Neurological Complications in Behçet's Syndrome

Brain (1999), 122, 21832194

Neurological complications in Behcets syndromeD. Kidd,1 A Steuer,2,3 A. M. Denman2,3 and P. Rudge1

1The National Hospital for Neurology and Neurosurgery, Correspondence to: Dr Desmond Kidd, Department ofLondon and the Departments of 2Immunology and Clinical Neurosciences, Royal Free Hospital, Pond Street,3Rheumatology, Northwick Park Hospital, Harrow, UK London NW3 2QG, UK

E-mail: [email protected]

SummaryThe neurological complications of Behcets syndrome have good, and the majority of those followed-up over a median

of 3 years (range 119 years) had only single attacks.not been characterized with clarity. We present the clinicalfeatures, imaging characteristics and CSF findings of a One-third of patients underwent further attacks, and four

underwent progressive deterioration leading to disability.series of 50 patients seen at the National Hospital forNeurology and Neurosurgery over the past 10 years. In Factors suggesting a poor prognosis are repeated attacks,

incomplete recovery, progressive disease course and athis series, vascular complications had a low prevalence,whereas involvement of the brainstem was common; high level of CSF leucocytosis during acute attack. These

data should be of help in the further definition of thespinal cord lesions, hemisphere lesions and meningo-encephalitis also occurred. Optic neuropathy, vestibulo- clinical characteristics of this rare neurological disorder

and in the planning of treatment trials.cochlear and peripheral nerve involvement occurred, butwere rare. The prognosis for recovery was in general

Keywords: neurological diseases; Behcets syndrome; MRI; CSF

IntroductionBehcets syndrome is an episodic disorder of unknown were sufficiently high have suggested a prevalence of 5.3%

in Istanbul (Serdaroglu et al., 1989), 16% in Casablancaaetiology or pathogenesis, characterized by recurrent oral andgenital ulceration and panuveitis. Constitutional disturbance is (Benamour et al., 1990), 25% in Alexandria (Assaad-Khalil

et al., 1993) and 3.3% in a nationwide survey in Irancommon, and there is malaise, fatigue and loss of weight. Skininvolvement, characterized by erythema nodosum, pustular (Davitchi et al., 1997). In an autopsy series, 20% of 170

cases of patients with Behcets syndrome showed pathologicaleruptions or pseudofolliculitis, is also common, and there isan oligoarthropathy of large joints such as the knees, ankles evidence for neurological involvement (Lakhanpal et al.,

1985).and shoulders. Involvement of the lungs, gastrointestinal tractand kidneys has also been noted, but is rare (ODuffy, 1994).

DiagnosisThe diagnostic criteria are summarized in Table 1Epidemiology

Behcets syndrome is most common in the countries around (International Study Group for Behcets Disease, 1990).These are based on a cohort of 914 patients from severalthe eastern shores of the Mediterranean, the Middle East and

Eastern Asia, particularly Japan, where the prevalence was centres around the world. Clinical features were comparedwith those of 308 patients with connective tissue diseases7/105 in 1974 (Yamamoto et al., 1974). In Turkey the

prevalence was found to be higher in rural than in urban who had also had recurrent oral ulceration. Use of the newcriteria offered an increase in diagnostic sensitivity andareas (37/105 versus 8/105) (Yurdakul et al., 1988). There

has been only one published survey of the disease in the UK specificity compared with previously published diagnosticcriteria. Although it was specified that recurrent oral(Chamberlain, 1977), in which the prevalence was found to

be 0.4/105. There has been no epidemiological study of cases ulceration was a prerequisite, it was acknowledged that casesexisted in which there was pathologically proven Behcetsof Behcets syndrome with neurological complications, other

than those that have reported the prevalence of such syndrome without oral ulceration; it was stated that thecriteria would exclude only 3% of patients in whom recurrentcomplications in hospital populations attending specialist

Behcets syndrome clinics. Authors whose patient populations oral ulceration was not a feature.

