Topic of the month: Radiological pathology of behcet disease

INDEX

INTRODUCTION

INTRODUCTION

Behcet's disease (BD) is an uncommon, relapsing and remitting, multisystem inflammatorydisorder characterized by the triad of oral ulceration, genital ulceration, and uveitis. 61 Anumber of additional features are commonly present, including arthritis, retinal andcutaneous vasculitis, thrombophlebitis, and gastroenteric disorders. The essential lesion is afocus of chronic inflammation, typically in the vicinity of a small blood vessel. Lesions inthe CNS resemble those in other organ systems. Characteristically there are multiple smallfoci of softening that may eventually become confluent. These correspond to myelin lossand, to a lesser degree, drop out of neural elements with replacement by foamymacrophages. The lesions are not fundamentally demyelinative and more closely resembleminute ischemic foci. As in the periphery, lesions tend to occur near blood vessels, but

vasculitis is uncommon. Pathologic findings are most extensive in the midbrain, pons(especially the basis pontis) and the medulla, and there is typically a lesser degree ofinvolvement of the spinal cord, internal capsule, globus pallidus, optic nerves, andhypothalamus. In some cases, the cerebral white matter, cortex, hippocampus, basalganglia, and thalamus are involved. The cerebellum is usually spared. The meninges aretypically thickened and adherent to the brain surface, and acutely there may beconsiderable meningeal inflammation; hence the common reference to neuro-Behcet'sdisease as a meningoencephalitis.

In general the most common presentation of parenchymal CNS involvement is a subacutebrainstem syndrome with cranial nerve findings, dysarthria, and cerebellar orcorticospinal tract signs. More infrequent presentations include a strokelike presentation(with the acute onset of unilateral neurologic findings and signs of cortical involvementincluding seizures) and psychiatric features, such as psychosis. Sinus venous thrombosismay evolve relatively slowly and results in intracranial hypertension, resulting headache,vomiting, and bilateral papilledema. Impaired memory (long-term verbal and nonverbal)and visuospatial skills occur frequently in patients with active disease who are taking largedoses of steroids. Pure spinal cord or PNS involvement is rarely reported. Impairment ofsensation is uncommon. (70)

Between 5% and 20% of patients have neurologic disease. (70) The most commonneurologic manifestation of Behcet's disease is a relapsing and remitting, but oftenprogressive, focal meningoencephalitis that most often affects the brain stem. (70) Patientspresent with a host of cranial nerve and long tract signs and eventually develop spasticquadriparesis and a bulbar or pseudobulbar palsy, frequently with rather dramaticemotional incontinence. (70) Cochlear and vestibular dysfunctions are common. Oftenthere are additional features of impairment in frontal lobe and memory functioncharacteristic of a subcortical dementia. A number of cases of nearly pure subcorticaldementia have been reported, but typically long tract signs are prominent, and bulbarinvolvement eventually develops. Patients may also present initially with features oftransverse myelitis, but bulbar signs characteristically appear as the disease progresses.Cerebral cortical involvement is unusual, but seizures and aphasia have been reported. Theoptic nerves are commonly involved, but symptoms are indiscriminable from those ofuveitis, which is usually present in patients with neurologic features. CNS vasculitis is rare,but stroke caused by large artery involvement has been reported. Pseudotumor cerebri isrelatively common and almost always caused by venous sinus thrombosis. Cerebral venousthrombosis may affect up to 10% of all patients with Behcet's disease and one third of thosewith neurologic involvement. CNS involvement generally manifests several years after theonset of systemic Behcet's disease, but occasionally it may be an initial feature and evenprecede other disease manifestations. As a rule, flares of neurologic disease parallel flaresof systemic disease.

Neuro-Behçet's syndrome can be classified as an acute type and as a chronic progressivetype (70). It should be pointed out that the two types of neuro-Behçet's syndrome arecurrently considered to represent different stages rather than independent clinical entities.Acute neuro-Behçet's syndrome is characterized by acute meningoencephalitis with a focal

midbrain pyramidal tract lesions, the lesions are anteriorly located in the cerebralpeduncles, bilateral, asymmetrical, extending up and down within the brain stem as alongitudinal linear lesion, and presenting high-intensity areas in the MRI T2-weightedimages or the fluid attenuated inversion recovery (FLAIR) images (70). Acute neuro-Behçet's syndrome responds to steroid therapy, and is usually self-limiting.

