J7ournal ofNeurology, Neurosurgery, and Psychiatry 1993;56:505-508

Ocular and neurological Behqet's disease withoutorogenital ulceration?

C J Lueck, M Pires, A C E McCartney, E M Graham

AbstractA 28 year old West Indian patient isdescribed who had a relapsing andremitting steroid-sensitive illness for 3years. The clinical features includeduveitis and widespread CNS involve-ment. The patient was treated as thoughhe had neurosarcoidosis. Post mortemexamination revealed histological changescompatible with a diagnosis of Behq:et'sdisease, but at no time did he suffer fromoral or genital ulceration or arthritis.The authors suggest a new term toencompass such an entity: the "Beh9et'sMINUS" syndrome (multifocal intermit-tent neurological and uveitic syndrome).

(7 Neurol Neurosurg Psychiatry 1993;56:505-508)

Departments ofNeurology,Neuropathology, andNeuro-OphthalmologyNational Hospital forNeurology andNeurosurgery London,UKC J LueckM PiresE M GrahamDepartment ofPathology Institute ofOphthalmology,London, UKA C E McCartneyDepartment ofMedicalOphthalmology StThomas's Hospital,London, UKEM GrahamCorrespondence to:Dr Graham, Department ofNeuro-Ophthalmology,The National Hospital forNeurology andNeurosurgery, QueenSquare, LondonWC1N 3BG, UKReceived 26 April 1992and is revised from13 August 1992.

Accepted 25 August 1992

Sarcoidosis is the most commonly diagnosedcause of anterior uveitis in the West Indianpopulation, and is well documented toinvolve the nervous system in 5-16% of allcases.' Behcet's disease is a vasculitic illnesscomprising recurrent oral ulceration plus any

two of recurrent genital ulceration, eye

lesions, skin lesions, and a positive pathergytest, in addition to various other features suchas thrombophlebitis and arthritis.2 It involvesthe nervous system in 4-29%.3 Beh9et's dis-ease typically occurs in patients from Turkey,the Middle East, and the Far East, and is veryuncommon in patients from the West Indies.

Case historyA 28 year old West Indian hospital nightporter, who had come to Britain fromJamaica ten years previously, presented inSeptember 1988 with blurred vision, and was

found to have bilateral vitreous haemor-rhages, keratitic precipitates, cells in the vitre-ous, and new vessel formation in both fundi.A fluorescein angiogram showed no evidenceof vessel closure, but several areas of perive-nous leakage. He had no past medical or fam-ily history of note, and was systemically quitewell. A chest x ray, Kveim test and Mantouxtest were normal or negative. This uveitic pic-ture was presumed to be due to sarcoidosis,and treated with topical steroids. His visionimproved, and he was not troubled againuntil August 1989 when he was admittedwith a two-week history of intermittentheadaches, vomiting, a tendency to fall to theright, right-sided incoordination, and urinaryincontinence. He was febrile (temperature

37.40), but his visual acuity was 6/9 on theleft and 6/12 on the right, with bilateraluveitis, new vessel formation at the posteriorpoles, but no papilloedema. His left pupil waslarger than the right, and there was a mild leftptosis. He had a right upper motor neuronfacial weakness, and a mild right hemiparesis.There was truncal and limb ataxia, moremarked on the right. Reflexes were brisk,more so on the right, and both plantarresponses were equivocal. Sensory examina-tion was normal.The full blood count, urea, electrolytes,

glucose and liver function tests were normalbut the ESR was raised at 46 and later 62mm/hr. Serum angiotensin convertingenzyme was normal (31 units/l), as were hisimmunoglobulins, chest and sinus x rays. AMantoux test at 1 in 10 000 was negative. Aninitial CSF contained 143 red cells, and 16white cells (mostly neutrophils)/mL, protein0-3 g/l, and glucose of 2-9 mMol/Il (blood5-6). Viral and fungal screens were negative,as were oligoclonal bands. A second CSFshowed 5 red cells and 45 white cells (75%lymphocytes)/mL, protein 0-2 g/l, andnormal glucose.