Oxford University Press 1999

2184 D. Kidd et al.

Table 1 International Study Group for Behcets disease describe a response to corticosteroids, which Evans andcriteria colleagues confirmed (Evans et al., 1957), although others

noted some cases in which no response was evident. All hadRecurrent major or minor aphthous or herpetiform ulceration ofnoted a propensity for relapse and remission. Further reviewsthe mouthhave been published from time to time (Wolf et al., 1965;Plus recurrent genital ulcerationODuffy and Goldstein, 1976; Al-Kawi, 1992; Serdaroglu,erythema nodosum

pseudofolliculitis 1998).papulopustular eruption Bienenstock and Margulies (1961) described a case inacneiform nodules which cerebral angiography revealed venous sinus thrombosispathergy test positivity

as the cause of their patients syndrome. Vascular complic-anterior or posterior uveitisations as a result of dural venous sinus thrombosis occurretinal vasculitiscommonly in some series (Bousser et al., 1980; el-Ramahiand Al-Kawi, 1991; Serdaroglu, 1998). Others present with

Aetiology isolated intracranial hypertension (Pamir et al., 1981; ShakirThe aetiology is unknown; an infective agent has long et al., 1990; Akman-Demir et al., 1996a); dural venous sinusbeen postulated but has never been identified. Neutrophil thrombosis is found in association with this in most (but nothyperfunction and an increase in the CD81/CD41 cell ratio all) cases, and the CSF is in general inactive. Arterialoccur. There is an increase in circulating T cells bearing thrombosis is rarer, and aneurysm formation has been reportedreceptors; indeed, peptides derived from the 65 kDa heat (Wechsler et al., 1989).shock proteins have been shown to stimulate T cells Involvement of muscle (Arkin et al., 1980; Lang et al.,specifically from patients with the disease (Suzuki et al., 1990), causing a polymyositis, appears to be rare. Peripheral1992; Lehner, 1997). Such cells have been shown to be neuropathy has been reported (ODuffy and Carney, 1971;uveitogenic to Lewis rats (Stanford et al., 1994). The Rougemont et al., 1982), with nerve biopsy and electrophysio-association with HLA B51 is well known and this is logical characteristics of a non-vasculitic axonal neuropathy.particularly associated with uveitis, although even in Japanese A predominately motor polyradiculopathy has also beenseries the prevalence of HLA B51 is only 57% (Mizuki et reported (Bakouche and Guillard, 1984).al., 1997). There is some evidence that HLA B51, as wellas B12, DR7 and DR2, may bear a relationship with thetissue location of the disease. Vascular complications may Neuropathologybe related to abnormal procoagulant activity, which may have The first paper to describe the neuropathology of such casesa primary role, or they may be secondary to endothelial cell was in 1944 (Berlin, 1944); in this report the basal meningesactivation. were seen to be thickened and multiple foci of cellular

infiltration within the meninges and parenchymal lesionswere observed. Silfverskiold described findings in a patient

Clinical picture of neurological Behcets who had died within 5 days of the onset of a severe brainstemsyndrome and saw that there was considerable swelling ofsyndrome

Neurological involvement in Behcets syndrome was first the brainstem with multiple foci of cellular infiltration andperivascular inflammatory cell cuffs (Silfverskiold, 1951).described in the early decades of this century. Pallis and

Fudge (1956) and Wadia and Williams (1957) described the McMenemey and Lawrence described these cases and twoothers; in these, as in the others published previously, theclinical syndromes and classified them into three types.

(i) Brainstem disturbance associated with systemic symptoms brainstem was predominately involved, and areas of softeningwith cellular infiltration and perivascular cuffing were seensuch as fever, arthralgia and skin eruption; the brainstem

signs developed subacutely with evolving cranial neuro- (McMenemey and Lawrence, 1957). Lesions also involvedthe cortex and other grey matter structures, in which loss ofpathies, ocular motor dysfunction, nystagmus and gaze

palsies, dysarthria and ataxia and, on occasions, bulbar muscle neurons was seen. Rubinstein and Urich reported a furthercase in which the patient died after a 6 year disease courseweakness. Headache with meningism was commonly cited,

and in these cases CSF pleocytosis and high protein content characterized initially by relapses and then progressivedeterioration (Rubinstein and Urich, 1961). Their findingswere observed. (ii) Meningomyelitis, comprising a meningitis

with varying neurological signs, including spinal cord and were typical of those previously described: there was a chronicmeningoencephalitis with inflammatory cell infiltration andhemisphere signs (Silfverskiold, 1951). (iii) A confusional

syndrome, in which meningoencephalitis without focal circumscribed areas of necrosis with loss of all tissueelements, accumulation of lipid-laden macrophages andneurological signs arose, which was in some instances chronic

and progressive, resulting ultimately in the development of gliosis. Although the white matter was more often involved,there was clear evidence for lesion formation within the greydementia, Parkinsonism, pseudobulbar palsy and quadri-

paresis. Pallis and Fudge (1956) also described a case with structures, including the cortex, basal ganglia and brainstemnuclei. A large series from Japan (Kawakita et al., 1967)acute myelitis. Wadia and Williams (1957) were the first to

