Annals of the Rheumatic Diseases, 1988; 47, 606-611

Case report

Extensive cerebral infarction due to involvement ofboth anterior cerebral arteries by Wegener'sgranulomatosisJ SATOH,' N MIYASAKA,12 T YAMADA,' T NISHIDO,' M OKUDA,'T KUROIWA,3 AND R SHIMOKAWA3

From the 'First Department of Internal Medicine, Tokyo Medical and Dental University; the 2Division ofClinical Immunology, Institute of Rheumatology, Tokyo Women's Medical College; and the 3Department ofPathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

SUMMARY The central nervous system is often affected in Wegener's granulomatosis (WG), butmassive cerebral infarction due to occlusion of branches of the anterior cerebral arteries (ACA)by granulomatous lesions or thrombosis, or both, has seldom been reported. A case is reportedhere of a 67 year old man with WG complicated by generalised necrotising vasculitis in the lung,kidney, and gastrointestinal tract, and cerebral infarction in the territory of both anterior cerebralarteries, probably caused by thrombosis and a contiguous invasion of granulomatous lesion fromthe nasal cavity.

Key words: bilateral occlusion of anterior cerebral arteries, cerebral vasculitis.

Wegener's granulomatosis (WG) is characterised bysystemic necrotising vasculitis and granulomatouslesions. Neurological complications have been esti-mated to occur in more than half of the patients withWG.' Extensive infarction of both cerebral hemis-pheres in WG, however, has rarely been recorded.In this report we describe the clinical course andhistopathological findings of a case of WG associ-ated with widespread infarction in the region of bothanterior cerebral arteries (ACA) attributable tothrombosis due to necrotising vasculitis and directinvasion of the granulomatous lesion from the nasalcavity.

Case report

A 67 year old man who had been diagnosed ashaving WG seven years ago was admitted to hospital

Accepted for publication 7 January 1988.Correspondence to Dr N Miyasaka, Division of Clinical Immu-nology, Institute of Rheumatology, Tokyo Women's MedicalCollege, Box 116, NS BLD 2-4-1, Nishi-Shinjuku, Shinjuku-ku,Tokyo 163, Japan.

because of severe frontal headache on 22 July 1983.One month before admission frontal headacheaccompanied by intermittent fever developedgradually and persisted. Two days before admissionfrontal headache became severe and he becameconfused and exhibited unusual behaviour. Thepatient had had tuberculous pleuritis at the age of 10years but since then had been well until seven yearsearlier when nasal obstruction, frequent purulentrhinorrhoea, polyarthralgia, and fever developed.Biopsy of the granulation tissue in the nasal cavityshowed a necrotising granulomatous lesion withinfiltrates of neutrophils, histiocytes, lymphoid cells,and multinucleated giant cells. While in hospital hesuddenly passed a massive bloody stool, andemergency subtotal gastrectomy was performed.The operative specimen of the stomach showedmultiple gastric ulcers associated with necrotisingvasculitis with fibrinoid necrosis (Fig. 1) and extra-vascular granulomatous lesions of the submucosa.The wedge biopsy specimen of the liver showednecrotising vasculitis with extravascular granulomasin Glisson's sheath and the subcapsular area.

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Cerebral infarction by Wegener's granulomatosis 607

Fig. 1 Operative specimen ofthe stomach. Necrotising vasculitiswith fibrinoid necrosis isprominent. (Haematoxylin andeosin.)

A diagnosis of WG was made, and the patient wastransferred to our department. He had proteinuriaand microscopic haematuria. Renal biopsy showedfocal necrotising glomerulitis with crescents. He wastreated with a combination of prednisolone andazathioprine, followed by maintenance treatmentwith low dose prednisolone and cyclophosphamide.Two short episodes of exacerbation occurred in thefollowing seven years, however. On his own decisionthe patient took no drugs in the two months beforean examination, which showed him to be stuporousand chronically ill. A saddle nose deformity wasnotable. Nostrils were filled with black crusts.Neurological examination revealed that the left eyehad no perception of light; the pupil was dilated anddirect light reflex was absent. Other cranial nerves,however, were intact. The neck was supple and thedeep tendon reflexes were normal. The urinecontained a trace of protein, and was '++' forglucose; the sediment contained numerous whitecells, red cells, and granular casts. Packed cellvolume was 0-34; the white cell count was 16 8x 109/lwith neutrophilia. The blood urea was 10(4 mmol/l,creatinine 114 9 p.mol/l, glucose 13 5 mmol/l, andserum protein 58 g/l. The erythrocyte sedimentationrate was 113 mm/h, C reactive protein 4+, and IgA3-23 g/l. x Ray films of the chest showed a discretenodular shadow with a thin walled cavity at the leftupper zone. The cerebrospinal fluid, with an initialpressure of 350 mmHg, contained 34 mononuclear