Whilst in hospital, he became drowsy anddysarthric. He developed a complete left thirdnerve palsy, a depressed gag reflex andslowed tongue movements. Two CT scanswere performed four days apart, and bothwere normal. The differential diagnosis ofsarcoidosis and tuberculosis could not be set-tled, and he was treated for both with 80 mgprednisolone/day, and triple anti-tuberculoustherapy.On this medication he improved and was

discharged. In outpatients his steroids werereduced to 40 mg/day, and his uveitis wasquiescent in September 1989. In October1989, however, he developed increasing som-nolence. Rather than increase his steroids, hewas started on azathioprine, 150 mg/day. AMRI scan was performed which showed alesion deep in the right hemisphere at theposterior end of the internal capsule and adja-cent thalamus.He remained stable until January 1990

when he developed increasing drowsiness andblurred vision. Examination at this pointshowed that his mild right-sided facial weak-ness and right hemiparesis had returned. Alumbar puncture showed 12 red cells, 1 whitecell/ml and a protein 0-2 g/l. A repeat MRIscan again showed the lesion in the right thal-amus and internal capsule extending down tothe midbrain, but it had clearly enlarged since

505 on A

pril 30, 2021 by guest. Protected by copyright.

http://jnnp.bmj.com

/J N

eurol Neurosurg P

sychiatry: first published as 10.1136/jnnp.56.5.505 on 1 May 1993. D

ownloaded from

Lueck, Pires, McCanney, Graham

Figure 1 Axial Tl-weightedMRI scanfollowing gadoliniumenhancement at the level ofthe midbrain. An area ofincreased signal is visiblein the right mesial temporallobe and cerebral peduncle.The patient's right is onthe left of the scan.

the earlier scan. His anti-tuberculous therapywas stopped, and his steroids increased to120 mg/day of prednisolone. His azathioprinewas also increased to 225 mg/day.

Once again he improved. During thecourse of 1990 he had several relapses and

Figure 2 Coronal brain slice through mamiUary bodies showing discoloured areas in theinternal capsules and thalami. There is a small cavitated area in the right thalamus(arrow).

remissions dependent on his steroid dose.When the prednisolone dose was lowered tobelow 25 mg/day (deliberately, or, on oneoccasion, due to non-compliance), his symp-toms would relapse. On increasing thesteroids to approximately 100 mg/day, theywould once again remit.He was readmitted on 9 April 1991, with a

two week history of dysarthria, somnolence,urinary incontinence, and chest pain. The lat-ter was worse on sitting up. Examination atthis point revealed him to be severelyCushingoid with gross obesity, striae andacne. He was somnolent, which limited test-ing of his higher mental function. Visualacuities were 6/12 bilaterally, pupils equaland reactive, and his fundi showed someperivascular sheathing. Extraocular move-ments were full. He had a brisk jaw jerk, aright upper motor neuron facial weakness,poor gag reflex, and a mild right hemiparesis.Both plantar responses were extensor, butsensory testing was normal.

Pericarditis was suggested by his ECGshowing. Repeat MRI scan showed that thelesion had all but disappeared, and thereremained only a tiny area of signal change inthe right thalamus.He developed a severe bilateral aspiration

pneumonia, was ventilated, treated withbroad spectrum antibiotics, but died on 2June 1991.

Pathological examinationMACROSCOPIC FINDINGSPost mortem examination showed severebilateral bronchopneumonia. The fixed brainweight was 1270 g. Coronal slices showedsmall symmetrical lateral ventricles with aslightly dilated third ventricle. There wereareas of dark discolouration affecting boththalami and basal ganglia, mainly the putami-na (fig 2). Both internal capsules showedirregular, discoloured lesions, and there werealso mottled areas in the midbrain and pons.The cerebellum and spinal cord were macro-scopically normal.

MICROSCOPIC FINDINGSThe main histological feature was the pres-ence of multiple small, necrotic lesions affect-ing both grey and white matter (fig 3). Thesewere more prominent in the deep grey nucleiand brain stem. Both right and left thalami,pallida and putamina were affected. Thelesion in the right thalamus extended to theinternal capsule and pallidum, and was tosome extent cavitated with severe astrocyticgliosis and macrophages replacing the neu-ropil. There were cuffs of inflammatory cells,mainly lymphocytes, around blood vessels.There was no vessel wall necrosis or evidenceof inflammatory cells invading it. No granulo-mas were present. The lesion involving theleft internal capsule and adjacent grey nucleiwas less prominent but included some smallnecrotic areas (see fig 3).The lesions extended to the midbrain

where the inflammatory changes around

506 on A

pril 30, 2021 by guest. Protected by copyright.

http://jnnp.bmj.com

/J N

eurol Neurosurg P

sychiatry: first published as 10.1136/jnnp.56.5.505 on 1 May 1993. D

ownloaded from

Neuro-Behket's disease without ulcers

**~~~* a

;

cOw

*~~ ~~~ * t° *

**

* ,

tA ,

f.

..; *eI

..

