eMedicine Specialties > Pediatrics: General Medicine > Rheumatology

Behcet Syndrome

Author: C Egla Rabinovich, MD, MPH,, Assistant Professor and Co-Division Director, Department of Pediatrics, Division of Pediatric Rheumatology, Duke University Medical Center
Coauthor(s): Linda Wagner-Weiner, MD, Assistant Professor, Department of Pediatrics, University of Chicago
Contributor Information and Disclosures

Updated: Aug 24, 2009

Introduction

Background

Behçet syndrome is a multisystem disease of unknown etiology probably first described by Hippocrates in the 5th century. The syndrome carries the name of the Turkish dermatologist Hulusi Behçet, who, in 1937, described a syndrome of recurrent aphthous ulcers, genital ulcerations, and uveitis leading to blindness. Although the cause of the disease is still unknown, it has become recognized as a multisystemic inflammatory disease.

Pathophysiology

Behçet syndrome is characterized by recurrent aphthous ulcers, genital ulcers, and uveitis or retinal vasculitis. Other manifestations of the disease include skin lesions, arthritis, GI lesions, CNS involvement, and vascular lesions, including aneurysms and thrombosis. In Behçet syndrome, the basic lesion is vasculitis. Biopsies have shown vasculitis near affected lesions, including the oral and genital ulcers and lesions of the CNS and the eyes; large vessels are affected by a vasculitis of the vasa vasorum. Vascular injuries may be superimposed on the hypercoagulability observed in some patients.

Neutrophilic hyperfunction is observed in patients with Behçet syndrome with neutrophilic infiltration of skin at the site of a prick with a sterile needle (the pathergy test). Lymphocyte function has also been reported as abnormal, with a clonal expansion of autoreactive T cells.

Frequency

United States

Frequency data for Behçet syndrome should be considered suspect because of problems with case ascertainment.¹ This problem is inherent in any disease where no specific diagnostic test exists and only a set of clinical criteria is used for diagnosis. Figures available from Olmstead County, Minnesota reveal prevalence in this community to be 5 cases per 100,000 persons. Other estimates of prevalence vary from 0.12-0.33 cases per 100,000 persons.

International

Behçet syndrome is thought to be more common along the ancient Silk Road, extending from Asia to the Mediterranean. Estimates from Turkey vary from 80-370 cases per 100,000 population, whereas prevalence estimates from Japan, Korea, China, and the Middle East vary from 13-20 cases per 100,000 population. In northern Spain, prevalence has been reported as 0.66 cases per 100,000 population, whereas estimates from Germany are 2.26 cases per 100,000 population.

Mortality/Morbidity

• Ocular: Uveitis occurs in 60-80% of patients. Retinal arterial and venous lesions are prognostic indicators for blindness, which is a major complication of Behçet syndrome. In Middle Eastern populations, the mean time from onset of disease to blindness is 3-4 years in untreated patients or in those treated only with corticosteroids.
• CNS: Neurologic involvement is one of the most serious manifestations of Behçet syndrome, occurring in 10-30% of patients and carrying a poor prognosis. Manifestations include meningitis or meningoencephalitis; psychiatric symptoms, including personality changes; neurological deficits, including hemiparesis; and brainstem symptoms. Neurological deficits may be progressive, with 30% of those patients with neurologic manifestations eventually developing dementia.
• Vascular: Vascular involvement in Behçet syndrome is unique in that it is the only vasculitic disease that involves both the arterial and venous systems. Vascular complications, which occur in 7-40% of patients, include venous and arterial thromboses, vessel occlusions and stenoses, and aneurysm formation. Venous involvement typically includes superficial thrombophlebitis or deep venous thrombosis, usually of the lower extremities. Vena cava thrombosis can also occur, with extension to the hepatic vein, leading to Budd-Chiari syndrome and its associated morbidity and mortality. Patients with arterial manifestations may present with thrombosis or aneurysm formation with possible fatal rupture, especially if pulmonary arteries are involved.
• GI: GI disease is associated with pyoderma gangrenosum and with papulopustular lesions, especially in children.²  GI involvement consists of small vessel disease that involves mucosa and results in ulcers or large vessel disease that results in ischemia and infarction. The ileocecal region is the area most commonly involved with ulcers; the ulcers may be superficial or more typically deep with increased risk of perforation.

Race

Behçet syndrome is thought to be more common in Turkish, Asian, and Middle Eastern populations. However, the severity of disease may be increased in these populations, with better case ascertainment as a result. An increased incidence of skin pathergy and HLA-B5 antigen is observed in Middle Eastern and Asian patients, compared with North American or northern European patients.

