Criteria and diagnosis

History: Signs and symptoms, which may be recurrent, may precede the onset of the mucosal membrane ulcerations by weeks to years.

• Generalized symptoms prior to the onset of an acute attack include
• Malaise
• Anorexia
• Weight loss
• Generalized weakness
• Headache
• Perspiration
• Decreased or elevated temperature
• Lymphadenopathy
• Pain of the substernal and temporal regions

• A history of (1)repeated sore throats, (2)tonsillitis, (3)myalgias, and (4)migratory erythralgias without overt arthritis is common.

• The most common and earliest sign of Behcet disease is recurrent oral ulcers.

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

The diagnosis of Behcet disease is based on clinical criteria because of the absence of a pathognomonic laboratory test. Unfortunately, the period between the appearance of an initial symptom and a major or minor second manifestation can be up to a decade long in many cases.

The number of different criteria/ classification systems that have been introduced over the past 25 years reflects the failure of any single one to meet clinical demands. 

The Behcet's Disease Research Committee of the Ministry of Health and Welfare of Japan first proposed formal diagnostic criteria in 1972. This set of criteria, which has been used throughout the world, classifies disease findings into 4 major and 5 minor criteria. When all 4 major criteria are met, the disease is said to be of the complete type, whereas the incomplete type consists of various combinations of major and minor criteria, with added weight given to ocular disease.The revised 1987 criteria of the Japanese group (Shimizu) have been widely applied (Table 1).

In 1990, the International Study Group for Behcet Disease (ISGBD- now called the International Society for Behcet's Disease, ISBD) have proposed a separate set of diagnostic criteria (Table 2). Based upon these criteria, a diagnosis of Behcet disease requires recurrent oral ulceration and at least 2 additional criteria, including recurrent genital ulcers, ocular lesions, skin lesions, and a positive pathergy test. 

The major limitation of these criteria, however, lies in the fact that recurrent oral ulceration is the linchpin for diagnosis of Behcet disease. For example, patients with uveitis and genital ulcer without oral aphthosis would not be considered to have Behcet disease, although this is in fact a far-advanced form of the disease.

Like Japan, certain nations tend to rely on their own criteria.

The O'Duffy criteria, mostly used in the US, suffers from a similar problem to that of the international set. The criteria require that, in addition to recurrent aphthous ulcerations, any 2 of following must be present: genital ulcers; uveitis; cutaneous pustular vasculitis; synovitis; meningoencephalitis; exclusion of inflammatory bowel disease, systemic lupus erythematosus (SLE), Reiter syndrome and herpetic infections. 

In Israel, diagnosis is often influenced by a possitive HLA-B5 test result.

As a general rule, we recommend that the Japanese criteria be applied concurrently with the ISGBD (now ISBD) criteria until a more exact system is devised.

Table 1 -

Diagnostic criteria of the Behcet Disease Research Committee of Japan (1987 revision)

Table 2 -

International criteria for classification of Behcet disease (1990)

Note: Findings are applicable if no other clinical explanation is present.

Similar diseases

There are many other diseases, particularly autoimmune diseases, that display similar symptoms, and therefore it is easy to be misdiagnosed. The list is too long to mention all of them, but some that should be considered are

Other considerations should include Herpes Simplex Virus Infection (HSV), Syphilis, Cytomegalovirus (CMV), viral retinitis and Acquired Immunodefficiency Syndrome (AIDS).

Systemic candidiasis and parasitic infections, as well as nutrient deficiencies should be considered even in diagnosed patients.

Lab Studies:

There are no specific clinical laboratory results to confirm Behcet disease.

• CBC: A mild anemia and leukocytosis are observed in some of chronic patients.

• Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), increased number of peripheral leukocytes and other acute phase reactants may be elevated during the active stage of Behcet disease, but they do not correlate well with the clinical activity.

• Increase of alpha 2-globulins is often seen. Serum immunoglobulins, especially IgA, may be elevated.

• Circulating immune complexes are often present.

• Rheumatoid factors (RF), anti-neutrophil cytoplasmic antibodies (ANCA), antinuclear antibodies (ANA) and antiphospholipid antibodies are usually negative.

• Serum complement levels are within the reference range, except for just prior to eye or mucous membrane involvement, at which time they may be decreased.

• HLA-B51 may be present, particularly in patients along the old silk-route. Almost all Isreali patients test positive.

• The pathergy test (or Behcetine test) - the test result is a nonspecific inflammatory reaction to a needle prick or an intradermal injection of saline. The reaction, which varies from an indurated erythema to pustule formation, occurs in 40-60% of patients who have Behcet disease, with great variations between different populations. (see picture and more information)

Other Considerations  and Tests:

Some tests are useful adjuncts in the evaluation of patients already diagnosed with Behcet disease:

• Anticardiolipin antibodies are present in up to 30% of patients.