By contrast, the chronic progressive type of neuro-Behçet's syndrome is characterized byintractable, slowly progressive dementia, ataxia and dysarthria, with persistent elevation ofcerebrospinal fluid IL-6 activity (> 20 pg/ml) (70). Most patients with the chronicprogressive type of neuro-Behçet's syndrome were HLA-B51-positive, and they had historyof attacks of acute type neuro-Behçet's syndrome prior to the development of progressiveneurological symptoms (70).

The neurological involvement in Behçet's disease is either caused by primary neuralparenchymal lesions (neuro-Behçet's syndrome, or brain stem meningoencephalitis) or issecondary to major vascular involvement. The latter type is rarely complicated with theparenchymal lesions and should be called vascular-Behçet's disease. This vasculo-Behçet'sdisease type generally has a better prognosis compared with the parenchymal type. (70)Both vascular and parenchymal types can coexist.

The typical intra-axial primary parenchymal neuro-Behçet type

o It is primary parenchymal neural disease, a focal brain stemmeningoencephalitis affecting the midbrain primarily with selectiveinvolvement of the corticospinal tract bilaterally. The most common clinicalfindings are pyramidal signs. Sensory symptoms or signs are much lessfrequent in neuro-Behcet disease. (73,74) The corticospinal tract lesionsextend cephalocaudally in a linear fashion from the mesencephalon down tothe pons and less frequently to the medulla and up to the posterior limb ofthe internal capsule. The cephalocaudal extension of the midbraincorticospinal tract lesions could be either due to wallerian degeneration orextension of vasogenic edema along the myelinated fibers of the corticospinaltract. (70,73,74)

o The corticospinal tract pathology is manifested by MR imaging as bilateraland asymmetrical longitudinal linear lesions extending from the posteriorlimb of the internal capsule down to the midbrain, pons and less frequentlythe medulla. The midbrain is more severely affected. The corticospinal tractlinear lesions are hyperintense on the MRI T2 images and hypointense on theMRI T1 images and show contrast enhancement in the acute stage. Contrastenhancement is due to break down of the blood brain barrier and this is infavour of the corticospinal tract MRI signal changes being due to vasogenicedema. (70,73,74)

The atypical intra-axial primary parenchymal neuro-Behçet type

The extra-axial vascular-Behçet's type

o Involvement of veins and arteries in Behçet's disease is usually calledvasculo-Behçet's disease. Venous thrombosis appeared to be the majorvascular involvement in 7–33% of patients with Behçet's disease, andrepresents 85–93% of vascular-Behçet's disease (70). The brain parenchymalinvolvement seen in the primary neuro-Behçet type is rarely seen in thevascular type of Behçet disease. Parenchymal involvement in the vasculartype of Behçet disease is more commonly secondary to venous sinusthrombosis. Deep vein thrombosis or cerebral sinus thrombosis aresignificantly associated with the male gender and a positive pathergy test(70). Venous thrombosis is a reflection of thrombophilia in vascular Behçet'sdisease. (70,73,74). To the best of the author's information, cerebralsinovenous thrombosis in the vascular-Behçet type is indistinguishable fromsinovenous thrombosis due to any other cause and is only distinct from theview point that it is commonly associated clinically with oro-genitalulcerations. Probably vascular-Behçet syndrome must be put in thedifferential diagnosis of cases presented with cerebral sinovenous thrombosisof undetermined aetiology.

o The clinical picture of vascular Behçet is different from that of primaryneuro-Behçet. The clinical picture of neuro-Behçet is dominated by a mainlymotor clinical picture with bilateral pyramidal tract signs, pseudo-bulbarpalsy, subcortical dementia, etc. and sensory symptoms are uncommon, whilethe clinical picture of vascular Behçet is that of acute and chronic cerebralsinovenous thrombosis and its parenchymal complications (headache,seizures, focal sensory and motor deficits, bilateral papilledema,pseudotumor cerebri).

o A number of studies have explored the pathogenesis of thrombophilia inBehçet's disease. Neither deficiency in protein C, in protein S, in factor VLeiden and in antithrombin III nor resistance to activated protein C andanticardiolipin antibody levels seemed to be correlated with vascularthrombosis in Behçet's disease (75,76). There were increased thrombingeneration, fibrinolysis, and thrombomodulin in Behçet's disease, but theseabnormalities were not related to thrombosis (76). These results therefore

o Parenchymal Behçet disease is seen as a space-occupying lesion ormasquerading as a unilateral brain tumor (Fig 10). Differential diagnosesinclude lymphoma, other types of malignant tumors, and abscess. Theseatypical manifestations of neuro-Behcet disease may make diagnosis moredifficult. In particular, diagnosis is difficult in cases in which the neurologicmanifestation does not occur simultaneously with a flare-up of Behçetdisease. Steroid administration may be a diagnostic and therapeutic option inuncertain clinical situations

suggest that thrombophilia in Behçet's disease might be related more toinflammation than to clotting disorder.

