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Behçet’s disease
- 1. Resident Case Series Sudden-onset visual disturbances and headache in a woman with a history of MS leads to a visit to the ER
- 2. Bellows College Presentation 2 • A 44-year-old Caucasian female presented to the ER complaining of sudden onset of seeing a “thousand shades of gray, which later turned to black patches” in her right eye associated with pain with eye movement and dull headache. Her symptoms began 10 days prior and were progressively worsening. • Review of systems was notable for fevers, chills, night sweats, a recent intentional 90-pound weight loss, tinnitus, nausea and vomiting. • She denied any muscle, joint, dermatologic or genitourinary complaints currently or in the past.
- 3. Bellows College Medical History 3 • She was diagnosed with multiple sclerosis 20 years prior, after having three episodes of “visual disturbances” in her right eye, presumably repeat bouts of optic neuritis. • After being treated with glatiramer acetate, discontinued 18 years ago, she denied any new visual complaints. • The remainder of her past medical history was remarkable for hypertension, controlled with verapamil and clonidine.
- 4. Bellows College Medical History 4 • She was a non-smoker and denied any recent travel or having pets. • Two months prior she underwent a non-emergent laparoscopic cholecystectomy with a complicated postoperative course, resulting in an extended admission. Since then, she states she just has not “felt right”.
- 5. Bellows College Examination • Vital signs were normal with a BP of 126/82. • VA uncorrected was 20/200 in her right eye with no improvement with pinhole and 20/20 in her left eye. • Pupils were significant for a RAPD in the right eye. • The patient was able to identify only the test plate in the right eye and 10/10 color plates in the left eye. • Confrontation visual fields and ocular motility were normal in both eyes. • IOP was 19 mmHg and 16 mmHg in the right and left eyes, respectively. 5
- 6. Bellows College Examination • The anterior segment examination of her right eye revealed: 1. Diffuse flat conjunctival injection. 2. Fine KPs inferiorly. 3. 1+WBC in the AC. 4. 2+WBCs in the anterior vitreous. • There were no posterior synechiae, iris nodules or visually significant cataract. • The left eye anterior segment examination was unremarkable with no signs of ocular inflammation. 6
- 8. Bellows College 8 • The posterior exam of the right eye revealed: 1. Significant vitreous cell. 2. Disc edema. 3. Peripapillary hemorrhages. 4. Cotton wool spots. 5. Occlusive arteritis along all four vascular arcades. 6. Macular edema. 7. The veins were slightly engorged but did not show any inflammatory changes. • Dilated funduscopic exam of the left eye was normal without evidence of prior inflammatory episodes. OD
- 9. Bellows College The patient, a 44-year-old immunocompetent Caucasian female with a diagnosis of MS secondary to presumed episodes of right eye optic neuritis, presented with 20/200 vision in the right eye and clinical findings of a unilateral occlusive arteritis, disc edema associated with peripapillary hemorrhages and macular edema. 9
- 11. Bellows College The differential of vasculitis is quite extensive and is best broken down according to conditions that affect arteries, veins or both. The differential of vasculitis is quite extensive and is best broken down according to conditions that affect arteries, veins or both. 11 Conditions that affect veins include: 1. Sarcoidosis 2. Syphilis 3. Par planitis 4. Eales’ disease 5. Multiple sclerosis Conditions that affect both arteries and veins include: 1. (SLE) 2. Wegener’s granulomatosis 3. HLA-B27 associated disease 4. Behçet’s disease. Conditions that affect arteries include: 1. Polyarteritis nodosa 2. Frosted-branch angiitis 3. Churg-Strauss syndrome 4. Acute retinal necrosis 5. Idiopathic retinal vasculitis, aneurysms and neuroretinitis (IRVAN).
- 12. Bellows College Differential Diagnosis? • Despite the patient’s prior diagnosis, MS was an unlikely cause for several reasons. First, MS causes a periphlebitis, not an arteritis.1 • Approximately 11 % of MS patients have venous sheathing on routine color fundus photography.2 • Second, according to the Optic NeuritisTreatmentTrial, optic disc edema associated with peripapillary hemorrhages was never found to lead to a diagnosis of MS. • Finally, MS does not cause macular edema. • 1. RuckerWC. Sheathing of the retinal veins in Multiple Sclerosis. Mayo Clinc Proc 1972;47:335-40. • 2.Young BR. Fluorescein angiography and retinal venous sheathing in multiple sclerosis. Can J Ophthalmology 1976;11:31-6. 12
- 13. Bellows College Laboratory workup 13 1. Anti-nuclear antibody (ANA) 2. Angiotensin converting enzyme (ACE) 3. ANCA, RPR/FTA 4. PPD 5. Bartonella antibodies 6. Rheumatoid factor 7. HIV antibodies 8. The ESR was 17 mm/hr and CRP was slightly elevated at 1.7 mg/L. 9. A chest X-ray was normal.
