.Iournal ot the Neurologtcal Sciences. 106 ( 1991) 19- 24 19 ," 1001 Elsevier Science Publishers B.V. All rights reserved 0022-510X/~)1/$03.50 JNS t13630 Cerebral angio- and neuro-Beh et's syndrome: neuroradiological and pathological study of one case Masaki Nishimura i, Ken-ichi Satoh 1, Masakazu Suga 1 and Masaya Oda 2 Departments of i Neurology and 2 Neuropathology, Tokyo Metropolitan Neurological Hospital, Tokyo (Japan) (Received 15 February, 19911 (Revised, received 18 May, 1991) (Accepted 26 June, 1991) Key words: Behqet's syndrome; Angio-Beh~et's syndrome: Neuro-Behqet's syndrome; Occlusive panarteritis; Angiography: Magnetic resonance imaging (MRI) Summary Cerebral angio-Beh§et's syndrome is extremely rare and pathological studies are scarce. We describe a 63-year-old man who developed left homonymous hemianopsia and hemiparesis 16 years after the onset of cardinal symptoms of Beh~et's syndrome. CT, MRI and PET studies disclosed cerebral lesion with reduced neuronal metabolism in the right hemisphere, which was resolved by glucocorticoid therapy. Cerebral angiography showed no filling of the right Rolandic, anterior and posterior parietal and angular arteries. The postmortem study revealed: (a) occlusive panarteritis of some medium-sized pial branches of the right middle cerebral artery, considered as angio-Behc~t's pathology, and small infarctions due to the vascular occlusion; (b) patchy or confluent demyelinated loci with perivaseular lymphocytic infiltration in the bilateral brain basis, predominantly in the right rctro- and sublenticular structures, being equivalent to neuro-Beh~et's pathology. Cerebral angio- and neuro-Beh~t's syndromes could have occurred and progressed concomitantly, which suggests a close relationship between the two subclassified processes. Introduction Beh~jet's syndrome is characterized by the clinical triad of recurrent oral aphta, genital ulcer and uveitis (Behqet 19371, while 3 special subclassifications are recognized, associated with the predominant lesion in the gastrointestinal tract, large vessels and central nervous system (CNS), designated intestinal-, angio- and neuro-Beh~et's syndrome, respectively. The incidence of Beh~jet's syndrome is relatively high in Japan as well as in Mediterranean countries in spite of the tendency to decrease, and about 10% of the patients develop the appropriate CNS involvement (Shimizu 1979). The first autopsy case of neuro-Beh~jet's syndrome was reported by Berlin (1944), and was followed by a number of neuropathologicai studies. In the previous reports, it was almost a consistent feature that the main lesion was localized in the brainstem inclusively and consisted of disseminated focal and relatively diffuse parenchy- Correspondence to: Masaki Nishimura M.D., Department of Neurology, Tokyo Metropolitan Neurological Hospital, 2-6-1 Musashidai. Fuchu, Tokyo 183, Japan. Tel: 0423-23-5111,, Fax: 0423-22-6219. mal destructions with perivascular lymphocytic infiltrations, predominantly in the white matter (Rubinstein and Urich 1963; Alema 1978). However, their etiology remains to be clarified, and it is left undetermined whether the pathogenesis is a demyelinative or vascular process. Intracranial vascular involvements were often found in small parenchymal vessels, especially venules and small veins, rather than in the arterial system. Change in large vessels was extremely rare, although dural sinus and venous thrombosis were occasionally reported (Ben-Itzhak et al. 1985). We recently observed a patient of neuro-Beh~et's syndrome with occlusive vasculitis of the major cerebral arte~'. Case report The patient was a 63-year-old Japanese man without notable family history. At the age of 46, he suffered from fever and erythema nodosum, and subsequently developed aphtous stomatitis, right uveitis and serotal ulcers. He was diagnosed as having Behc,jet's syndrome and experienced complete remissions through glucocorticoid therapy. In June 2(I 10,"17. :it the age of ~~3. hu developed slight fever, right head hca~,incss and lumhago. ('ranial computed tomography (('T) ~:ls performed, anti hc ~as admitted to our hospital for A suspected brain tumor in Jul.~ 1987. Neurological ux:lminalion rc,,ualcd a left-tipper qtladrant Ilerllianopsia, hut 11o otllui ahnornlalitics. Altur admission, hc gradually dc,,clopcd nlcmi+r~, dJslurhancc, umtllion:ll hlbJlity, devastation of pcr.,,onalily and dcnlunti:l. Al+out the 4(Ith day of admission, Icl+t homonynltms hcnfianopsi:l and left hcmiparc,4s gradually bcC[IlllL' ~.l[lp;ll'C 111. "l'hc folh~ing blood studies were normal: complete blood cell count, li'~.;r and renal functions, serum clcctrol),lcs, gluco',c, immunoglobulins and autoantihody tilers, l.umbar puncture yielded clear ccrcbrospinal fluid (('SF) with lymphllc.