David Elleray* had been sent to me by his optometrist for a second opinion regarding possible cataracts. He had a “fog” over both eyes, black spots in his vision and reported a black ring around the central vision in his left eye for the past four days. The 37-year-old man also had a terrible headache. While he had had similar symptoms one month before, his past ocular history was unremarkable and he had enjoyed excellent vision.
On examination, we found the following. Mr. Elleray had a BCVA of 20/ 100 in the right eye and 20/60 in the left eye. His IOP was 8 mmHg in each eye. His visual fields were full to confrontation. He had no relative afferent pupillary defect. His extraocular motility and external examination were normal. His anterior segment was remarkable for grade 3+/4 cell and flare and fine clear stellate keratic precipitates in both eyes. The remainder of his anterior segment was normal, including clear crystalline lenses bilaterally. His anterior vitreous had 2 to 3+/4 vitreous cells. His conjunctiva was mildly injected in each eye. Dilated fundus examination revealed marked disc edema with disc hemorrhages in both eyes. He had 3+/4 vitritis present bilaterally. Although I had a difficult view through the vitritis, his maculae appeared normal. On both eyes, there was ischemia and hemorrhages in all layers of the retina and patchy chorioretinal edema. Inferiorly, some vascular sheathing was noted adjacent to the hemorrhages. The arterioles were narrowed, while the veins were tortuous and dilated (still present in photos taken four years later: Figs 1,2).
His review of systems was interesting for the presence of night sweats. These were so severe that Mr. Elleray occasionally had to get up and dry off with a towel. He reported no respiratory symptoms, weight loss, genital sores, nausea or vomiting, decreased energy, malaise, neurologic symptoms or joint pain. He did admit to having a “bad back.” He stated that he had one mouth sore, which he attributed to recent dental work. Mr. Elleray denied history of IV drug abuse or risky sexual behavior. He smokes. Past medical history was significant only for epilepsy, which was well-controlled on phenytoin.
We performed a thorough lab work-up. This included a complete blood count with differential, chemistry panel, TB skin test, rapid plasma reagin and MHA-TP, HIV antibodies, chest x-ray, toxoplasmosis titer, blood urea nitrogen, antinuclear antibodies and angiotensin converting enzyme. The chest x-ray was read as “evidence of old granulomatous disease” consisting of calcific densities noted in both perihilar areas. The CBC was remarkable for a profound microcytic anemia with otherwise normal differentials. The BUN was slightly high. The ACE was high at 66 IU/liter (normal 8 to 52 IU/L). All of the other lab values were within normal limits or negative.
Diagnosis and Treatment of Mr. Elleray
|What’s Your Diagnosis?|
|Caption: (1) In the right eye, epiretinal membrane, disc pallor, dilated veins, sclerosed and sheathed arterioles are still visible four years after initial presentation. (2) In the left eye, extensive epiretinal membrane, optic disc pallor and dilated veins are present.|
My initial diagnosis was sarcoidosis.
I placed him on oral prednisone comanaged by his internist. He also began prednisolone acetate drops every three hours and cyclopentolate three times a day. He had slow, steady improvement of his panuveitis over the next several weeks, and the prednisone dosage was tapered down to a maintenance dose of 30 milligrams/day. After the first two weeks, there was full resolution of the anterior inflammation and the prednisolone acetate and cyclopentolate were discontinued.
But problems persisted. Mr. Elleray, who was very active and fit, developed a series of deep venous thromboses. He was admitted to the university hospital for a pulmonary embolism. The physicians were puzzled about the etiology of his thrombotic state, since this is not characteristic of sarcoid. He continued to have frequent relapses of the uveitis in each eye. He developed bilateral posterior subcapsular cataracts, which I removed.
Suddenly, it all made sense. The diagnostic “break” in the case came when Mr. Elleray mentioned that he had just visited the dermatologist for sores on his legs and in his mouth. After his dermatologist confirmed that the patient had vasculitic skin lesions and aphthous oral ulcers, we made the diagnosis of Behçet’s syndrome. This was confirmed by the university hospital rheumatologists. Now the hypercoagulable state made sense.
Mr. Elleray’s eyes did remarkably well for three years. His eyes retained 20/20 vision despite uveitic flare-ups every one to six months. Sub-Tenon’s injections of triamcinolone acetonide worked well to resolve posterior segment inflammation. However, within the last year he had a series of strokes that resulted in motor weakness and a complete right homonymous hemianopsia. He also manifested several branch retinal artery occlusions in each eye. Currently, his visual acuity is 20/200 in the right eye and 20/40 in the left eye with severe visual field constriction. His optic nerves are pale, and there are sclerosed arterioles noted in each eye.