Neurological complications in Behcets syndrome 2185

Table 2 Clinical presentation in the 50 patientssummarized the findings in nine cases from that country andcompared them with the 13 published from Europe and North

Meningoencephalitis with brainstem involvement 25America. No difference was noted. Miyakawa and colleagues Spinal cord involvement 7and Yamamori and colleagues described cases in which Hemisphere involvement 5

Meningitis 4marked cerebral atrophy was seen; in these cases involvementIsolated intracranial hypertension 4of the cortex with marked loss of neurons was observed inCerebral venous sinus thrombosis* 2addition to the white matter findings noted in previous reports Cranial neuropathy* II 1(Miyakawa et al., 1976; Yamamori et al., 1994). Lueck and V 1 VII 2

co-authors, from this institution, published the post-mortem VII 2VIII 3findings of their case, who had presented with a relapsing then

progressive meningoencephalitis without systemic features in*Some patients shared different clinical subgroups.

which the neuropathology showed features characteristic ofBehcets disease (Lueck et al., 1993). Hadfield and colleagueshave shown that there is a marked infiltration by neutrophils

and/or uveitis. The median latency from onset of systemicand eosinophils as well as by lymphocytes, and there is at

symptoms to neurological presentation was three (028)times marked axonal degeneration within lesions (Hadfield years. Twelve patients presented first with neurologicalet al., 1996). No evidence for vasculitis has been found in

symptoms. In one case, published previously (Lueck et al.,this or other pathological studies. 1993), the diagnosis was made only at autopsy, following a

neurological illness without any evidence of a systemicdisturbance at all.Current study

The purpose of this study was to define further the variousclinical syndromes associated with this disorder, tocharacterize the various immunological and imaging Neurological presentation (Table 2)

Twenty-five patients presented with a meningoencephalitisabnormalities seen and to attempt to identify clinical andimmunological prognostic factors for subsequent disease involving the brainstem, seven with spinal cord syndromes

and five with hemisphere signs. Four presented withactivity. We also investigated possible differences in thesecharacteristics between patients of European stock and those symptoms and signs of meningitis and encephalopathy alone.

One patient had signs of an optic neuropathy for which noborn in regions with higher disease prevalence.other cause has been found. One presented with bilateralfacial weakness, two with acute vestibular disturbance dueto an isolated vestibular lesion, and one with isolated bilateralPatients and methods

The medical notes of all patients admitted to the National sensorineural deafness. Vascular complications were rare inour series; two presented with cortical venous thrombosis.Hospital for neurological investigation and treatment with a

diagnosis of Behcets syndrome over the past 15 years were Four patients presented with intracranial hypertension alone.In the patients with isolated brainstem disturbance, thereviewed. Most had been under the care of one of the authors

(P.R.). Many had been referred by another (A.M.D.), and in disorder had a tendency to arise subacutely over days. Twentypatients presented with ataxia and ocular motor dysfunction,order to follow-up their cases the medical notes of such

patients were scrutinized at Northwick Park Hospital. The one having signs indicating a pontine disturbance and twohaving bulbar symptoms, with dysarthria and dysphagia. Thediagnosis of Behcets syndrome was accepted if the clinical

course and features fulfilled the International Study Group severity of the accompanying long tract signs was variable.In two cases the patient presented acutely with a severecriteria (International Study Group for Behcets Disease,

1990). Statistical comparison of groups used the Mann brainstem encephalitis requiring intensive and ventilatorycare. Isolated cranial nerve lesions also occurred; in theseWhitney test.cases lesion of nerve VII was the most prevalent (three cases,of which two also had trigeminal involvement).

