Postgrad. med. J. (June 1968) 44, 453-459.

Major vascular complications in Behcet's syndrome

B. ANTHONY ENOCHB.Sc., M.B., Ch.B.(Liverpool)

Medical Registrar

T. C. L. KHOOM.R.C.S.(England), L.R.C.P.(London)

Medical Registrar

J. L. CASTILLO-OLIVARESL.M.C., D.M.(Madrid)

Research Fellow

R. G. GRAINGERM.D.(Leeds), M.R.C.P.(London), D.M.R.D., F.F.R.

Consultant Radiologist

L. HENRYM.D.(Birmingham), M.R.C.P.(London), M.C.Path.

Senior Lecturer in PathologyThe Royal Hospital, Sheffield and Regional Cardio-Thoracic Unit,

Northern General Hospital, Sheffield

SummaryTwo patients with Behcet's syndrome are

described. One patient developed spontaneousbilateral popliteal artery aneurysms and the otherspontaneous thrombosis of the superior venacava. These cases emphasize that primary inflam-matory lesions of large vessels, with arterialaneurysm formation and thrombosis may be afeature of the syndrome.

IntroductionSince Behcet in 1937 described a triad of oro-

genital ulceration and ocular lesions, a numberof additional features has been recognized aspart of the complex now known as Behcet'ssyndrome. These include erythema nodosum,pustular dermatitis, arthritis, a variety of centralnervous system lesions, abnormal skin sensitivity,and recurrent thrombophlebitis (Mounsey, 1966).

Involvement of large veins, possibly withthrombosis of the superior or inferior vena cavais a recognized though rare complication of thedisease (Forman, 1960, 1967). Only five casesin which there were lesions affecting majorarteries have so far been recorded in the litera-ture (Mishima, Ishikawa & Kawase, 1961;Oshima et al., 1963 (two cases); British MedicalJournal, 1965; Hills, 1967). In this paper wepresent two cases of Behcet's syndrome, the firstof which was complicated by the spontaneousdevelopment of bilateral popliteal arteryaneurysms, and the second by spontaneousthrombosis of the superior vena cava.

Case 1The patient, J.F., is a 16-year-old apprentice

tool-maker. In September 1965, at the age of15 years, he was referred to an ophthalmologiston account of irido-cyclitis. Subsequently hedeveloped aphthous ulceration of the oral mucosaand erythema nodosum. In spite of the absenceof ano-genital lesions, a tentative diagnosis ofBehcet's disease was made. The ocular manifes-tations were treated with topical steroids andmydriatics, and in June 1966 oral steroids werecommenced.On 3 November 1966 he was referred to the

Professorial Medical Unit of the Sheffield RoyalHospital. Within the preceding 3 weeks therehad been marked deterioration in vision, generalmalaise with anorexia, fever, and recurrentarthralgia in both legs.On examination, he was pale and febrile

(100°F). He was of small stature with unbrokenvoice, absent facial and axillary hair and scantypubic hair; the testes were small. A few redmacules were present on the left upper arm.There was swelling and restricted movement ofthe right ankle joint and superficial thrombo-phlebitis of the right calf. The eyes showedsevere bilateral pan-uveitis with marked impair-ment of visual acuity (R 3/60 L 1/36). The ano-genital region was normal. Pustules developedat sites of venepuncture. He improved dramatic-ally following treatment with ACTH andoxyphenbutazone. The oral lesions respondedto hydrocortisone pellets and the uveitis wascontrolled by topical atropine and hydrocorti-