- 14. Bellows College Workup • While the laboratory tests were pending, the patient was admitted to the ophthalmology inpatient service and started on 1g intravenous methylprenisolone daily for three days. • Given the retinal vasculitis and possible history of MS, MRI & MRA of the brain were ordered. • Imaging revealed non-specific scattered subcortical and periventricular white matter lesions on FLAIR imaging and no signs of cerebral vasculitis. 14
- 15. Bellows College 15 FFA (arterial-venous phase and late phase) showing areas of retinal non- perfusion, corresponding to cotton-wool spots and leakage around disc and arteries.
- 16. Bellows College 16 OCT of the right eye. Note vitritis, macular edema and subretinal fluid.
- 17. Bellows College The absence of aneurysms on FA helped ruled out IRVAN. OCT demonstrated macular edema and subretinal fluid seen on clinical exam 17 Fluorescein angiography helped confirm the findings of an occlusive arteritis
- 18. Bellows College Workup 18 • HLA typing revealed our patient was HLA-B51 positive. • Dermatology was consulted to administer a pathergy test, which was negative. • In addition, a full exam of her skin and mucous membranes did not show any evidence of oral or genital sores.
- 19. Bellows College Hulusi Behçet Despite the lack of additional findings, the leading diagnosis was possible Behçet’s disease 19
- 20. Bellows College 20A stamp (1980) in honor of Dr. Hulusi Behcet (1889-1948)
- 21. Bellows College 21 Behçet’s disease is a chronic relapsing, idiopathic, multisystem, obliterative vasculitis that can affect both arteries and veins of all calibers, characterized by recurrent aphthous oral ulcers, genital ulceration and uveitis. Vasculitis is a key Pathogenetic Component
- 22. Bellows College 22 The disease typically affects patients fromTurkey, the Middle and Far East (the ancient ‘Silk Road’ route), with a lower prevalence in Europe and North America.
- 31. Bellows College Ocular features • Ocular inflammation occurs in about 70%, and tends to be more severe in men; it is the presenting manifestation in about 10%. • Signs are virtually always bilateral eventually. • Relapsing/remitting acute onset panuveitis with retinal vasculitis and often spontaneous resolution even without treatment is the classical pattern of eye involvement. • Retinal vascular disease (vasculitis and occlusion) is the main cause of visual impairment. 31
- 32. Bellows College Ocular features • AAU, often bilateral, is typical. It is not granulomatous. • A transient mobile hypopyon in a relatively white eye is characteristic. • Vitritis may be severe; it is universal in eyes with active posterior segment disease. • Retinitis: Transient superficial white infiltrates that heal without scarring may be seen during acute systemic disease. • There may be deeper more diffuse retinitis similar in appearance to viral inflammation. • Exudative detachments can also occur. • Inflammatory deposits analogous to KPs may be seen on the inferior peripheral retina. 32
- 36. Bellows College Ocular features • Retinal vasculitis : • Arteritis as well as phlebitis, in contrast to pure venous involvement in sarcoidosis – can manifest with sheathing, perivascular haemorrhages and occlusion. • Vascular leakage may give rise to diffuse retinal oedema and CMO. • Optic disc hyperaemia and oedema. Raised intracranial pressure can also cause optic disc swelling and optic atrophy in BD. • Disc and retinal neovascularization may be seen as a response to inflammation and ischemia. 36
- 39. Bellows College Ocular features • Uncommon manifestations: conjunctivitis, conjunctival ulcers, episcleritis, scleritis and ophthalmoplegia from neurological involvement. • End-stage disease is characterized by optic atrophy, retinal atrophy and gliosis, and sheathing, attenuation and ghosting of affected vessels ; the vitreous tends to clear. 39
- 43. Bellows College Ocular features • Other complications include posterior synechiae, cataract, glaucoma and, uncommonly, retinal detachment and phthisis. • Severe visual loss in males is up to two-thirds of patients at 10 years has been reported, but is probably much lower with aggressive management; the rate in women is about half that in men. 43
- 44. Bellows College Investigation • HLA-B51. • Pathergy test. • Inflammatory markers (e.g. ESR, CRP, complement levels, WBCs) may be elevated. • Thrombophilia screening is appropriate in some patients to exclude other causes of thrombosis. • FA delineates ischaemic areas and aids detection of posterior segment inflammation and monitoring of disease activity. 44