Seven patients presented with spinal cord disease; two ofResultsFifty patients were studied; their mean age was 31 years (SD these patients presented with a severe transverse myelitis

with paraplegia, two with a BrownSequard syndrome and6 years). Thirty-one (62%) were male. Thirty-nine were ofEuropean stock, three were born in Iran, three in Turkey, the others with sensory disturbance with increased reflexes

and sphincter disturbance but without weakness.two in the Indian subcontinent and three in North Africa. Allbut one had had mouth ulcers, 41 had had orogenital ulceration Of the patients with hemisphere disturbance, four presented

with hemiparesis and one with hemisensory disturbanceand 29 had developed uveitis. Systemic symptoms, such asoligoarthritis (20 cases) and skin lesions (22 cases), were alone. Three had seizures, including one patient who presented

de novo with hippocampal complex partial seizures.relatively common, although in 30 cases the neurologicalsyndrome arose in conjunction only with orogenital ulceration Symptoms of meningitis that preceded or were an important

2186 D. Kidd et al.

of CSF and imaging abnormalities was also non-significantlydifferent.

Imaging resultsImaging showed MRI abnormalities in the clinically affectedarea in all but one case of those presenting with a brainstemsyndrome (Table 3). The other was a normal CT scan. Inthree cases in addition to the brainstem lesion, multiplepredominantly periventricular white-matter lesions were seenin the hemispheres bilaterally. Lesions correlated well withthe clinical syndrome; 20 showed lesions within the midbrainor superior cerebellar peduncle (Fig. 2), sometimes extendingto the diencephalon, one showed a single lesion within thepons, and two showed medullary lesions. Severe atrophy wasnoted in cases with progressive disease (Fig. 2). In two cases,in whom the clinical syndrome was of a severe acutebrainstem disturbance, the entire brainstem was seen to beinvolved (Fig. 3) and considerable brainstem swelling wasobserved in the acute phase (Fig. 4).

All those with hemisphere syndromes showed multiplewhite matter lesions in both hemispheres, which tended not

Fig. 1 FLAIR (fluid attenuated inversion recovery) sequence MRI to be localized to the periventricular regions. Among patients[1.0 T; TR (repetition time) 7000 ms, TE (echo time) 150 ms] of with cord syndromes, spinal cord imaging was undertakena patient who presented with seizures and hemiparesis due to in three cases; the image was abnormal in two cases, onecortical vein thrombosis with infarction.

showing a high signal intensity lesion with and one withoutadjacent cord swelling (Fig. 5). In two other cases the brainalone was scanned, and this was normal in both cases.part of the clinical syndrome in those with parenchymal

In the single patient with an isolated optic neuropathy,involvement were common, arising in 16 out of the 39 cases.imaging showed no abnormality, including the optic nerves.Two patients presented with an isolated vestibulopathy;In the two patients with isolated vestibulopathy and the singleone of these patients showed evidence for canal paresis andcase with bilateral deafness, imaging of the brain was normal.a preponderance of directional rotation on electronystagmo-

In patients presenting with meningitis alone or isolatedgraphy.intracranial hypertension, imaging of the brain was normalCortical vein thrombosis was seen in two cases, onein each case.of whom showed evidence of concurrent meningitis. One

presented with a hemisphere lesion with seizures due tocortical vein thrombosis (Fig. 1) and the other with intracranial CSF resultshypertension. Isolated intracranial hypertension was seen in

CSF examination was carried out in 18 of 25 patients withthree other cases, in whom no evidence for meningitisbrainstem disturbance; CSF was active in 17 cases, in whichwas found.leucocytosis was seen. In 11 of the latter cases there was anincrease in protein concentration (Table 3). Those withmeningitis and encephalopathy had abnormal CSF in all fourcases, whilst half of the samples examined were abnormalEthnic differences

Eleven (22%) patients were not born of Northern European in patients with hemisphere and spinal cord disturbance.Among those presenting with isolated intracranial hyper-stock. There was no difference in the age of onset of the

disease [23 years (range 1052 years) versus 27 years (range tension the CSF was abnormal in one case, and in the singlecases of those with dural vein thrombosis, optic neuropathy1044 years), P 5 0.34], age at onset of neurological

complications [31 years (range 1452 years) versus 28 years and isolated vestibulopathy, CSF was normal. Intrathecalsynthesis of immunoglobulin was not observed in the cases(range 1844 years), P 5 0.54] (non-European and European

subjects, respectively), characteristics of the systemic disease studied; matched serum/CSF bands were seen in seven cases(18%). In one case a monoclonal band was seen which hadand the characteristics of the neurological disorder. Similar

conclusions have been drawn in a series from France disappeared 6 months later when the CSF examination hadbeen repeated during a reappraisal of the diagnosis.(Wechsler et al., 1988). Six patients had had a brainstem

syndrome, two a cord lesion, two a hemisphere disturbance The difference between median CSF protein concentrationin the brainstem group and the meningoencephalitis groupand one isolated intracranial hypertension. The prevalence