Sex

In Japan and Korea, Behçet syndrome is more common in females, with a male-to-female ratio of 1:2, but it is more common in males in the Middle East, with a male-to-female ratio of 2:1. In the literature, estimates of male-to-female ratios range from 11:1 to 0.2:1. Despite the variability of the reported sex ratios, the disease tends to run a more severe course in males.

Age

Onset typically occurs in patients in the late third and early fourth decades of life. Onset during the childhood years is well recognized, but Behçet syndrome rarely occurs before school age. Mean age of onset for pediatric patients in a large Turkish series was 11.7 years.

Clinical

History

Two sets of criteria are commonly used for diagnosis of Behçet syndrome: an international criteria for Behçet syndrome, derived in 1990, and the O'Duffy criteria. Both sets of criteria may be too stringent for application in children who have lower risk for oral or genital ulcerations from other causes.

• The international criteria include recurrent oral ulcerations, plus 2 of the following:
  • Recurrent genital ulcerations
  • Eye lesions
    • Anterior uveitis
    • Posterior uveitis
  • Cells in the vitreous
  • Retinal vasculitis
  • Skin lesions
    • Erythema nodosum
    • Pseudofolliculitis
    • Papulopustular lesions
    • Acneiform nodules (in a postadolescent patient not taking corticosteroids)
  • Positive pathergy test
• The O'Duffy criteria require the presence of recurrent aphthous ulcerations, plus any 2 of following:
  • Genital ulcers
  • Uveitis
  • Cutaneous pustular vasculitis
  • Synovitis
  • Meningoencephalitis
  • Exclusion of inflammatory bowel disease, systemic lupus erythematosus (SLE), Reiter syndrome, and herpetic infections
• Oral ulceration, the hallmark of this disease, is usually the initial clinical symptom and can precede other manifestations by years. Ulcers are typically painful, appear in crops, and are nonscarring. For diagnostic purposes, at least 3 episodes in a 12-month period are required. In one study of pediatric Behçet syndrome, the average time interval between the initial oral ulceration and the second manifestation was 8.8 years.
• Genital ulcers appear in the vulva and vagina in females and scrotum and penis in men. Ulcers are painful, recurring, and scarring.
• Ocular manifestations may be asymptomatic initially, or may present quite dramatically with hypopyon uveitis. Patients may report blurred vision, eye pain, photophobia, increased lacrimation, and erythematous conjunctiva.
• Skin manifestations are nonspecific and include erythema nodosum, folliculitis, and pustular rash.
• Arthralgias and arthritis can occur in small or large joints. Sacroiliitis has been described in HLA-B27–positive patients.
• Gastrointestinal symptoms are common and include abdominal pain, diarrhea, and melena. Perforation may occur.
• CNS involvement may occur in up to 25% of children and is the most severe manifestation of the disease. Patients with meningoencephalitis present with headache and stiff neck; focal neurological abnormalities can also be observed. Neuropsychiatric symptoms include hallucinations and personality changes. Other features that have been described include brainstem lesions; pseudotumor cerebri; cranial nerve palsies; and pyramidal, extrapyramidal, and cerebellar symptoms.
• Vascular manifestations are varied and depend on the type and location of the vessel involved. The most common vascular complaints are secondary to venous thrombosis, often of the superficial veins. This can occur after venipuncture. Patients who develop superficial thrombophlebitis are more at risk than other patients with Behçet syndrome for the development of deep vein thrombosis and arterial disease. Well-known syndromes of large venous occlusions, such as Budd-Chiari syndrome or superior vena-caval syndrome, may occur. Patients with cerebral venous thrombosis develop signs and symptoms of increased intracranial pressure, such as headache and visual blurring. Arterial occlusions may present with symptoms related to ischemia. Cigarette smoking may be a risk factor for arterial disease in Behçet syndrome.
• Pulmonary manifestations include pulmonary vasculitis and pulmonary arterial aneurysm formation; patients may present with hemoptysis, dyspnea, chest pain, or cough.