~lic l~lcoc}tosis, 44,.ram ~ of cull coulll, alld increased ]cvcb, ol Inla] protein and Ig(L 136 nlg/dl and 4().5 nag/dl. rc',pcclivcl~. Cuhurc of bacteria was negative. ,tnd viral tilers did not increase. An cluctrocnccphahlgram (HE(;)~howcd focal sltm,ing in the right paricto-tcmpllral region. ('crchral angiography demonstrated no filling of the right I,ttfl:lndic. g r a d u a l l y n o r m a l i z e d and al lhc fifih inOlllh', afl¢'r adllii~.sJoll, il sliowud 3 / n l n l ~ o f ccll COUlll. 51) n l g / d l o l l o l a l pi-otciil alld 5.3 m g / d l o f lg(l. ( i n c r arid ~,,IRI. : l h l l o i n l a l density or inicn,~ity ~.iro~.l was iCrllarkably dimini~hud in size (Fig. 2t31. i-hal y.ubsequcnl EE(i ~ho~cd ditfusc ~lowing ~.hich was composed of ahundanl Ihula and ~mall dclla aclivil).. In the 61h nl()nlh aflcr admission, hc died ~t lobar pn¢l.illlOilia. /'% gt~ll¢'ral poSllllorler11 cXiilllillalJon ~,[is pcrhlinlcd 4 h afll.'r tlcalh. Pathological findings (N.S. The fresh brain weighed 129(I g. The leptomeningcs wcrc opaque and thickened over the bilateral vcrlex. The main trunk arteries of the brain basis showed fibrous intimal thickening and mild lymphocytic infiltration in the adventitia, and cholesterol clefts were Fig. I. A: lateral vi¢~.~.,of right retrograde hrachial angiography. No filling of the Rolandic. anterior and posterior parict:ll and ~lngtll~lf artcuic,, is shov,n. B: cnhanc~.'d ct'~lllpiZlud Ionlography ol I+rain on adnlission. [.tl',,,,.dcnsJly al'c-a ',~,ilh pailui] cnhallCCm+'nl anti mild I1HI~,'~ cff~_',,:l is l)r~_'SClll in lll~.' cxtclnal alld illlCfll[ll c'ap~,ulc~, and pt+MClJOf tlccp ,Mfitu 111allcr tfl the rJglll hclnisfJhcrc (+: oxygen CtllIMiillplJtlll {cerebral illeHl['~llJJc tiilc +~1 t~xH~cn) Jlllil[2~.'s ill lit)siltill1 cnlission tomograph$ ',~,ith !'() Mcatl~,-'.,talc technique. Ilypi+rilclahlliJsnl Js shov,.n Jr1 the ~amc rcgilm a'~ al'~ilOrllla] d¢llhil). Oil ('['. sccn in some of then1. In particular, the t r u n k of the right middle cerebral artery showed ~(Y',; n a r r o w i n g of the lumina. In addition, pial hranches of the right middle cerebral artery, namely Sylvian t r u n k and R o l a n d i c and a n t e r i o r parietal arteries, disclosed pan- artcritic changcs (Fig. 3A-C). The internal elastic lamina and muscular layer was disrupted and fragmented, and the advcntitia was thickened with fibrosis. Various grades of lymphocytic infiltration throughout the hiyers were observed. The intimal thickening with edema, fibrin precipitation and librohlaslic scarring caused narrowing and complete obliteration of the lumina. Organized thrombi with rccanalizalion were encountered. "lherc was no giant cull or granuloma formation. Panartcritic i n f l a m m a t i o n s became p r o m i n e n t toward the periphery, and round ecll i n f i l t r a t i o n invaded into the ,tdjacent leptomcningcs which was thickened by edema, exudation and loose tihro,,is. 21 Corresponding to those localized vascular changes, several small infarctions wcrc scattered about the right postccntral and insular cortices and whitc matter underlying the above-mentioned affected arteries (Fig. 4). They containcd gliomesenchimal ccil proliferation and lymphocytic infiltration free in thc tissuc and around the vessels. /ks another conspicuous finding, disseminated and confluent demyelitated inflammation with several necrotic loci was observed in the brain basis, which was more widely dispersed in the right hemisphere than in the left. The lesion included the anterior commissure, rctro- and sublenticular portions of thc internal capsulc. optic tract and radiation, external capsule, stria tcrminalis and ansa lenticularis. The fimbria and fiber strands of thc stratum lacunosum in the hippocampus wcrc also affected in the right sidc (Fig. 5A). The subthalamic nucleus, Mcynert's basal nucleus and vcntral part of the globus pallidus and putamcn were also involved, but without any neuronal loss. in these foci, axons wcrc prcservcd compared to marked myelin loss. although axons were definitely diminished in number and spheroids were scattered in places. Perivascular. predominantly pcrivenulous and perivenous, infiltra- tion of lymphoplasma cells was prominent in and around the loci, and massive cuffings led to compressive narrowing of the lumina (Fig. 5B). Reactions of hypertrophic astrocytes and macrophages were m a r ~ d in some areas, but very scarce in other areas where slight cystic necrosis occurred. A small