• In patients with CNS findings, cerebral spinal fluid pleocytosis (increased number of white blood cells in the cerebrospinal fluid) may be present.

• In addition to thrombosis associated with antiphospholipid antibodies, reports exist of thrombosis in Behcet disease associated with factor V Leiden mutations and with prothrombin G20210A mutations.

• Endoscopy of the gastrointestinal (GI) tract is useful for detecting gastrointestinal ulcerations.

• A thorough eye examination by an experienced ophthalmologist is important, and fluorescein angiography is often performed. Follow-up visits with an ophthalmologist should be scheduled every 6-12 months.

• Neuropsychologic testing may be useful with CNS involvement, revealing memory impairment or personality changes, as well as in monitoring neuropsychologic status.

Histologic Findings: The etiology and pathogenesis of Behcet disease remain obscure although many reviews describe a "lymphocytic vasculitis."

Vasculitis is said to affect vessels of all sizes; the various skin lesions are thought to be secondary to a small vessel vasculitis. Biopsy of the buccal and genital ulcers reveals lymphocytic and plasma cell invasion in the prickle cell layer of the epidermis. Dermal vessels are infiltrated with lymphocytes and plasma cells with immune deposits of immunoglobulin M (IgM) and C3. Occasionally, necrotizing vasculitis is observed.

In patients with ocular manifestations, histopathologic changes include necrotizing, leukocytoclastic, and obliterative vasculitis, which affect arteries and veins of all sizes and are probably immune-complex mediated. Only a few eyes that have had active disease have been examined histologically. Vasculitis is said to be the key feature of Behcet disease (see above). Underlying changes seen in the eye are considered similar to those that occur in other organs of the body.

During acute inflammation, the iris, ciliary body, and choroid show diffuse infiltration with neutrophils. In late stages, there is proliferation of collagen fibers, thickening of the choroid, formation of cyclitic membrane (a fibrovascular membrane spanning the ciliary processes), and sometimes hypotonia (decreased muscle tone) and phthisis bulbi (shrinking of the eye). Lymphocytic and plasma cell infiltration occurs during remission. Of all ocular tissues, the retina suffers the most damage. In the phase of acute inflammation, there is severe vasculitis with marked infiltration of leukocytes in and around blood vessels. Recent and old hemorrhages are present. Retinal vessels have thickened basement membranes with swollen endothelial cells, which can lead to thrombus formation and vascular obliteration.

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.

Gonioscopy may reveal an occult hypopyon in many cases. A slit lamp examination is necessary for diagnosis of uveitis. 

T-cell subsets with a preponderance of helper-inducer cells over T suppressor-cryptotoxic (hidden poison) cells were observed in lesions.

Round cell infiltration may be found in cardiac valve lesions. 

Electron Microscopic Observations: Examination of erythema nodosum-like lesions showed microvascular changes and lymphocyte-mediated fat cell lysis. Additionally, small dermal blood vessels embolized by thrombus were observed at the sites of needle prick reaction as well as erythema nodosum-like lesions.

The early changes in fat cells may be caused by vascular changes brought about by the specific degeneration of endothelial cells and vascular stenosis associated with the delayed-type hypersensitivity reaction.

Imaging Studies: In patients with CNS involvement, brain MRI and/or computed tomography (CT) scanning for visualization of the neurological lesions is often helpful. Focal lesions may be observed anywhere in the CNS on the MRI, appearing as high signal on the T2-weighted images and low signal on the T1-weighted images. Enlargement of ventricles or subarachnoid spaces may be observed. However, the MRI findings of the brain may be normal even in the presence of neurologic involvement, while lesions may also be seen in patients who do not demonstrate CNS symptoms. Neuropsychologic testing results may be abnormal prior to any detectable lesions on neuro-imaging.

In patients with ocular involvement, fundus fluorescein angiography shows diffuse retinal vascular leakage and occlusion of retinal vessels. Fluorescein leakage from retinal vessels may be seen before any clinical signs of vasculitis. Fluorescein angiography also may reveal macular ischemia and cystoid macular edema.

Angiography shows areas of aneurysm formation and thrombosis.

In patients with murmurs, echocardiography can be useful for diagnosing the valve vegetations observed in many patients.

(The above material has been amended by the author and does not necessarily reflect the views of the sources)

Sources

e-medicine - Behcet Disease - Sungnack Lee, M.D. et al (March 2003)   

e-medicine - Behcet Disease - Jeffrey R Lisse, M.D. et al (March 2003)   

e-medicine - Behcet Disease - C Egla Rabinovich, M.D. et al (March 2003)   

-medicine - Behcet Disease - Mounir Bashour, M.D. et al (March 2003)   

Vanderbilt University Medical Center - Allergy/Immunology - Behcet Disease (June 1998)