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sone. Anaemia, which was associated with ironand folic acid deficiency, and for which no causewas found, responded to appropriate oral supple-ments. The patient was discharged on mainten-ance therapy with ACTH.On 23 January 1967 he was re-admitted as an

emergency because of severe pain and swellingof the left knee and coldness of the left foot,which had been present for 3 days. On examina-tion, the left knee was held in 30° of flexion,and the joint appeared swollen and tender. Flex-ion from 30° was possible, but attempts to ex-tend the joint beyond this angle caused severepain behind the knee. In the left popliteal fossathere was a firm, ill-defined, pulsatile, tenderswelling approximately 2-5 cm diameter overwhich a systolic bruit was audible. The left footwas cold and white. The dorsalis pedis pulse waspresent although much diminished, and theposterior tibial pulse was absent. The patient wasafebrile and the heart was clinically normalapart from sinus tachycardia. The clinicaldiagnosis of a left popliteal artery aneurysm wasconfirmed on angiography by retrograde catheter-ization via the right femoral artery (Fig. la).An aneurysm (3-0 x 4-0 cm) was demonstrated

on the left popliteal artery, situated behindthe knee joint. The aneurysm retained the

FIG. 1. (a) Left femoral arteriogram showing an

aneurysm of the left popliteal artery (26 Jan). (b) Rightpopliteal artery aneurysm (14 Feb).

contrast medium for several seconds and therewas only faint opacification of the poplitealartery distal to it. The lower abdominal aortaand both iliac arteries appeared normal but theright popliteal artery was not examined.

Other investigations were as follows: ChestX-ray: Essentially normal. Skeletal survey: Nobone lesions seen. Haemoglobin: 13-7 g/100 ml.WBC: 12,000/mm3 (82% neutrophils). ESR:37mm/hr (Wintrobe). Platelets: 190,000/mm3.Bleeding time: 3½min. Plasma proteins: albumin4.3, globulin 2-5, fibrinogen 0-34 g/100 ml.Electrophoresis showed raised c2-, f- and y-globulins. Blood cultures (x 3): sterile after 7days incubation. Whole blood clot lysis time:over 24 hr. Prothrombin time: 12sec. Tannedred cell haemagglutination titre against oralmucosa 1:320 (controls approx. 1:40). LE cellpreparation: no LE cells seen. Mantoux test:negative 1 in 1000. Kveim test: negative.Toxoplasma antibody titre (dye test) 1:8. Kary-otype: sex chromatin (buccal smear) negative,chromosome analysis (blood culture), 46chromosomes. Sex chromosomes XY. Throatswab: no pathogens cultured. ASO titre: 400Todd units. Serum calcium: 8-1 mg/ 100 ml. WR:negative.After blood cultures had been taken, penicillin

and streptomycin were given as it was thoughtthat the aneurysm might be mycotic. ACTH andoxyphenbutazone were given daily.On 31 January the left popliteal fossa was

explored (Mr D. G. Taylor). It was found thatthe true aneurysm had ruptured and much ofthe swelling was due to an extravasation ofhaematoma into the arterial wall causing a falseaneurysm. The process involved the origin ofthe posterior tibial artery. The aneurysm wasexcised and replaced by an autogenous saphen-ous vein graft from the proximal poplitealartery to the anterior tibial artery. Histologicalstudies of this aneurysm were not made. Post-operative progress was satisfactory.During convalescence, scrotal ulcers typical

of Behret's syndrome were observed for the firsttime. It was noted that, although the patienthad no symptoms referable to the right leg, theright popliteal pulse was unduly prominent andan arterial aneurysm at this site was suspected.On 14 February an aortogram was performedby retrograde catheterization via the rightfemoral artery. An aneurysm (20 cm diameter)was demonstrated on the right popliteal artery.projecting medially in the femoral intercondylarnotch (Fig. Ib). It had a very narrow neckand attachment from the popliteal artery. Therewas no interruption or delay in the passage of

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Beh9et's syndromecontrast medium distally beyond the aneurysminto the tibial arteries (Fig. 2).

1FIG. 2. Aortogram showing an aneurysm of the rightpopliteal artery and obstruction of the proximal leftpopliteal artery (14 Feb).