- 47. Bellows College Treatment • Topical steroids alone may be adequate if – rarely – there is no trace of posterior segment involvement. • Systemic steroids and azathioprine (2.5 mg/kg/day) in combination are recommended for the initial management of posterior uveitis in (EULAR) 2008 BD guidelines. • Steroids should be tapered only slowly.Topical and/or regional steroids may also be used. • Azathioprine may have a role in prophylaxis. 47
- 48. Bellows College Treatment • Ciclosporin (2–5 mg/kg/day) or infliximab, in combination with azathioprine and systemic steroids, is recommended by EULAR for severe eye disease (> 2 lines reduction in visual acuity and/or retinal vasculitis or macular involvement). • A recent study recommended a single infliximab infusion as initial treatment of posterior uveitis. • Intravitreal administration is a novel alternative route of administration for infliximab. • Infliximab or adalimumab should be considered early for vision-threatening Behçet disease (American Uveitis Society recommendation). 48
- 51. Bellows College Treatment 51 • Interferon- alfa (6 million IU per day subcutaneously initially, gradually tapered) with or without steroids is a EULAR-recommended alternative to the ciclosporin/ infliximab/azathioprine/steroid regimen for severe disease; it should not be used in combination with azathioprine (risk of myelosuppression). • Anticoagulants are not recommended.
- 54. Bellows College Follow up 54 • After three days of IV methylprednisolone, our patient was transitioned to oral prednisone. • Over the next month, the inflammation and macular edema resolved. Her visual acuity returned to 20/30 with full recovery of her color vision. • Rheumatology did not recommend steroid-sparing agents and continued tapering her oral prednisone with no recurrence to date.
Editor's Notes
- Color fundus photo of right eye. Note the peripapillary hemorrhages, disc edema, cotton wool spots and arterial sheathing.
- Frosted-branch angiitis OPTIC NEURTIS IN MS BEHCEBT DISEASE IRVAN ACUTE RETINAL NECROSIS
- the Turkish dermatologist and scientist who first recognized the three main symptoms of the syndrome in one of his patients in 1924 and reported his research on the disease in Journal of Skin and Venereal Diseases in 1936.
- Vasculitis is a key pathogenetic component and may involve small, medium and large veins and arteries
- The U.S. prevalence is 0.4 per 100,000 with a female predominance
- It is strongly associated with HLA-B51; the ethnic groups with a higher prevalence of BD also have a higher rate of HLA-B51 positivity. The peak age of onset is the third decade; reported gender prevalence varies with ethnicity. Theories exist that Behçet’s disease is an autoimmune condition triggered by an infectious agent in a genetically predisposed individual.. Mortality is around 5% at 5–10 years, typically due to cardiovascular or CNS complications.
- Diagnostic criteria of the Behçet's Disease Research Committee of Japan (2003 revision). The criteria were developed by the Behçet’s Research Committee of Japan in 1974 and were later revised in 2003 to give greater weight to the presence of ocular inflammation.3 Our patient only satisfied one major criterion. recurrent oral ulceration : characterized by oral ulcers at least three times in a 12-month period, plus at least two of genital ulceration, ocular inflammation, characteristic skin lesions (erythema nodosum , pseudofolliculitis, acneiform nodules, papulopustular lesions) Vascular lesions. Aneurysms, including pulmonary and coronary, and venous thrombosis/thrombophlebitis Arthritis occurs in 30%, though arthralgia is more common. Dermatographia , similar to the pathergy reaction, indicates skin hypersensitivity and consists of the formation of erythematous lines following stroking or scratching. Neurological manifestations (5%) such as meningoencephalitis of the brainstem, dural sinus thrombosis and cerebral aneurysms. Gastrointestinal inflammation, especially ileocaecal. Hepatic and renal lesions are relatively uncommon.
- (B) superficial thrombophlebitis; (C) dermatographia
- Ocular involvement occurs in approximately 70 to 90 percent of cases and tends to affect both anterior and posterior structures.
- associated with a hypopyon, which shifts with gravity and head position. Posterior segment inflammation occurs in up to 93 percent of patients with ocular disease and portends a poor prognosis.
- (B) retinal infiltrates; Recurrent exudative retinal detachment
- Vascular occlusive episodes are a feared complication and if it involves the macula, visual acuity is reduced. Optic nerve involvement occurs in about 25 percent of patients.
- occlusive vasculitis;
- Inflammatory retinal vein occlusion with associated vitritis and retinal vasculitis before (A) and after (B) treatment with high dose oral steroid.