and six polymorphonuclear white cells per mm3;protein was 430 mg/I. Cultures of cerebrospinal fluidwere negative. Brain computed tomography (CT)showed a large midline mass 4 cm in diameter withcontrast enhancement in the frontal region adjacentto the falx cerebri (Fig. 2). The lesion was sur-rounded by extensive perifocal oedema that spreadinto the frontal white matter on both sides. Inaddition, the low density area extended to bothcingulate gyri. Ventricles were slightly enlarged.Orbital ultrasonography showed a left retrobulbarmass surrounding the optic nerve. Cerebral angio-graphy was not performed because of his poorcondition.The diagnosis considered at that time was intra-

cerebral granulomatous lesion and secondary brainoedema due to WG. The patient was given intra-venous infusions of glycerol, 16 mg of dexametha-sone, and 100 mg of cyclophosphamide daily,resulting in improvement of the severe headache.Even one month later, however, on neurologicalexamination he was still somnolent, mute, andemotionally labile. The cerebrospinal fluid containedonly two mononuclear cells and one polymorpho-nuclear white cell per mm3 and protein was in-creased (3.05 g/l). An indwelling urinary catheterwas inserted because of urinary incontinenceand dysuria. About two months after admission thepatient developed intermittent fever rangingbetween 38 and 40°C. Repeated cultures of urine,

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608 Satoh, Miyasaka, Yamada, Nishido, Okuda, Kuroiwa, Shimokawa

Fig. 2 Brain CTshows a large midline mass with contrast enhancement adjacent to the falx cerebri. The lesion issurrounded by extensive perifocal oedema spreading into the frontal white matter.

Fig. 3 Brain CTshows significant reduction of the mass lesion adjacent to the falx cerebri.

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Cerebral infarctiotn by Wegener's granulomatosis 609

sputum, and blood for bacteria and fungi were allnegative. Brain CT showed that the midline masslesion adjacent to the falx cerebri had almostdisappeared (Fig. 3). The low density area noticedpreviously in both cingulate gyri was enlarged,however, indicating the presence of cerebralinfarction at the ACA on both sides. The lowdensity area was rimmed with ring enhancement,indicating possible secondary infection in the brain(Fig. 4). He suddenly passed a massive bloody stool,and transfusions of packed red cells and fresh frozenplasma were given. No site of bleeding was identifiedby colonic endoscopy and mesenteric angiography.He had several attacks of generalised convulsionand died on 13 October 1983.

PATHOILOGICAI FINDINGSGeneral necropsy showed a fist sized, greyish white,soft mass with central cavitation at the left upperlobe, and several scattered foci of greyish whitenodules in both lungs. Histologically, these werecomposed of necrotising vasculitis and granulomaswith epithelioid cells, Langhans-type multinucleatedgiant cells, histiocytes. monocytes, lymphocytes,plasma cells, and neutrophils. Ulcerative lesionswere present in the right main bronchus and theposterior wall of the mesopharynx, which were alsoassociated with necrotising vasculitus and granulo-

mas. Multiple small greyish white nodules werelocated at the cortices of both kidneys, and thehistology showed focal necrotising glomerulitis,periglomerular granulomatous lesions, and fibrinoidnecrosis of the arcuate and interlobular arteries.Multiple shallow ulcers and erosions were scatteredin the sigmoid colon and rectum.

Neuropathological examination showed that thebrain weighed 1190 g, and the meninges werediffusely clouded and thickened, especially in thefrontal poles. Suppurative meningitis of both frontallobes and the base, involving the left optic nerve,was present. A notable finding was cerebral infarc-tion with symmetrical massive lytic and coagulationnecrosis of the area supplied by the branches (A2) ofboth ACA (Fig. 5). Microscopically, medium tolarge sized branches of the ACA were occluded withorganised mural thrombi, though some of them,were recanalised (Fig. 6). Changes in the vascularwalls were not so prominent, but there was somefibrinoid necrosis in these arterial branches of theACA. By contrast, there were necrotising granulo-niatous lesions with multinucleated giant cells andvarious features of necrotising vasculitis of smallarteries and veins spread diffusely in the frontal areaof the brain base, medial part of the anterior lobes,and meninges, suggesting a contiguous invasion ofthe granulomatous lesion from the nasal cavity.

Fig. 4 Brain CTshows enlargement ofa low density area with rim enhancement.

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Discussion

Wegener's granulomatosis is a systemic disease ofunknown cause, characterised by granulomatouslesions in the upper and lower respiratory tract withgeneralised necrotising vasculitis of both arteriesand veins, and focal glomerulitis.2 Initial symptomscommonly originate from the upper respiratorytract, but multiple organs can be involved. Before

Fig. 5 Necropsy specimen ofthe medial part of the left anteriorlobe shows occlusion ofamedium sized branch of theanterior cerebral artery, organisedand recanalised. Scattered foci offresh and old vasculitis ofmeningeal arteries and veins areseen. Foci of lytic and coagulationnecrosis ofbrain parenchymaare also observed. (Haematoxylinand eosin.)