On the left side, there was complete obstruc-tion at the upper end of the popliteal arterywhich showed no filling, presumably due tothrombosis. There was, however, an adequatecollateral circulation providing good opacifica-tion of the tibial arteries. The aorta from thearch to the bifurcation, both iliac and bothfemoral arteries appeared normal.On 5 May the patient developed pain and

further swelling at the back of the right kneeand on 9 May the right popliteal fossa wasexplored (Mr D. G. Taylor). A true saccularaneurysm (approx. 4-0 x 3-0 cm) containingthrombus was found on the distal portion of thepopliteal artery. A roof-type autogenous saphen-ous vein graft was inserted, and most of theaneurysmal wall excised along with amacroscopically normal portion of poplitealartery immediately adjacent to the neck of theaneurysm. Histological studies (Fig. 3) of the

FIG. 3. (a) The wall of the aneurysm showing inflam-mation and destruction of the arterial wall. (H & E,x 35). (b) The wall of the aneurysm showing inflamma-tion and formation of new fibrous tissue. (H & E, x 42).(c) Adventitia adjacent to the aneurysm. The small bloodvessels show obliterative endarteritis. (H & E, x42).

aneurysm showed a severe active inflammationwith an exudate of plasma cells, lymphocytes,

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456 B. A. Enoch et al

eosinophils and polymorph leucocytes. Therewas complete destruction of the arterial wallwith replacement fibrosis and formation ofgranulation tissue. No muscle or elastic tissueelements could be identified. Areas of recenthaemorrhage were present with haemosiderin inmacrophages. The adventitial blood vessels andvasa vasorum showed an obliterative endarteritisbut there was no fibrinoid necrosis. There wasno granuloma or giant-cell formation and noforeign material, bacteria or fungi could bedemonstrated. The lumen of the aneurysm con-tained recent laminated thrombus with earlyorganization. The popliteal artery adjacent to theaneurysm showed similar but less severe changeswith formation of granulation tissue but againno normal arterial wall could be seen. Thepopliteal vein was normal. A small lymph nodenear the aneurysm showed only reactive hyper-plasia.

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FIG. 4. Right femoral arteriogram showing recurrentright popliteal aneurysm (19 June).

Post-operatively, oral phenindione was given,but this was withdrawn at the end of 4 weekson account of haematuria and bruising.On 19 June the patient developed a recurrent

painful swelling at the back of the right knee.A right femoral arteriogram demonstrated anirregular elongated aneurysm (5-0 x 20 cm)projecting from the medial aspect of the rightpopliteal artery. This was at the same site asthe aneurysm previously demonstrated (Fig. 4).Three days later the right popliteal fossa was

again explored and ligation of the popliteal arterywas carried out proximal to the aneurysm whichwas left in situ. After operation the right footwas warm and a dorsalis pedis pulse waspalpable, the vessel presumably being fed fromcollaterals. The patient made an uneventfulrecovery and was discharged home on a smallmaintenance dose of prednisolone.

Case 2An obese 38-year-old builder, P.T., was admit-

ted to the Northern General Hospital, Sheffield,on 25 November 1966, with increasing swellingof the neck of 1 week's duration. He gave ahistory of recurrent mouth ulceration for 3 yearsand episodic arthralgia for 4 years. Six weeksprior to admission he developed deep veinthrombosis of his right leg and at this timenoticed scrotal ulceration.On examination he had classical signs of

superior mediastinal obstruction. Three punched-out ulcers were present on the scrotum and a

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FIG. 5. Right subclavian venogram showing obstructionof the superior vena cava.

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Behcet's syndromefew days following admission he developed anaphthous ulcer on the tongue. There was noclubbing, lymphadenopathy or peripheral phleb-itis. Full ophthalmological examination revealedno evidence of uveitis. A straight X-ray of thechest showed mediastinal widening and a rightsubclavian venogram was performed on28 November (Dr R. G. Grainger) (Fig. 5).The subclavian vein was dilated and completely

occluded at its inner end. There was markedreflux into the right jugular vein and other neckveins, mainly on the right. A large vein conveyedcontrast medium to the azygos vein in which itpassed retrogradely downwards. Very littleopacification of the right atrium was observeddue to the very slow entry of contrast medium.The venous pressure in the right arm was ex-tremely high.Other investigations were as follows: Hb:

