of both sexes. In males, scrotal involvement is most characteristic; however, lesions can also develop on the penile shaft. In females, the labial area is most commonly involved, with lesions occasionally developing in the vagina and on the perineum. Genital ulcerations typically heal with scarring and are more painful in men. Development of ulcerations in women may correlate with menstruation.
Nodules that resemble erythema nodosum are more common in the lower extremities of females. They are tender, erythematous, and nodular and usually resolve after 2-3 weeks but often recur. Erythema nodosum may be an indicator of mild Behçet disease.
Acneiform papulopustular lesions are more common in men and are usually found on the trunk and extremities, although they may develop anywhere on the body.
Extragenital ulcerations that heal with scarring are rare and affect only 3% of patients. [45] These are very specific for Behçet disease. They can be found in the axillae, neck, breast, interdigital skin of the feet, and groin.
Positive pathergy test is more common in Turkish and Japanese populations, as well as patients with ophthalmic and neurologic manifestations.
Ocular lesions
Ocular presentations (anterior or posterior uveitis, hypopyon, retinal vasculitis, cystoid macular degeneration) represent the first manifestation of disease in 10-20% of patients with Behçet disease. In most cases, however, ocular involvement follows the oral and genital ulcers by 3-4 years. [20, 46]
Symptoms and signs commonly include blurred vision, periorbital pain, photophobia, scleral injection, and excessive lacrimation.
Men, particularly of Iranian and Japanese descent, tend to present with more severe eye involvement.
Highly recurrent posterior uveitis can lead to blindness.
Ocular involvement resulting in blindness commonly develops within the first 7 years. The prognosis is better for persons who develop symptoms later in the disease course.
Ocular involvement is seen in 50-75% 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. Ophthalmic manifestations of Behçet disease are characterized by severe recurrent attacks of intraocular inflammation. Symptoms are characteristic of uveitis - light sensitivity, photophobia, pain, decreased vision, floaters. 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. [46]
Neurologic manifestations
Collectively, neurologic signs and symptoms tend to be an unusual late manifestation, 1-8 years after disease onset. They include the following:
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Memory tends to be affected in most cases, particularly affecting recall and learning. Orientation, arithmetic, and language are often unaffected.
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Symptoms are usually parenchymal in nature, predominantly with brainstem involvement. [36]
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Behavioral changes, primarily apathy or disinhibition, occur in 54% of patients.
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Seizures and bulbar signs with ophthalmoplegia are less common.
Other less common findings include the following:
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Infarctions due to vasculitis or thrombosis
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Meningoencephalitis
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Lymphocytic meningeal infiltration
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Demyelinization
Vasculopathy
Behçet disease can cause aneurysms in the pulmonary arterial tree that often prove to be fatal. Pulmonary artery aneurysmal involvement is associated with right-sided cardiac thromboses and can manifest as hemoptysis, cough, chest pain, or dyspnea. [17]
Vasculitis of the small and large vessels can cause a panoply of symptoms depending on location of the lesions.
Arterial disease predominantly affects males and only rarely occurs in women. [47]
Venous involvement (usually in the form of superficial thrombophlebitis) is more common than arterial involvement. [45] Superficial thrombophlebitis presents in a linear fashion with overlying erythema and is often confused with erythema nodosum. In males, formation of these linear areas of vasculopathy leads to sclerosis and stringlike thickening in the affected areas.
Symptoms correlate with the vessel involved and may be devastating. For example, extension of an inferior vena caval clot to the hepatic vein may be the mechanism of Budd-Chiari syndrome in Behçet disease. [47]
Arthritis
Arthritis and arthralgias occur in as many as 60% of patients and primarily affect the lower extremities, especially the knee. Ankles, wrists, and elbows can also be primarily involved.
The arthritis is nondeforming and asymmetric in nature and can assume a monoarticular, oligoarticular, or polyarticular pattern of involvement.
Symptoms relapse and remit and rarely become chronic.
Diffuse arthralgias are also common.
Gastrointestinal (GI)/genitourinary manifestations (GU)
GI involvement affects 3-16% of patients with Behçet disease. [48] Areas affected often include the esophagus and ileocecal area. Symptoms include abdominal pain, bloating, and GI bleeding. Complications often result from deep ulceration of intestinal sections.
GU involvement can include epididymitis, neurogenic bladder, and sterile urethritis. Neurogenic bladder can present with typical symptoms of urinary retention.
Renal manifestations
Renal manifestations may be underreported. One study found that 1-29% of patients with Behçet disease developed such manifestations. [49]
Associated amyloidosis may develop.
The first presentation is often nephritic-range proteinuria found incidentally. Crescenteric and proliferative glomerulonephritis, as well as IgA nephritis, have also been reported in some cases. [49, 50, 51]
Cardiac manifestations
Cardiac manifestations (5-17% of cases) include the following::
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Coronary vasculitis and thrombosis
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Pericarditis
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Endocarditis with granulomatous changes or fibrosis
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Regurgitation
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Diastolic dysfunction
Pulmonary manifestations
Lung involvement occurs in up to 18% of patients with Behçet disease. Pulmonary vasculitis, hypertension, and pleural effusions have been reported. Pulmonary aneurysms represent a dreaded complication of Behçet disease and may result in massive hemoptysis. The detection of a pulmonary aneurysm in the setting of a vasculitic illness is highly suggestive of Behçet disease. [52]
Physical Examination
Oral ulcers
Recurrent oral ulcers are the first clinical manifestation of Behçet disease in 50-70% of cases and eventually develop in as many as 98% of patients. Ulcers are aphthous or herpetiform in nature and can occur in various keratinized areas of the oral cavity, including the gingiva, lips, tongue, buccal mucosa, hard palate, uvula, and posterior pharynx. White or yellowish pseudomembrane usually covers the surface of the ulcers.They can be very painful. Ulcers tend to develop in crops, which recur at various frequencies.