Table 3 MRI and CSF results in patient subgroups, divided into the clinical syndromes with which they presented

Patient Number MRI CSFsubgroup

No data Normal Local Local 1 No data Protein Total WCC % % % OB OB OBperiventricular (mg/mm3) (cells/mm3) polymorphs lymphocytes monocytes / 1/ 1/1

median median(range) (range)

Brainstem 25 2 1 19 3 7 0.51 40 9.5 80 0 14 0 4(0.17-3.70) (1360) (080) (20100) (050)

Cord 7 2 3* 2 0 2 0.57 67 0 75 0 3 0 2(0.372.4) (10103) (050) (0100) (0100)

Hemisphere 5 1 0 0 4 1 0.69 2 6.0 67 5 4 0 0(0.280.79) (122) (553) (4090) (05)

Meningitis 4 0 2 n/a 2 0 1.01 15 82 10 0 4 0 0(0.622.5) (2368) (090) (10100) (08)

ICH 4 0 4 0 0 0 0.53 2 4.0 95 0 3 0 1(0.30.66) (128) (020) (80100) 0

OB x/x 5 oligoclonal immunoglobulin bands in CSF/serum; WCC 5 CSF white cell count; ICH 5 intercranial hypertension. *Twonormal brain MRI, one normal cord MRI.

Fig. 2 T2-weighted MRI (1.5 T; TR 3000 ms, TE 91 ms) of a patient with multiple brainstem attacksand a progressive disease course, showing a lesion within the midbrain, and brainstem and cerebellaratrophy.

2188 D. Kidd et al.

Fig. 3 T2-weighted MRI (0.5 T; TR 3800 ms, TE 92 ms) of a patient who presented with an acutebrainstem syndrome with apnoea requiring prolonged ventilatory support, showing very pronouncedhigh signal intensity abnormalities throughout the brainstem.

was significant (P 5 0.042); in all other cases CSF protein well without residual disability. Three patients (one withtransverse myelitis and two with a brainstem disturbance),and white cell count were not significantly different between

groups (P . 0.05). however, made no improvement and are left with severeneurological impairments. Further attacks occurred in 12patients, in whom a median of one relapse (range 16) hasarisen to date. Relapse occurred frequently in patients withEvoked potentials

The visual evoked potential was measured in 10 cases; it brainstem involvement at onset (Table 4), and eight patientshad further brainstem attacks. One patient with cordwas abnormal in one case. Sensory evoked potentials were

measured in eight cases and were normal in each case. involvement initially had a further cord syndrome, and oneeach with cord involvement and hemisphere involvement hadBrainstem auditory evoked potentials were measured in 12

cases and abnormalities were detected in two cases, in which a brainstem attack at a later point. Four patients havesubsequently undergone progressive deterioration leading tothere was a delay in conduction at the level of the pons in

patients with brainstem dysfunction. severe impairment and disability; all of these patients hadbrainstem disturbance initially and all have had furtherattacks. There were two deaths, both owing to aspirationpneumonia with severe brainstem impairment.Clinical follow-up

Thirty-five (70%) patients have been followed-up for a In an attempt to identify significant prognostic factorsduring the first neurological attack, CSF protein and whitemedian of 3 years (range 119 years). All four cases of

intracranial hypertension underwent shunting procedures and cell count were measured. There was no significant differencein CSF protein or white cell count between patients followedhave remained well. Recovery from attacks with parenchymal

lesions was in general good; the majority of patients recovered up who had had a single attack and those whose attacks were


Fig. 4 T1-weighted MRI (0.5 T; TR 420 ms, TE 15 ms) following injection of gadoliniumDTPA ofthe same patient as in Fig.3, showing swelling of the brainstem and enhancement of the lesion withinthe pons.

recurrent. However, the median CSF white cell count was suggest. This may also account for the lower incidence ofprogressive disease than that noted in other studies, althoughhigher in patients who subsequently became disabled or died

[103 (range 5368)] than in those who were not disabled at we did take care to follow up patients who returned to therheumatology clinics in order to minimize this potential bias.follow-up [12 (range 1180)] (P 5 0.02).