13-0 g/100 ml. WBC: 13,600/mm3 (neutrophilia).ESR: 82mm/hr (Westergren). Throat swab: nopathogens on culture. Swab from scrotal ulcers:sterile. ASO titre: 100 Todd Units. Bloodculture: sterile after 7 days incubation. WR,Kahn, Reiter: negative. LE cell preparation: noLE cells seen. Plasma proteins: albumin 3-8,globulin 2-9 g/100ml. Electrophoresis showed aslight increase in y-globulin.On 6 December a right thoracotomy was per-

formed (Mr D. G. Taylor). The right lung wasdensely adherent to the mediastinum which wasextremely vascular. Both the superior vena cavaand the azygos vein were solid with thrombus.Due to technical difficulties an attempt to dis-obliterate the superior vena cava was not made,but the azygos vein was freed from clot and a waymade for drainage through the azygos vein tothe superior vena cava and right atrium. Biopsieswere taken from the mediastinum and the wallof the superior vena cava. Bronchoscopy re-vealed no abnormality.On histological examination the tissue from

the pleura showed only dense fibrous tissue withhyalinization. Few cells were present and therewas no evidence of active inflammation. Thevena cava contained recent laminated thrombuswith early organization at the periphery. Noneof the vein wall was present and no organismscould be demonstrated. The mediastinal materialconsisted of areolar tissue showing a mild non-specific inflammation with areas of fibrinous ex-udate and formation of granulation tissue.Several small veins were occluded by recentthrombus but there was no evidence of arterialdegeneration. No granulomata or giant cells werepresent (Fig. 6).

Initially, the patient had a stormy post-

operative course during which he developedthrombosis of his left antecubital veins despiteanticoagulant therapy. He gradually improvedand his neck size returned to normal.

FIG. 6. (a) Organizing thrombus from the superior venacava (H & E, x 50). (b) Mediastinal tissue showingvascular thrombosis and focal inflammation (H & E,x56).

A second right subclavian venogram was per-formed on 11 January 1967 (Dr R. G. Grainger).The subclavian vein was considerably less

dilated but there was still complete occlusion ofits medial end. The opacification of the cervicalveins was not as marked as on the earlier ex-amination. The azygos vein again conveyedcontrast medium retrogradely away from theright atrium. The right intercostal veins opacifiedfrom the axillary vein and carried contrastmedium retrogradely towards the sternum. Thepressure in the right arm veins was considerablyless than on the earlier examination (Fig. 7).When last seen, the patient remained well but

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still had complete block of his superior venacava and persistent aphthous ulceration. Steroidtherapy was not given at any stage.

FIG. 7. Right subclavian venogram after operation.

DiscussionTheories advanced to explain the pathogenesis

of Behcet's syndrome include those of rheumaticdisease, bacterial allergy, viral infection andautoimmunity, and although there is a certainamount of evidence in support of each of these,none has been widely accepted or confirmed(Oshima et al., 1963). Current opinion favoursthe concept that the syndrome is basically adisease of blood vessels, probably a manifestationof an hyperergic state as shown by the hyper-reactivity of the skin not only towards a specificantigen Behcetin, but following other stimuli ofvaried nature.

In the case described by Mishima et al. a

38-year-old male with Behcet's syndrome under-went a successful resection of an aortic aneurysmwhich was replaced by a graft. Histology of theaneurysm showed thickening of the adventitia,disruption of the elastic fibres of the media,hypertrophy of the intima and occlusion of thelumen by thrombus. Although Oshima et al.refer to two cases of Behcet's syndrome in whicharterial aneurysms occurred, they describe onlyone. This was an aneurysm of the right ulnarartery in a woman aged 36 years. The aneurysmwas resected and histology showed that 'smallarteries near to aneurysm' had obstruction oftheir lumina with fibrous tissue, swelling of thelamina elastica interna, splitting of the elasticfibres of the media, and slight perivascular cell