- (D) end-stage disease
- (A) Acute branch retinal vein occlusion. (B) Total vascular obliteration and optic atrophy secondary to recurrent vascular occlusion
- Intracranial venous thrombosis. (A) Male patient presents with headaches and disc oedema. (B) Magnetic resonance imaging and (C) magnetic resonance angiography demonstrating superior sagittal sinus thrombosis.
- HLA-B51 has a high association with Behçet’s, but is not part of the diagnostic criteria.
- a pathergy reaction: pustule 24–48 hours after a sterile needle prick (>95% specific, but often negative in European and North American patients). Other tests that can help support a diagnosis of Behçet’s disease, but are not pathognomonic, are the pathergy test (skin prick) and HLA-B51 testing. During the pathergy test the forearm is pricked with a sterile needle and observed for two days. A positive test occurs if a pustule forms at the site of skin trauma. Only a minority of patients demonstrate this finding. The reaction is not common in the United States, while about half of all patients in Japan and Middle Eastern countries have this phenomenon.
- right retinal oedema with relative cilioretinal sparing, mild papillary hyperaemia and venous congestion. Multiple dot–blot haemorrhages were not present initially but developed within a few days Fundus photography and fluorescein angiography obtained 3 days after presentation. Note grossly impaired perfusion, retinal whitening and relative cilioretinal sparing.
- Immunosuppressants are the mainstay of treatment; availability and expense may limit therapeutic options in many regions. The initial goal of therapy is swift control of intraocular inflammation, typically accomplished using a combination of high-dose intravenous, oral, periocular, intravitreal or topical corticosteroids. Equally important is preventing additional inflammatory episodes. Long-term treatment with steroids should be avoided in cases of significant posterior uveitis, as chronic steroid use has not been found to reduce recurrences or improve the visual prognosis.6 Many steroid-sparing agents currently exist to prevent recurrence of inflammation. Some of the most commonly employed steroid-sparing medications include infliximab, azathioprine, cyclosporine-A, cyclophosphamide, tacrolimus and methotrexate.
- Hypertension, nephrotoxicity and neurotoxicity are concerns with ciclosporin, which should be avoided in patients with CNS involvement unless it is determined that severe eye disease warrants the risk. Infliximab may lead to activation of tuberculosis, and screening-positive patients should receive prophylactic treatment (e.g. isoniazid).
- This 20 year old woman had Behcet's disease with retinitis that responded rapidly to oral prednisone and subcutaneous injection of adalimumab. A - Initial fundus appearance of retinitis. The yellow arrow indicates white paravascular retinitis. Subretinal fluid is present but is difficult to appreciate in this photograph (see OCT, panel C). B - One month after beginning oral prednisone 40 mg/day and after one injection of subcutaneous adalimumab, the retinitis has regressed, as has the subretinal fluid. The blue arrow indicates residual retinal pigment epithelial metaplastic changes. C - An optical coherence tomograph line scan showing the retinal edema and subretinal fluid (orange arrow) at the initial presentation. D - One month after treatment, the edema and subretinal fluid have resolved. The retinal pigment epithelial metaplasia is indicated by the red arrow.
- Active Behçet uveitis showing vitritis and retinal infiltrates, located close to the fovea (A) and in the retinal periphery (B). HD-OCT of a patient with active Behçet uveitis showing vitritis and cystoid macular edema with a small serous foveal detachment (C); (D) complete resolution of the vitritis and the macular edema 5 weeks after starting Golimumab therapy
- Fundus photography and fluorescein angiography of one patient (Case 4) with Behçet uveitis. (A) Before vascular occlusion (at the 4-month follow-up): retinal vasculitis of the left eye. Fluorescein angiography (FA) shows diffuse leakage of fluorescein dye from the whole retinal vasculature and the optic disc. (B) Retinal vascular occlusion (before interferon alfa-2a treatment, at the 8-month follow-up): branch retinal vein occlusion with intraretinal edema of the left eye. FA shows blocked vascular filling at the inferotemporal venous branch. (C) After interferon alfa-2a treatment (at the 14-month follow-up): tortuous retinal vessels at the inferotemporal area, with improved retinal hemorrhage and edema. FA shows reperfusion; however, narrow inferotemporal venous branch with wide peripheral non-perfusion areas are also noted.
- . Color fundus photo of right eye. Note resolved disc and macular edema. Intraretinal hemorrhages still present.
- OCT of the right eye. Note resolved macular edema and subretinal fluid. Hard exudates are present.