A Second Case
Graham Poll is a 29-year-old white male, a personal fitness trainer, who presented with two months of aching and redness in the right eye. He also complained of hearing loss and tinnitus in both ears for the past year. He had been having large joint aches, and paresthesia in the small finger of his right hand. He had been fatigued for two weeks.
On examination, Mr. Poll had 20/20 vision in each eye. He had 1+ cell and flare in his right eye with a small amount of conjunctival redness. Dilated fundus examination revealed indistinct disc margins in both eyes, worse on the right. Because of the question of disc edema, an MRI of the head was ordered, as well as a CBC, ACE, lysozyme, ANA, RPR, TB skin test and a Lyme titer. All tests were normal, with the exception of a borderline high ANA (1:40 titer) with a nucleolar pattern. His internist investigated the possibility of lupus, and found that he did not meet diagnostic criteria. His ANA reverted to negative on subsequent testing.
Mr. Poll was treated with topical prednisolone acetate drops and cyclopentolate drops. His clinical course over the next six months consisted of resolution of the iritis and recurrence in either eye. He also would get IOPs from 25 to 45 mmHg during flare-ups. The pressure was treated with timolol 0.5 percent. Disc edema was absent after the initial week of treatment.
Six months after his initial presentation to the eye clinic, Mr. Poll was admitted to the local hospital with ataxia and vertigo. It was determined that he had sustained a posterior fossa stroke and his laboratory studies revealed a hypercoagulable state. When I examined him as an inpatient, he had torsional nystagmus and a Horner’s syndrome. He complained of multiple oral ulcerations. A diagnosis of Behcet’s disease was made and later confirmed by the university hospital rheumatologists. He has been maintained on prednisone and cyclophosphamide and has exhibited steady improvement of all signs and symptoms.
A Puzzling Condition
The syndrome is a multisystem vasculitis. Behcet’s key features include uveitis, recurrent oral and genital ulcers, and vasculitic skin lesions. Associated features include arthritis, central nervous system involvement, erythema nodosum, intestinal ulcers and vascular lesions such as thrombophlebitis, arterial occlusions and aneurysms.
The cause and pathogenesis is unknown. It is thought to be autoimmune in nature. Bacteria and viruses have been suggested as the causative agents, but there is no convincing evidence. Circulating autoantibodies to human oral mucous membrane and immune complexes are found in about 50 percent of cases. HLA-B5 is associated with Behcet’s syndrome and a poor visual prognosis. The split antigen HLA-B51 is more specific for the disease, with a relative risk of 7.9 for this marker.
Prevalence varies. In the United States, the prevalence of Behçet’s is estimated at one in 30,000 people per year. In contrast, in Japan and Turkey the prevalence is one in 10,000 and three to eight in 10,000 per year, respectively. It affects mainly young adults and is more common in men than in women.
Seventy percent of patients have eye involvement. In 20 percent of cases, the ocular disease is the initial presentation of the disease. It is characterized by severe and recurrent attacks of intraocular inflammation. Common symptoms include blurred vision, pain, redness, floaters and photophobia. The classic finding of the disease, iridocyclitis with hypopyon, is present in roughly one-third of patients. Gonioscopy may reveal an occult hypopyon, as the hypopyon can change position with head movement and form and disappear rapidly. Secondary glaucoma, synechiae and iris atrophy may occur with repeated attacks.
Retinal disease is the most sight-threatening manifestation of this syndrome. Retinal vasculitis affecting both arteries and veins is the classic finding. Venous dilation, exudates, hemorrhages, white focal retinal infiltrates, retinal edema, vascular sheathing and optic disc edema may be noted. Thrombosis of vessels and secondary ischemic consequences such as neovascularization may occur. Vitritis is almost always present during the acute phase. Up to 6 percent of patients get neovascular glaucoma, which may lead to phthisis bulbi. Chorioretinal scars and nerve atrophy may result from episodes of posterior segment inflammation.1
The condition is difficult to diagnose. Unfortunately, there is no diagnostic lab test specific for Behçet’s syndrome. The diagnosis is made based on clinical findings. The International Study Group for Behçet’s Disease2 has proposed the following criteria for diagnosis: recurrent oral ulceration plus two from the following list—recurrent genital ulcerations, eye lesions, skin lesions or a positive pathergy (or Behçetine) test. During episodes of acute inflammation, patients may have an elevated erythrocyte sedimentation rate, C-reactive protein level or larger numbers of peripheral leukocytes. Fundus fluorescein angiography may reveal dilatation of retinal capillaries with dye leakage during acute inflammation. Dilatation and occlusion of any retinal vessel may be seen. Early leakage and late staining of retinal and optic nerve vessels is typical. Macular ischemia or cystoid macular edema may be present.