infiltration. In the case reported from Hammer-smith Hospital a 24-year-old man with Behqet'ssyndrome died following rupture of an abdom-inal aortic aneurysm. At autopsy there wasseptic inflammation of the aortic wall and anold septic osteomyelitis of the adjacent vertebralbodies so that the aneurysm in this case may nothave been due to a primary inflammatory lesionof the aorta. Our sections show some similarfeatures to the previously reported cases but inaddition emphasize that a primary acute arteritismay be a feature of Behcet's syndrome althoughthe histological appearances are in no wayspecific. In the case reported by Hills, a malepatient with Behcet's syndrome developedaneurysms of the thoracic and abdominal aorta,but histological studies of the lesions were notmade.The most frequent complication of popliteal

aneurysms is acute thrombosis of the sac whichsuddenly occludes the lumen of the poplitealartery. In a recent study of twenty patients withtwenty-nine popliteal aneurysms (Hara, 1967),acute obstruction developed in thirteen casesterminating in supra-condylar amputation ofeight extremities. One required bilateral amputa-tion. In this series ten patients had grafting witheither autogenous saphenous vein or plastic'Dacron' prosthesis with excellent results. In ourfirst case we considered that severe pain and thedanger of an acute episode of thrombosis werejustifiable indications for surgery.

In the second case, a diagnosis of Behcet'ssyndrome was considered justified in spite ofthe absence of ocular lesions. Most authoritiesregard the diagnosis as tenable in the presenceof two of the three features comprising theoriginal triad (Mounsey, 1966).Although no sections of the vena caval wall

itself were obtained, the histological appear-ances of the adjacent tissues suggested that thevein wall had probably been involved in aninflammatory process. In this case operation wasundertaken in the hope of carrying out someform of disobliterative or by-pass procedure. Theformer was not possible because of the extentof the thrombus, but by producing a free wayto the right side of the heart through the azygosvein, we may have helped the patient duringthe acute stage. The vascular material affectedby the disease was very poor and unsuitable forany sort of repair.

AcknowledgmentsWe wish to thank Professor C. H. Stuart-Harris and Dr

E. G. Rhind for permission to publish these cases. We arealso grateful to Mr Desmond Taylor, who performed all

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BehVet's syndrome 459

the operations, for his interest and encouragement, and toMiss Mary A. C. Jones for referring the first case. Histo-logical material in the second case was kindly made availableby Dr A. J. N. Warrack.

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ein Virus Verursachte Geschune am Mund, am Auoe undan den Genitalien. Derm. Wschr. 105, 1152.

British Medical Journal (1965) Clinico-Pathological Con-ference. Postgraduate Medical School of London. Brit.med. J. i, 357.

HILLS, E.A. (1967) Behqet's syndrome with aortic aneurysms.Brit. med. J. iv, 152.

FORMAN, L. (1960) Thrombophlebitis und Arteritis in derPatholgie des Behget-Syndroms. Hautarzt, 11, 363.

FORMAN, L. (1967) Vascular basis of the pathology ofBehoet's disease. Excerpta Med. 16, Sect. 13.

HARA, M. (1967) The hazards of popliteal aneurysms. Surg.Gynec. Obstet. 124, 358.

MISHIMA, Y., ISHIKAWA, K. & KAWASE, S. (1961) Proc. Jap.Circ. Soc., Tokyo 1960. Jap. Circulat. J. 25, 12111.

MOUNSEY, J.P.D. (1966) Behget's syndrome-a spectrum.Trans. St John's Hosp. derm. Soc. (Lond.), 52, 197.

OSHIMA, Y., SHIMIZU, Z., YOKOHARI, R., MATSUMOTO, T.,KARINO, K., KAOAMI, T. & MAOAYA, H. (1963) Clinicalstudies on Behqet's syndrome. Ann. rheum. Dis. 22, 36.

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