Fig. 6 Necropsy specimen ofthe medial part of the left anteriorlobe shows fresh necrotisingand granulomatous panvasculitisof the meningeal artery withinfiltration ofneutrophils,histiocytes, monocytes,lymphocytes, plasma cells,and multinucleated giant cells.(Haematoxylin and eosin.)

the emergence of combination treatment with cyclo-phosphamide and corticosteroids the incidence ofneurological complications was as high as 50%, andit could be fatal.' Recently, the incidence of suchcomplications has been about 20%.3 Drachmanclassified the nervous system involvement in WGinto three forms: contiguous invasion of granuloma-tous inflammation from the primary nasal or para-nasal lesions, remote granulomatous lesions, and

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Cerebral infarction by Wegener's granulomatosis 611

vasculitis. Vasculitis of the vasa nervosum is themost common manifestation, and is responsible forcranial and peripheral neuropathies, which take theform of mononeuritis multiplex or polyneuritis.4Vasculitis in the central nervous system is infrequentbut may induce cerebrovascular disease'namely, subarachnoid or intracerebral haemor-rhage, cerebral arterial thrombosis, and sinusthrombosis.The present case differs from others in the

widespread distribution of the infarcted area. Nec-rotising granulomatous lesions were extensive inthe brain base and medial part of the anteriorlobes, suggesting a contiguous invasion from thenasal cavity. Furthermore, medium to large sizedbranches of the ACA were occluded with muralthrombi, which were organised and partly re-canalised. We therefore speculate that boththrombosis of the branches of the ACA due tonecrotising vasculitis and direct invasion of thegranulomatous lesion might have caused cerebralinfarction in this case. It is not clear which of thesepathological changes is the dominant factor causingcerebral infarction. Clinically, bilateral infarction inthe region of the ACA may produce symptoms andsigns of frontal lobe dysfunction, e.g., behaviouraldisturbance, motor inertia, suck and grasp reflexes,incontinence, abulia, muteness, and akineticmutism. Our case presented neurological deficitsthat could be attributed to bilateral frontal lobedisturbance.

Immunosuppressive agents, particularly cyclo-phosphamide, have a dramatic therapeutic effi-cacy in WG when used in combination withcorticosteroids.3 Continuous regular monitoring ofpatients is essential, however, and treatment needsto be continued for a very long time to preventrecurrence of the disease. In the present case thepatient had a fatal recurrence of WG after discon-tinuing treatment, and the administration of cyclo-phosphamide and dexamethasone could not changethe clinical course of the late stage of the disease,though some improvement was evidenced on CT

scan. This could be explained by the massivecoagulation necrosis of the brain caused by infarc-tion. On the other hand, immunosuppressive treat-ment can cause opportunistic infection, and sup-purative meningitis was observed in this case. Thelow density area with rim enhancement, as shown inbrain CT (Fig. 3), suggested the association ofbacterial infection with necrosis of the brain. Cere-brospinal fluid findings also support the associationof suppurative meningitis with the late stage ofimmunosuppressive treatment. It is unlikely thatthis could contribute to cerebral infarction in theACA, however.To our knowledge this is the first clinical and

histopathological presentation of extensive infarctionof ACA directly caused by occlusion of the vessels,probably resulting from thrombosis due to necro-tising vasculitis and direct invasion of extravasculargranulomatous lesions from the nasal cavity in WG.

The authors wish to thank Dr Takeshi Tabira of the NationalInstitute of Ncuroscience, National Center of Neurology andPsychiatry, and Professor G Palffy of the University of PecsMedical School, Hungary, for critically reviewing this paper. Wealso thank Ms Hiromi Kishi for her secretarial work.

References

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2 Godman G C, Churg J. Wegener's granulomatosis. Arch Pathol1954; 58: 533-53.

3 Fauci A S, Haynes B F, Katz P, Wolff S M. Wegener'sgranulomatosis: prospective clinical and therapeutic experiencewith 85 patients for 21 years. Ann Intern Med 1983; 98: 76-85.

4 Moore P M, Cupps T R. Neurological complications ofvasculitis. Ann Neurol 1983; 14: 155-67.

5 Fahey J L, Leonard E, Chung J, Godman G. Wegener'sgranulomatosis. Am J Med 1954; 17: 168-79.

6 Fauci A S, Wolff S M. Wegener's granulomatosis: studies ineighteen patients and a review of the literature. Medicine(Baltimore) 1973; 52: 535-61.

7 Sahn E E, Sahn S A. Wegener's granulomatosis with aphasia.Arch Intern Med 1976; 136: 87-9.

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9 Hearne C B, Zawada E T. Survival after intracerebralhemorrhage in Wegener's granulomatosis. West J Med 1982;137: 431-4.

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