Early treatment can prevent death or blindness. In patients with recurrent uveitis, remain alert for symptoms and signs consistent with Behçet’s syndrome. A careful review of symptoms at every uveitis visit together with good communication with the patient’s other medical providers is key to making the diagnosis.
The most common nonocular manifestation of Behcet’s syndrome is oral aphthous ulcers. They are estimated to occur in 97.7 percent of Japanese Behcet’s patients. Mostly nonscarring, the ulcers appear in crops and heal within seven to 10 days.
Erythema nodosum acneiform lesions, thrombophlebitis and cutaneous hypersensitivity are common skin lesions in this disease. The cutaneous hypersensitivity may result in small pustules that form after the skin is pricked, scratched or shaved.
Painful punched-out lesions similar to the oral ulcers may form on the genitals. The scrotum or vulva is the most common site. Scarring may occur and offers a clue to the presence of the disease.
Transient, recurrent, nondestructive, nonmigratory arthritis of large joints may be present.
Over half of patients with Behcet’s have gastrointestinal symptoms. Intestinal erosions and ulcers may cause melena, pain and even perforation. It may look quite similar to Crohn’s disease or other inflammatory bowel disease and result in diagnostic obscuration.
Thrombophlebitis is found in 15 percent of Behcet’s patients. Arterial occlusion, thrombophlebitis obliterans and aneurysm may occur in vessels of any size.
Cranial nerve, cerebellum, pyramidal and extrapyramidal tract neurologic complications may occur in up to 25 percent of patients.
The goals of treatment for Behcet’s syndrome are to suppress inflammation and reduce the frequency and severity of recurrences in order to minimize inflammatory and ischemic tissue damage. Corticosteroids, cytotoxic agents, cyclosporine and colchicines are mainstays of therapy for Behcet’s syndrome.
Systemic corticosteroids can suppress all types of ocular inflammation in this disease but have not been found to prevent visual deterioration.3 Prednisone may be given as a 1 gram bolus IV over one hour and repeated every day for three days. It may be repeated every month or as needed. Periocular injections of corticosteroids can be used to reduce acute ocular inflammation. This has proven to be most useful in the treatment of my patients.
Chlorambucil, cyclophosphamide and azathioprine are the most common chemotherapeutic agents used in the treatment of Behcet’s disease. Because of the possibility of bone marrow suppression and effects on reproductive organs, all of these cytotoxic agents must be used with caution and systemic monitoring. Sole chlorambucil therapy may result in visual acuity of less than 20/200 in 75 percent of treated eyes.4
Cyclosporin is usually safer than the cytotoxic agents but may lead to renal toxicity. Its mechanism of action inhibits T-lymphocyte activation. In a Japanese study, a starting dose of 5mg/kg per day limited the frequency of ocular inflammation in 70 percent of Behcet’s syndrome patients who previously had refractory disease.5
Colchicine is a plant alkaloid that inhibits neutrophils. It is used along with other drugs in order to decrease the dose required of other immunosuppressents and thus reduce the systemic side effects. In Japan, colchicine is the drug of first choice.
1 Yanoff, M. and Duker, J. Ophthalmology, 2nd edition (St. Louis: Elsevier, 2004).
2 Lancet 1990;335:1078–1080.
3 Mishima S. et al. Behcet’s Disease in Japan: Ophthalmic Aspects. Trans Am Ophthalmol Soc 1979;77:225079
4 Tabara K. F. Chlorambucil in Behcet’s Disease: A Reappraisal Ophthalmology 1983;90:906–908
5 Kotake S. et al. Low Dose Cyclosporine Treatment for Ocular Lesion of Behcet’s Disease. Nippon Ganka Gakkai Zasshi. 1992;96:1290 – 1294 (as quoted by Yanoff and Duker in Ophthalmology1)
* Patient name is fictitious.