* ~ . 5*

*;

Xto,* t

:.e'' S0w

blood vessels were marked. Lesions were seen

in the substantia nigra which showed gliosisand moderate loss of pigmented cells. Bothsuperior cerebellar peduncles showed myelinpallor, and both optic tracts showed patchyloss of myelin. The corticospinal tracts were

severely damaged showing loss of axons andof myelin.The pons was affected by several necrotic

lesions containing macrophages with severe

gliosis and small inflammatory infiltrates.Microglial nodules were common. The

medulla and spinal cord were better pre-served but showed pallor of the pyramids andcorticospinal tracts. The cerebellar vermisand the cerebellar hemispheres, other thansome myelin pallor and astrocytosis, did notshow the necrotic lesions. There was mildmeningitis mainly affecting the basal regionsand both Gasserian ganglia showed thickenedmeninges where some vessels had prominentinflammatory cuffs. In the cerebral hemi-spheres the cortex was well preserved, butthere was some astrocytic gliosis in the sub-cortical white matter.

Histological examination of both eyesshowed a chronic uveitic picture confinedpredominantly to the anterior uvea, the irisand ciliary body, with a lesser involvement ofthe choroid. There were ill defined granulo-mas in the choroid, but the bulk of the chron-ic inflammation was in the form oflymphocytes, predominantly T cells. Nomicroabscesses were present, a featuredescribed in some cases of ocular Behget's,although not a common finding in a recentseries of five cases.4 In that study, the pre-dominant T cell subset was CD4 +. We were

unable to define the T cell subsets in this case

as the material had been formalin fixed andparaffin embedded.

Besides the presence of chronic inflamma-tory changes in the lungs, histological exami-nation of other organs was normal.

DiscussionThis 28 year old patient had a three year his-tory of a relapsing and remitting steroid-sen-sitive illness. The features of this illnessincluded anterior uveitis with retinal new ves-

sel formation and periphlebitis, and relapsingand remitting cranial nerve palsies, long tractand cerebellar signs. All clinical investigationswere normal or negative apart from a mildlyraised ESR, a raised CSF lymphocyte count,and an abnormality in the right hemisphereon MRI which had all but disappeared imme-diately before death. There were no systemicsigns of vasculitis, and, in particular, no evi-

dence of oral or genital ulceration, and no

arthritis.While uveitis, retinal new vessels and

periphlebitis may all be features of Behcet'sdisease,56 the most likely ophthalmologicaldiagnosis was considered to be sarcoidosis,mainly because of the patient's ethnic originand lack of systemic involvement. Similarly,the neurological disease was consistent withneurosarcoidosis,' although the radiologicalappearances at the time of his most recentpresentation with pericarditis were atypicaland more suggestive of a vasculitic illness ofsome sort. Possible vasculitides includedthose of infective aetiology (for example,syphilis, Lyme disease), connective tissue dis-eases (such as, systemic lupus erythematosus,mixed connective tissue disease, Sj6gren'ssyndrome), or necrotising vasculitides (suchas, polyarteritis nodosa, Wegener's).However, the clinical features, laboratorytests, and histology were not supportive ofany of these diagnoses.The neuropathology of Behcet's is that of a

disseminated meningo-encephalo-myelitis.Histologically, there are circumscribed foci ofnecrosis with a marked inflammatory cellreaction in both grey and white matter, par-

ticularly in the brainstem, deep grey nuclei,and spinal cord. There is perivascular cuffing,predominantly with mononuclear cells, andgliosis. Degenerative changes in nerve cellsare not obvious, and intranuclear inclusionbodies are absent. The blood vessels are usu-

ally normal, though minor changes have beenreported.' 7-11

The histological appearances in our case

were entirely compatible with previousreports, suggesting that the most likelypathology was that of Behcet's syndrome.The clinical and CSF features would be con-

sistent with such a diagnosis,' 12 and the MRIfindings were also compatible." 14 However,in the absence of a specific test for the condi-tion, a diagnosis of Behcet's disease is cur-

rently untenable in the absence of oralulceration.215

Sigal3 mentions that Behcet's disease maypresent with neurological symptoms beforethe ulceration becomes apparent. Alema andBignami7 suggested that "it is possible that insome cases of Behcet's disease with involve-ment of the nervous system the disease is notrecognised because of the lack of mucocuta-neous and ocular lesions". They went on tosay that "in one case where only ocular and

Figure 3 Photomicrographshowing a necrotic lesion inthe thalamus. There is totalreplacement of the neuropilby macrophages andreactive astrocytes.Haematoxylin and eosinx 120.