One patient presented with signs of optic neuropathy, forwhich no alternative cause has been found; imaging wasnormal and CSF immunoglobulin oligoclonal bands wereDiscussion

In this large clinical series of patients with neurological absent. Optic neuropathy is rare in Behcets syndrome, onlya handful of cases having been published (Colvard et al.,involvement in Behcets syndrome the incidence of brainstem

involvement was high (52%) and that of vascular 1977; Kansu et al., 1989). Pathological examination of onecase has shown gliosis and demyelination within the nervecomplications low (4%). Involvement of the hemisphere,

spinal cord and optic nerves was also seen. No difference (Colvard et al., 1977).Of particular interest are the three patients who presentedwas noted between the small number of non-Northern

European-born patients and the others. Patients with active with or developed vertigo or hearing loss. There has beenonly one report of auditory findings, in a small series ofdisease showed a mixed lymphocyte and neutrophil

pleocytosis and there was no evidence for intrathecal synthesis patients with Behcets syndrome (Brama and Fainaru, 1980).In two of our patients, initial asymmetrical hearing lossof immunoglobulin. Imaging revealed lesions localized to

the clinically affected areas in most cases examined, with progressed to involve both ears, but there were fluctuations,often over a period of weeks, in the magnitude of the hearingevidence for lesion dissemination in a further three cases.

The prognosis for recovery following acute relapse was in deficit. Extensive tests of auditory function showed that thehearing decline was due to hair cell loss; both patientsgeneral good, the majority of patients becoming symptom-

free. However, of those who were followed-up 28% showed recruitment on assessment of loudness discomfortlevel and the stapedius reflex measurement; they had normalunderwent further attacks and 14% became significantly

disabled as a consequence of either the absence of recovery brainstem auditory evoked potentials and absent echoes. Theintolerance of loud sounds reported by one patient is alsoor the development of a progressive disease course. It should

be noted, however, that in this series the median follow-up consistent with hair cell loss. Both had recurrent attacks ofsevere vertigo that resolved over 14 weeks. Only one ofwas 3 years (range 119 years); a longer follow-up may

reveal a more frequently relapsing disease than these data the patients had abnormal caloric responses, indicating loss

2190 D. Kidd et al.

Fig. 5 T2-weighted MRI (1.5 T; TR 5000 ms, TE 130 ms) of a patient who presented with an acutedisturbance of sensation in the upper and lower limbs, with urgency of micturition, showing a cordlesion adjacent to C2.

of horizontal canal function on one side. Ultimately this submitted that this may offer prognostic information. In ourseries, disabled patients at follow-up had a higher medianpatient developed complete vestibular failure. Both patients

had normal vestibulo-ocular reflex suppression on rotational CSF white cell count during the acute attack than those whohad improved and remained stable. More recent reportsand caloric testing, indicating a peripheral origin of the

dysfunction. Thus the three patients with auditory vestibular (Akman-Demir et al., 1996c; Bohlega, 1996; Siva et al.,1998), in which larger patient groups have been studied,abnormalities or symptoms all had a progressive peripheral

rather than a central nervous system disorder, which to some have shown a frequency of relapse similar to that in our ownseries, but a greater frequency of progressive disease courseextent mimicked Menie`res syndrome.

Previous clinical series have been small with a variable (3040%). They suggest that adverse prognostic factorsinclude young age of onset, brainstem involvement, highfollow-up. In one of the larger series (Serdaroglu et al., 1989;

Akman-Demir et al., 1996b), which followed-up 15 patients frequency of relapse and the presence of CSF abnormalities. Inaddition, one group has suggested that a primarily progressivewho had had abnormal neurological signs out of a series of

45 who had had neurological symptoms, seven were stable (progressive from symptom onset) disease course may exist(Akman-Demir et al., 1996c). Our series and those of othersand three had died (one during a relapse); of the remaining

five, one had had two further relapses and four had undergone suggest that in general the prognosis for isolated intracranialhypertension and dural venous sinus thrombosis is goodprogressive deterioration without superimposed relapse. In

this group of patients the incidence of CSF abnormalities following satisfactory treatment. For those with parenchymalinvolvement it appears that prognosis is related to thewas higher than in those who were stable, and the authors