Ulcers are usually small and heal within 7-10 days with no scarring. However, can vary in size, and may last up to 3-5 weeks. Fusion of several small ulcers may produce a large ulcer (> 10 mm in diameter). Large ulcers heal with scarring, as do their genital counterparts.
Skin
Approximately 70% of patients have skin involvement. Behçet disease may produce a variety of skin lesions; the most common are erythema nodosum, acneiform lesions, thrombophlebitis, and cutaneous hypersensitivity.
Erythema nodosum occurs in more than two thirds of patients with Behçet disease and is more common in females. Lesions usually appear on the anterior surface of the legs but may also occur on the face, arms, and buttocks. These lesions are slightly raised, red nodules with subcutaneous induration and tenderness. They tend to involute in 10-14 days without ulceration. The concomitant present of ulcers, which are more characteristic of Behçet disease, may help limit the differential diagnosis in patients with erythema nodosum.
Pseudofolliculitis and acneiform lesions, found more commonly in males with Behçet disease, primarily affect the trunk and extremities. However, Acneiform lesions are seen 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.
Eyes
Ocular involvement is described in 75% of patients with Behçet disease. Findings may include the following:
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Anterior uveitis with and without hypopyon formation
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Posterior uveitis that may cause blindness
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Glaucoma
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Synechiae
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Retinal vasculitis
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Infarctions
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Hemorrhage
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Edematous appearance of the disc, with retinal detachment
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Leaky retinal vessels revealed by fluorescein angiography, leading to atrophy and fibrosis in some cases
The classic ocular 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.
In a retrospective observational case series of 132 patients with Behçet-associated uveitis, the most common presentation was panuveitis, which occurred in 118 patients (89.4%). Bilateral episodes were observed in 100 patients (75.8%). At baseline, best-corrected visual acuity (BCVA) was 20/125 in both eyes. [53]
Other ocular manifestations at presentation included retinal vasculitis (61 eyes, 26.3%), occlusive vasculitis in (59 eyes, 25.4%), and macular edema (42 eyes, 18.1%). Anterior segment complications included glaucoma in 44 eyes (19%) and cataracts in 34 eyes (14.7%). Optic nerve atrophy was the most commonly observed posterior segment complication. BCVA was better than 20/50 at last follow-up in 131 eyes (56.5%). [53]
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 < 0.05).
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 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. On Kaplan-Meier survival analysis estimated the risks of losing useful vision (P > 0.10) at 5 and 10 years in male patients and female patients, with results of 21% versus 10% and 30% versus 17%, respectively
Nervous System
Pyramidal tract lesions with spastic paralysis and dementia have been demonstrated in some patients with Behçet disease. [36] Neurologic signs may include the following:
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Mental status changes
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Seizures
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Clonus
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Positive Babinski sign
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Difficulty with speech and swallowing
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Emotional lability
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Acute deafness
Apathy or disinhibition is common. Difficulty with recall and learning has been demonstrated. Peripheral nerve involvement is rare.
Vascular system
Lower-extremity superficial thrombophlebitis often presents in a linear fashion with overlying erythema and tenderness. Palpation of sclerosed thrombophlebitis yields subcutaneous stringlike quality.
Deep venous thrombosis (DVT) develops in some cases and typically manifests as local tenderness or as disparity in limb girth.
Saadoun et al found that cerebral venous thrombosis (CVT) was present in 7.8% of a large cohort of patients with Behçet disease. The main complication of CVT was severe visual loss due to optic atrophy. Papilledema and concurrent prothrombotic risk factors were independently associated with the occurrence of sequelae; peripheral venous thrombosis and concurrent prothrombotic risk factors were associated with relapse of thrombosis. Anticoagulant therapy proved safe and effective in up to 90% of patients. [54]
Arterial vasculitis may manifest as claudication symptoms.
Musculoskeletal system
The arthritis has predominance for the lower extremities, especially the knees, but may occur in any pattern. Joint involvement tends to be transient but recurrent.
Arthritis is usually not destructive or deforming. Joint-fluid content often reflects only inflammatory properties. Aseptic necrosis develops in rare cases.
Gastrointestinal system
Ulcerative lesions can cause abdominal pain, bloody diarrhea, and occasional intestinal perforation. GI lesions are indistinguishable from those associated with inflammatory bowel disease but commonly occur in the ileocecal region.
Genitourinary system
Genital ulcers occur in 80% of patients. They are painful punched-out lesions similar to those that occur in the mouth. In females, genital lesions commonly appear in the labial folds but can also be found in the vulva and vagina. In males, they usually occur on the scrotum but can also develop in the perianal region and penile shaft. Epididymitis manifests as scrotal tenderness.
Genital ulcers last longer than oral lesions, are deeper, and typically scar after healing.
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Oral aphthous ulcers secondary to Behçet disease.
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Behçet disease. T2-weighted magnetic resonance images show brainstem involvement with meningoencephalitis in an 11-year-old girl with neurologic Behçet disease.
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Histology of Behçet disease ulcers revealing neutrophilic infiltrate and vasculitis.
Tables
Sign/Symptom |
Points |
Genital aphthosis |
2 |
Oral aphthosis |
2 |
Skin lesions |
2 |
Neurologic manifestations |
1 |
Vascular manifestations |
1 |
Positive pathergy test (optional) |
1 |