number of perivascular demyelinated loci were also scattered in the right frontal and left parietal white matter. Diffuse myelin loss of the right cerebeilar white matter was pronounced with moderate gliosis. There was neither necrotic focus nor cnccphalitic lesion in the brain stem and spinal cord. A relatively well demarcated myelinolytic focus without any neuronal damage and reactive cells was observed in the central portion of the pontine base. Mild tract degenerations were presented in the middle one-third of the right cerebral peduncle and bilateral pyramidal tracts of the medulla oblongata and spinal cord as well as in the fasciculus gracilis of the cervical cord. General organs. There was multiple focal Candida albicat~s pneumonia and pleuritis. Scattered ulcerations with Candida albicans invasion were observed in the esophagus, stomach and ileo-cecal junctional region, where phlebitis with fresh thrombi was encoun- Fig. 2. Magnetic resonance images (I.).5 tesla, axial 5 mm slices, s~:2(~X)/100). A: on admission, diffuse abnormal high-inlensity area includes the right basal ganglia, thalamus, external anti internal capsules, optic radiation and midbrain as well as the right cerebral white matter. B: after administration, of prednisolone, the abnormal intensity area markedly reduces in size, 22 Discussion • The major neuropathologieal findings of this case were as fi~llows: (I) panarteritis restricted within pial branches of the right middle cerebral artery, and small infarctions which were causally related to it; (2) patchy and confluent demyelinatcd foci with marked perivascular cuffings in the brain basis: (3) chronic leptomeningitis, emphasized around the artcritic lesions. Regarding demyelination of the pontine base, for it was free of inflammatory and vascular changes, wc assumed it was central pontinc myelinolysis which occurred in the terminal stage. Among these findings, scattered demyelinated lesions and necrotic lk~ci with chronic meningitis lk)rmed the denominator of the neuro-Bchc+et's pathology (Rubinstein and Urich 1963: Alcma 1978). Although sparing of the brain stem was unusual and exceptional, the brain basis was the second preferential site of ncuro-Behc+et's lesion. Therefore, taken in connection with the past history of typical Beh£et's syndrome with the cardinal symptoms, one of the essential processes in the C'NS of thc present case was considered to be ncuro-Beh~ct's syndrome. The change in the pial medium-sized arteries was a significant finding in the present case, corresponding to the angiographic abnormality. Bch~et's syndrome with the involvement of large or medium-sized vessels, namely angio-Beh~et's syndrome, is divided into 3 groups: venous occlusion, arterial occlusion and aneurysm formation (Park ct al. 1984: Urayama el al. 1982). Among these conditions, arterial occlusion is rare: the incidence was estimated to be 1.0% in 868 cases and 1.3c~,:: in 450 cases of Beh~ct's syndromc in the large clinical series of Urayama et al, (1982) and Hamza (1987), respectively. In thesc series, occlusion of cerebral artery was observed only in two cases. C Fig. 3. Panarteritis in pial branch of the right middle cerebral arters'. The internal elastic lamina and muscular layer are disrupted and fragmented, and mononuclear cells infiltrate into all layers• The intimal proliferation causes narrowing and complete obliteration of the lumina. Inflammatory change in the suprainsular segment (A) is more prominent and fresh than that in the upper part of the insular segment (B). That in the lower part of the insular segment (C) is less s~ than that in (B). I tematoxylin and eosin, x 20. tcrcd in thc submucosal layers and some subserosal arteries showed thickened walls with fragmented elastica and media. Some vasa vasorum in the aortic media were associated with mild lymphocytic infiltration, although atherosclerotic change of the aorta was limited to a slight degree. Fig. 4. Inflammato~, and obliterating change of the small pial arteries. scattered infarctions in the inst, lar cortex and necr¢~tic inflammat o ~ l'oci with lymphocytic infihration fil the subiacent white matter. t lcmatoxylin and costa. ;, 3.3. 