Table 4 Frequency of relapse and site of further attacks Wechsler et al., 1993; Coban et al., 1996; Tali et al., 1997).according to clinical subgroup at presentation In acute lesions there may be oedema, and enhancement is

present in the majority of cases (Kazui et al., 1991; TaliClinical subgroup No. of No. of cases Site ofet al., 1997). T1-weighted hypointensity is seen in chroniccases with relapse relapselesions. There is a close clinicalradiological correlation

Brainstem 25 8 Brainstem (Morrissey et al., 1993; Wechsler et al., 1993; Akman-DemirCord 7 1 Cord et al., 1998). A striking feature noted by many (Kermode1 Brainstem

et al., 1989; Al-Kawi et al., 1991; Nussell et al., 1991;Hemisphere 5 1 BrainstemGerber et al., 1996; Akman-Demir et al., 1998) is that T2-Meningitis 4 1 Meningitis

1 Brainstem weighted white matter lesions reduce in size markedly inIntracranial 4 0 conjunction with clinical recovery and often become invisible,hypertension at least on low-strength magnets (Kermode et al., 1989; TaliCranial neuropathy II 1 0

et al., 1997). Brainstem atrophy may be striking, as evidentVII 4 0in several of our cases (Fig. 2) and noted by others (MorrisseyVIII 3 1 Progressive

vestibular failure et al., 1993; Wechsler et al., 1993; Coban et al., 1996).The largest published study involved 15 patients with

parenchymal involvement; atrophy was seen in three cases,involvement of the brainstem and basal ganglia alone in eightfrequency and number of further attacks and the development

of a progressive disease course. The pathophysiology of this cases, and in three further cases periventricular lesions wereseen in addition to brainstem lesions. MRIs were normal inis not clear but is likely to be linked to progressive axonal

degeneration leading to atrophy, as has been intimated in two cases, scanned at least 11 months after resolution of theclinical attack (Wechsler et al., 1993). In a further 10 patientsmultiple sclerosis (Kidd et al., 1996, 1998; Trapp et al.,

1998). Further prospective studies are required in order to with cerebral vein thrombosis, MRI of the brain was normaland the imaging abnormality was restricted to the venousdefine further the pathophysiology of the disease course and

the prognostic features. system. In a further five cases with headache alone withoutintracranial hypertension, three of whom had CSF pleocytosis,In our series no patient showed intrathecal synthesis of

immunoglobulin. Other papers (Sharief et al., 1991; McLean MRI was normal. More recently (Akman-Demir et al., 1998),a study of a series of 59 patients with brainstem involvementet al., 1995; Serdaroglu, 1998) have reported series in

which the majority showed evidence of bloodbrain barrier and 14 with intracranial hypertension has shown similarfindings.dysfunction but few papers have shown intrathecal synthesis

of IgG, and Gille and colleagues reported that oligoclonal Magnetic resonance spectroscopy investigations have beenpublished for only three cases (Nussel et al., 1991), inimmunoglobulin bands disappeared from CSF following an

acute attack (Gille et al., 1990). This is in stark contrast to which a reduced NAA/Cr (N-acetyl aspartate/creatine 1phosphocreatine) ratio was seen in the acute phase, whichmultiple sclerosis, in which persistent oligoclonal bands are

present in the CSF of 97% of patients (McLean et al., 1990; subsequently normalized following clinical recovery; in allthree cases substantial radiological recovery had occurred.Zeman et al., 1996). Sharief and colleagues found a greater

incidence of IgA and IgM bands (Sharief et al., 1991), which No long-term or systematic studies have been published.Few electrophysiological studies have been publishedmay suggest an alternative antigenic stimulus, and Jongen

and colleagues in a single case found that IgM and IgA (Nakamura et al., 1980; Besana et al., 1989; Rizzo et al.,1989; Stigsby et al., 1994); abnormalities of brainstembands disappeared following recovery from episodes of

meningoencephalitis (Jongen et al., 1992). In neurosarcoid- auditory evoked potentials are most frequent, and are moreprevalent in patients in acute attacks than in patients studiedosis, oligoclonal bands are also infrequent (McLean et al.,