The extra-axial-meningitic type

o Aseptic meningitis is one of the uncommon manifestations of Behçet disease,with a frequency ranging from 0.05% from 8%. Meningeal thickening withenhancement associated with dural sinus thrombosis could also be present.See figure 6A

Table 1. Lesion characteristics in the primary parenchymal neuro-Behçet type The lesion in the primary parenchymal neuro-Behçet type is a focal brain stem

meningoencephalitis affecting the midbrain primarily with selective involvement ofthe corticospinal tract bilaterally.

The most common clinical findings are pyramidal signs. Sensory symptoms or signsare much less frequent in neuro-Behcet disease.

The corticospinal tract lesions extend cephalocaudally in a linear fashion from themesencephalon down to the pons and less frequently to the medulla and up to theposterior limb of the internal capsule. The cephalocaudal extension of the midbraincorticospinal tract lesions could be either due to wallerian degeneration or extensionof vasogenic edema along the myelinated fibers of the corticospinal tract.

The corticospinal tract pathology is manifested by MR imaging as bilateral andasymmetrical longitudinal linear lesions extending from the posterior limb of theinternal capsule down to the midbrain, pons and less frequently the medulla. Themidbrain is more severely affected. The corticospinal tract linear lesions arehyperintense on the MRI T2 images and hypointense on the MRI T1 images andshow contrast enhancement in the acute stage. Contrast enhancement is due tobreak down of the blood brain barrier and this is in favour of the corticospinal tractMRI signal changes being due vasogenic edema. (70,73,74)

The corticospinal tract linear lesions are sometimes surrounded by a hypointenseedema area with positive mild mass effect.

o Arterial involvement, although rare, does occur in Behçet's disease. Thearterial manifestations in Behçet's disease resemble those of Takayasu'sarteritis, including arterial occlusion and aneurysm formation.Histopathological studies revealed that the number of vasa vasorum withinfiltration of neutrophils and lymphocytes was significantly increased invascular-Behçet's disease compared with in Takayasu's arteritis and otherinflammatory aneurysms (70). It was therefore suggested that arterialinvolvement in vascular-Behçet's (vasculo-Behçet) disease might be causedby a neutrophilic vasculitis targeting the vasa vasorum, leading todegeneration of the arterial wall. (70,73,74)

Table 2. The differences between the primary parenchymal neuro-Behçet type and thevascular-Behçet's type

Parameter The primary parenchymal neuro-Behçettype

Vascular-Behçet's type

Clinical picture

The clinical picture of neuro-Behçet isdominated by a mainly motor clinicalpicture with bilateral pyramidal tractsigns, pseudo-bulbar palsy, subcorticaldementia etc. Sensory symptoms areuncommon

The clinical picture of vascular Behçet isthat of acute and chronic cerebralsinovenous thrombosis and its parenchymalcomplications (headache, seizures, focalsensory and motor deficits, bilateralpapilledema, pseudotumor cerebri, etc.).

Incidence More common (70-93%) Less common (7-33%)

Pathology &pathogenesis

It is primary parenchymal neuraldisease, a focal brain stemmeningoencephalitis affecting themidbrain primarily with upward anddownward extension (along thepyramidal tract fibers to the posteriorlimb of the internal capsule, the basispontis and the medulla) and withselective involvement of thecorticospinal tract bilaterally.

Venous thrombosis is a reflection ofthrombophilia in Behçet's disease.Thrombophilia in Behçet's disease might berelated more to inflammation than toclotting disorder.

Radiological findings

The corticospinal tract pathology ismanifested by MR imaging as bilateraland asymmetrical longitudinal linearlesions extending from the posteriorlimb of the internal capsule down to themidbrain, pons and less frequently themedulla. The midbrain is more severelyaffected. The corticospinal tract linearlesions are hyperintense on the MRI T2images and hypointense on the MRI T1images and show contrast enhancementin the acute stage. Contrastenhancement is due to break down ofthe blood brain barrier and this is infavour of the corticospinal tract MRIsignal changes being due vasogenicedema. (70,73,74)

The MRI picture is that of sinovenousthrombosis and its parenchymalcomplications (70)

PrognosisBad, higher incidence of beingtransformed into the progressive typewith subcortical dementia, etc.