507

0 41

-

i

6'o

-,-

0

$ a

0

. . .0I

on April 30, 2021 by guest. P

rotected by copyright.http://jnnp.bm

j.com/

J Neurol N

eurosurg Psychiatry: first published as 10.1136/jnnp.56.5.505 on 1 M

ay 1993. Dow

nloaded from

Lueck, Pires, McCarney, Graham

neurological symptoms were present, thediagnosis of Beh9et's disease seems justifiableon the basis of neuropathological findings."'Furthermore, the International Study Groupfor Behcet's disease admits that it is notimpossible for the condition to exist without ahistory of oral ulceration.2 Nevertheless, thelatter group points out that such cases consti-tute at most 3% of all those diagnosed tohave Behget's disease.We suggest that in our patient a diagnosis

of BehcXet's disease would be unquestionableif the patient had had oral ulceration. It ispossible that the condition currently definedas Behget's disease (see above) may be onlyone end of a spectrum of this type of vasculi-tis. Perhaps a new term is required whichembraces a "Behget's-like" vasculitic picturewithout the full complement of clinical fea-tures. A possible term to encompass such anentity would be "Beh9et's-MINUS" (multifo-cal, intermittent neurological and uveitic syn-drome). Interestingly, Behqet's disease ismuch more common in patients fromTurkey, the Middle East, and Asia (the "silkroute"), and uncommon in patients of WestIndian extraction. It may be that the underly-ing vasculitic process manifests itself differ-ently in different races.The important aspect of suggesting a new

term to include patients who would fulfil thecriteria for Behcet's disease but who do notexhibit oral ulceration, is that of manage-ment. The treatment of neurosarcoidosis isgenerally accepted to include corticosteroidsand azathioprine, as were used in our case.Although azathioprine is a reasonable treat-ment for Behget's,'6 had the patient beendiagnosed as either Behget's, or Behget's-MINUS, stronger immunosuppressive agentssuch as cyclosporine or colchicine would havebeen considered.17

We thank Dr R Ross Russell for helpful comments on themanuscript.

1 Chapelon C, Ziza JM, Piette JC, et al. Neurosarcoidosis:signs, course and treatment in 35 confirmed cases.Medicine 1990;60:261-76.

2 Editorial. Criteria for Diagnosis of Behcet's Disease.International Study Group for Behcet's Disease. Lancet1990;335:1078-80.

3 Sigal LH. The Neurologic Presentation of Vasculitic andRheumatologic Syndromes. A Review. Medicine1987;66:157-80.

4 Charteris DG, Barton K, McCartney ACE, Lightman SL.CD4 + T Lymphocyte Involvement in Ocular Behcet'sDisease. Auroimmunity, (in press).

5 Sanders MD. Retinal arteritis, retinal vasculitis andautoimmune retinal vasculitis. Eye 1987;1:441-65.

6 Graham EM, Stanford MR, Sanders MD, Kasp E,Dumonde DC. A Point Prevalence Study of 150Patients with Idiopathic Retinal Vasculitis: 1.Diagnostic Value of Ophthalmological Features. Br YOphthalmol 1989;73:714-21.

7 Alema G, Bignami A. Involvement of the Nervous Systemin Behpet's Disease. In: Monacelli M, Nazzao P, eds.Behget's Disease: proceedings of an InternationalSymposium on Behcet's disease, Rome. Basel: Karger,1966: 52-66.

8 Rubinstein LJ, Urich H. Meningo-encephalitis of Behcet'sdisease: Case report with pathological findings. Brain1963;86:151-60.

9 Wolf SM, Schotland DL, Phillips UL. Involvement of ner-vous system in Behget's syndrome. Arch Neurol1965;12:315-25.

10 Inaba G. Behcet's Disease. In: McKendall RR, ed.Handbook of clinical neurology, vol 12 (56): Viral Diseases.Amsterdam: Elsevier, 1989: 593-610.

11 Esiri MM, Kennedy PGE. Virus Diseases. In: Adams JH,Duchen LW, eds. Greenfield's Neuropathology, 5th ed.London: Arnold, 1992: 335-99.

12 Serdaroglu P, Yazici H, Ozdemir C, Yurdakul S, Bahar S,Aktin E. Neurologic Involvement in Behget'sSyndrome. A Prospective Study. Arch Neurol1989;46:265-9.

13 Besana C et al. Electrophysiological and MRI evaluationof neurological involvement in BehSet's disease. J NeurolNeurosurg Psychiany 1989;52:749-54.

14 Al Kawi MZ, Bohlega S, Banna M. MRI findings inneuro-Behget's disease. Neurology 1991;41:405-8.

15 O'Duffy JD. Behget's syndrome. New Engl J Med1990;322:326-7.

16 Yazici H, Pazarli H, Barnes CG, et al. A Controlled Trialof Azathioprine in Behget'sSyndrome. New Engl J Med1990;322:281-5.

17 Masuda K, Nakajima A, Urayama A, et al. Doublemasked trial of cyclosporin versus colchicine and long-term open study of cyclosporin in Behpet's disease.Lancet 1989;1:1093-6.

508 on A

pril 30, 2021 by guest. Protected by copyright.

http://jnnp.bmj.com

/J N

eurol Neurosurg P

sychiatry: first published as 10.1136/jnnp.56.5.505 on 1 May 1993. D

ownloaded from