23 Fig. 5. A: disseminated and partially fused necrotic l'~ci and sinrounding dcmyelinaaion in the right brain busis in horizontal section. The lesion includes the subthalamus, posterior limb and rctrolenticular parl ol internal capsule, optic radiation, posterior parts ol the putamcn zmd globus pallidus, and hippa~campus. KILivcr-Barrcrit. B: dcmyclinatcd lesion in the right brain basis. Diffuse lymphocytk: infiltration ~tnd proliferation ~ff reactive elements zlrc ohsem,cd its well as prominent pcrivascuhtr cuffings of mononuclcar cells. I lcm:~toxylin and cosin. :~: N. Although angiographical non-filling or mild inflammatory changes of the cerebral artery were described in a few other case reports (Bienenstock and Margulis 1961: Stefani et al. 1971; Totsuka 1984; lragui and Maravi 1986), occlusive arterial change was revealed in none of the pathologically examined cases. So the arteritic change of the present case should be discussed further among various vascular disorders. We believed the panarteritis to be closely associated with certain unclarified processes of Behqet's syndrome for the following reasons. (1) Clinically, lymphocytic pleocytosis and elevated protein level of the CSF, correspondent to the cerebral arteritis and leptomeningitis, were most prominent in the acute phase which was simultaneous with the developing period of encephalitic inw~lvement on neuroimagings. Pathologi- tally, severe vasculitis of the pial arteries was located nearby the demyelinated parenchymal lesions. These observations suggested that both processes could have developed concomitantly. (2) lntracranial arteritic involvement included all layers of the wall without fibrinoid necrosis, giant cell or granuloma formation, which could bc distinguished from specific non-infectious arteritis such as polyarteritis nodosa, Buerger's disease. Takayasu's arteritis, giant cell arteritis and Wegcncr's granulomatosis. The possibility of infectious arteritis was eliminated, for there wcre no clinical or pathological data indicating any septic general infection except for candidiasis of the lung and gastrointestinal tn~ct in the terminal stage and no Candida infection was detected in thc CNS. Pathological findings of our case wcre reconciled with the previous descriptions of cxtracranial angio-Bch~.ct's syndrome (Shimizu st :d. 1978; Fukuda 1982). Therefore, it was reasonablc to assume that panartcritis and demyelinative encephalitis coexisted ira ~ closely related pathomechanism associated with Behqet's syndrome. In other words cerebral anglo- and neuro-Behqet's syndrome coexisted in the present case. The aortic lesion and old vascular lesions in the gastric subserosa might be also compatible with angio-Behqet',, syndromc. In the postmortem study of Murakami and Shimamine (1974), neuro-Behqet's syndrome was frcqucntly associated with subclinical aortitis. A multifactorial analysis of large series (Shimizu and lnaba 1976~ showed some correlation between neuro- and angioBch~ct's syndrome. Both subclassificd syndromes arc usually manifested several years after the onset of the cardinal symptoms and have a mo~c obvious predilection for men than the common type of Beht;ct's svndromc. Our case and these studic,s suggest a close pathogenetic relationship between ncuro- and angioBchqet's syndrome among the l~t~ad spectrum of Bchqct's syndrome. The inflammatory changes of the right middle cerebral artery became prominent and fresh toward the periphery and appeared to have migrated distally. The right internal carotid artery proximal to severe arteritic lesions showed some changes resembling atherosclcrosis. That provided us with the following two speculations: one was that the pre-existing atherosclerotic change prcwoked arteritic involvcmcnt, or artcritis preferentially developed in the sclerotic artery; the other was that vasculitis in the right carotid artery existed subclinically before the onset of neurologic symptoms when it spread distally, and the morphological findings of the healed stage mimicked atherosclcrotic change. The abnormalities on Cl" and MRI at the acute phase masqueraded as tumor, especially as glioblastoma, which slowly enlarged with mild mass effect. Neurologic symptoms were relatively mild compared to 24 MRI abnormalitics, which was explained by the fact that PET showed a more restricted region of hypon3el;lbolism than abnormal intensity on MRI. Imaging lesions werc dr;lmlitically rcsolved by glucocorticoid lhcrilpy. MR1 findings of Bch~ct's syndrome wcrc rcporled in s e v e r a l bling our (It)87) case alld c a s e s , lind t h e o b s e r v a t i o n s havc bccn describcd Kcrmode ctal. (1989). rcscnl- by l . i t v a n In o u r ct al. ciisc, t h c : l b m l r n l l i l i i l t e i l s i l y o n M R I ill t h e ilCtllC p h a s e : I'lroilder than the plithologically to relict! latory pcrifocal disturbancc in a n d a r o u n d verified edema due lesion, was considered caused by obliterating to marked thc dem.~clinalion perivcnous circucuffings loci. References \Ionia. (i. 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