Physical

• Physical findings vary, reflecting the disease manifestations in a particular patient.
  • Oral ulcerations: Ulcers are typically 2-15 mm in diameter, with a necrotic center and surrounding red rim. A white or yellow pseudomembrane covers the surface of the ulcer. The ulcers are typically painful, nonscarring, and found on the lips, buccal mucosa, tongue, tonsils, and larynx. Most last 7-14 days and occur in crops.
  • Genital ulcerations: These typically occur less often than the oral ulcerations. The ulcers occur on the scrotum and vulva, are painful and heal with scarring, especially on the scrotum. Genital ulcerations tend to be deeper and larger than the oral lesions. Females can have asymptomatic ulcers, especially in the vagina.
  • Ocular manifestations: Uveitis can occur in both the anterior and posterior chambers of the eye.³ Frank pus (hypopyon) may be observed in the anterior chamber. Retinal vasculitis is the most serious ocular finding. Vaso-occlusive lesions of the retinal vessels may cause a progressive decreased visual acuity. A slit lamp examination is necessary for diagnosis of uveitis, and fluorescein angiography is useful to identify retinal lesions.
  • Skin manifestations: Erythema nodosum lesions typically occur on the extremities, especially the lower legs, but they can also be observed on the face, neck, and buttocks. The lesions are painful and resolve spontaneously, although some may ulcerate or leave hyperpigmentation. A folliculitislike rash, resembling acne vulgaris, appears on the face, neck, chest, back, and hairline of patients. Some lesions become more pustular; 24-48 hours after a sterile needle prick, some patients develop erythema with a nodule or pustule at the prick site. This pathergy response is commonly observed in patients from Asia and the Middle East and is uncommon in northern European and North American patients.
  • Skeletal involvement: Monoarthritis or polyarthritis occurs in at least 50% of patients. Knees are the most commonly affected joints, followed by wrists, ankles, and elbows. The arthritis is typically nonerosive.
  • GI manifestations: In addition to the oral mucosa, ulcerative lesions may occur anywhere in the GI tract. Most commonly, ulcers occur in the ileocecal region. Other involved areas include the transverse and ascending colon and the esophagus. Anticoagulation is controversial in patients with Behçet syndrome because of the risk of bleeding from one of these ulcers.
  • CNS involvement: CNS involvement occurs in as many as 25% of patients and may be the most serious manifestation of disease. The immune-mediated meningoencephalitis that is most commonly seen predominantly involves the brainstem. Dural venous sinus thrombosis is less common. Findings may include meningitis, encephalitis, focal neurological deficits, and psychiatric symptoms. The CNS lesions may have exacerbations and remissions. In some patients, irreversible dementia ultimately results.
• Vascular involvement
  • Venous involvement includes migratory superficial thrombophlebitis of the skin and deep venous thrombosis. Patients with lower extremity deep vein thrombosis may have distal edema. With chronic venous occlusion, collateral circulation may develop.
  • Arteritis may involve the aorta or its branches and lead to aneurysm formation. Rupture of aneurysms may be fatal. Pulmonary artery involvement may result in aneurysm formation with pulmonary artery–to–bronchus fistula formation and resultant hemoptysis. Aneurysm formation carries a worse prognosis than occlusive disease. Patients with pulmonary aneurysms often have extrapulmonary vascular complications, such as superficial or deep vein thrombosis.
  • Cardiac valves may develop vegetations with subsequent emboli. Clinically, these lesions are similar to bacterial endocarditis, but cultures are negative, and round cell infiltration is most typically observed on histology. Right ventricular thrombi may also develop, and are frequently found in patients with pulmonary aneurysms.
  • Nephrotic syndrome and kidney amyloidosis have rarely been described in patients with Behçet syndrome.
• Muscular involvement: Myositis has been described in pediatric Behçet syndrome.

Causes

• The etiology of Behçet syndrome is unknown. Behçet syndrome is thought to be caused by a combination of hereditary and environmental factors. The HLA-B51 allele (one of the split antigens of B5) is commonly found in patients from Asia and the Middle East, yet it is rarely found in northern European and North American patients. Infections may play a pathogenic role, as patients who have Behçet syndrome have a higher incidence of antibodies to herpes simplex virus, hepatitis C virus, and parvovirus B19. Streptococcal antigens have also been implicated; a trial of prophylactic penicillin treatment decreased the number of acute arthritis episodes in patients with Behçet syndrome.
• Patients who have a parent with Behçet syndrome have disease onset at a younger age (genetic anticipation). In addition, pediatric patients are more likely to have a family history of Behçet syndrome, compared to patients with disease onset as an adult.

• Search for CME/CE on This Topic »

• Aseptic Meningitis (Neurology)
• Hairy Leukoplakia (Dermatology)
• Behcet Disease (Rheumatology)
• Behcet Disease (Dermatology)