1995); indeed, there is recent evidence to suggest that they in remission. Visual evoked potential abnormalities are alsocommon in other series, although not in ours; this is interestingmay also be absent, as in Behcets syndrome (V. Chamoun

and L. J. Thompson, personal communication). The mixed in view of the fact that the optic nerve is involved clinicallyin a small minority of cases (Colvard et al., 1977; Kansupleocytosis and high frequency of neutrophils was noted in

early publications and was subsequently confirmed et al., 1989). Characteristically, recordings show reducedamplitude with little or no prolongation in latency. This is in(Nakamura et al., 1980). These authors also noted that the CSF

cell count diminished in response to steroid administration, contrast to that of demyelination, in which it is characteristicto see prolonged latency with temporal dispersion but normalprompting speculation that there is an anti-inflammatory role

for steroids rather than simply an anti-oedema mode of action. amplitude (Halliday et al., 1972). Visual evoked potentialabnormalities occurred in patients without uveitis withOur series confirms the findings of previous MRI studies

that have shown that involvement of the clinically affected frequency equal to that in patients who had had ocularinvolvement (Stigsby et al., 1994). A study of central motorregion alone is most common. Most prevalent is the lesion

of the midbrain extending to the basal ganglia or internal conduction times in 20 patients, 13 of whom had neurologicalsymptoms and signs, has shown that abnormalities comprisingcapsules (Kermode et al., 1989; Morrissey et al., 1993;

2192 D. Kidd et al.

Akman-Demir G, Baykan-Kurt B, Serdaroglu P, Gurvit H, Yurdakulmild conduction slowing and reduction in amplitude wereS, Yazici H, et al. Seven year follow-up of neurologic involvementpresent in half of those with abnormal neurological signs,in Behcet syndrome. Arch Neurol 1996b; 53: 6914.and also arose in those without signs (Parisi et al., 1996). In

our series the prevalence of evoked potential abnormalities Akman-Demir G, Serdaroglu P, Tasci B, Baykan-Kurt B, Gurvitwas low (two out of 12 patients in whom data were available). IH, Bahar S, et al. Neurological involvement in Behcets disease.

There has been no prospective placebo-controlled trial of Rev Rheum Engl Ed 1996c; 63: 549.any form of treatment in Behcets syndrome with neurological Akman-Demir G, Bahar S, Coban O, Tasci B, Parman Y, Serdaroglucomplications. Anecdotal evidence has pressed forward the P. Cranial MRI findings in Behcets disease: a study of 134 MRIopinion that use of corticosteroids is mandatory in acute of 98 cases [abstract]. J Neurol 1998; 245: 362.attacks and possibly thereafter. Intravenous methylpred-

Al-Kawi MZ. Neuro-Behcet disease: a review. J Trop Geographnisolone is often given in acute attacks. Other forms ofNeurol 1992; 2: 4956.immunosuppressive treatment, such as azathioprine, cyclo-

phosphamide, chlorambucil and cyclosporin A, have been Al-Kawi MZ, Bohlega S, Banna M. MRI findings in neuro-Behcetsadvocated as maintenance therapy (Serdaroglu, 1998). disease. Neurology 1991; 41: 4058.Colchicine is thought to act by inhibiting neutrophil Alpsoy E, Yilmaz E, Basaran E. Interferon therapy for Behcetschemotaxis (Matsumara and Mizushima, 1975). For adequate disease. J Am Acad Dermatol 1994; 31: 6179.treatment trials one must turn to the ophthalmologists, who

Arkin CR, Rothschild BM, Florendo NT, Popoff N. Behcet syndromehave shown clearly that the use of cyclosporin A in uveitiswith myositis: a case report with pathologic findings. Arthritisresults in an alteration of the visual prognosis in thisRheum 1980; 23: 6004.complication of the disease (Graham et al., 1985; Masuda

et al., 1989). More recently, reports of beneficial effects on Assaad-Khalil S, Abou-Seif M, Abou-Seif S, El-Sewy F, El-Sewysystemic features of the disease with tacrolimus (Ishioka M. Neurologic involvement in Behcets disease: clinical, genetic

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22631.

Stigsby B, Bohlega S, al-Kawi MZ, al-Dalaan A, el-Ramahi K. Received February 8, 1999. Revised June 6, 1999.Accepted June 14, 1999Evoked potential findings in Behcets disease. Brain-stem auditory,

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Neurological Complications in Behçet's Syndrome