Better

Management Steroid responsive Anticoagulants, steroid may play a role

Figure 1. A case with Neuro-Behcet showing anteriorly located midbrain hyperintenselesions in the presumed anatomical position of the cortico-spinal tract.

Currently, the most widely used diagnostic criteria of Behcet's disease is the InternationalStudy Group's classification, which requires recurrent oral ulcerations plus two of thefollowing in order to establish a definite diagnosis: recurrent genital ulcerations, skin oreye lesions, or a positive pathergy test (13). The epidemiology of disease shows geographicvariation, encountered more commonly along the Silk Road, which extends from theMediterranean region to Japan (15). This is coupled with a similar variation in HLA B51(human leukocyte antigen), which has been reported to be strongly associated with thedisease in the high prevalence areas (16–19). Despite broadened clinical understanding ofthis disease, the etiologic factors remain obscured and speculative: viral agents,immunologic factors, genetic causes, bacterial factors, and fibrinolytic defects have all beenimplicated (3, 20–25). Vessel wall and perivascular mononuclear cell infiltration, which isconsistent with vasculitis involving both arterial and venous systems, has been shown inhistopathologic studies (20, 21). It has been postulated that genetic susceptibility togetherwith a possible trigger by an extrinsic factor, such as an infectious agent, is responsible forthe observed vasculitis (24, 26).

Table 3. The International Study Group criteria for the diagnosis of Behcet disease

At least 3 episodes of oral ulceration must occur in a 12-month period. They must be observed by a physician orthe patient and may be herpetiform or aphthous in nature.

At least 2 of the following must occur:o Recurrent, painful genital ulcers that heal with scarring.o Ophthalmic lesions, including anterior or posterior uveitis, hypopyon, or retinal vasculitis.o Skin lesions, including erythema nodosum, pseudofolliculitis, or papulopustular lesions (may also

include atypical acne).o Pathergy: defined as a sterile erythematous papule larger than 2 mm in size appearing 48 hours after

skin pricks with a sharp, sterile needle (a dull needle may be used as a control).

Neurologic involvement in Behcet's disease, was first reported in 1941 by Knapp (27), andthe term neuro-Behçet syndrome was introduced by Cavara and D'Ermo in 1954 (28). Thereported rate of development of neurologic involvement among Behcet's disease patients

ranges from 4% to 49% (9, 29). This rate was found to be 6.7% in a large nonselectiveseries of patients (30).

Figure 2. A case with Neuro-Behcet showinganteriorly located midbrain hyperintense lesions inthe presumed anatomical position of the cortico-spinal tract.

Neuro-Behçet syndrome may present as an acute focal or multifocal CNS dysfunction, andthe clinical picture of neuro-Behçet syndrome may resemble multiple sclerosis (MS) (7, 31–35). It has been observed that a substantial number of patients with neuro-Behçetsyndrome will have a relapsing-remitting course while others may develop a secondary-progressive course; some neuro-Behçet syndrome patients have an insidious onset, withprimary-progressive CNS dysfunction, and others may display symptoms attributable tointracranial hypertension associated with dural venous sinus thrombosis (12, 36, 37).Although non-neurologic involvement generally precedes neurologic findings, the non-neurologic involvement may go unrecognized in some cases or it may appear late in thepatient's course, thus posing diagnostic difficulties (38–40). Peripheral nerve involvement,although reported in neuro-Behçet syndrome, is relatively uncommon (41).

The most common imaging lesion seen in the acute or subacute stage of neuro-Behçetsyndrome is an asymmetric mesodiencephalic junction lesions (7–9, 33). These lesionsextend along long fiber tracts and spare the red nucleus, suggesting that this downwardextension is due to edema. The reversibility of the extension, leaving small residual lesionsat the center, as observed on follow-up MR studies, further supports their edematous

nature. This feature was also noted in earlier publications (9, 11, 42). Accordingly,pontobulbar involvement is an extension of lesions located at other sites, particularly themesodiencephalic junction. The distribution and intensity of changes of the residual lesionsclosely corresponded to pathologic descriptions of secondary demyelination (20, 21, 43, 44).In the chronic cases, Changes may extend to the cervical cord, along the corticospinal tract,and this might be explained by wallerian degeneration. This was noted in some pathologicstudies as well (20, 43, 44).

Figure 3. A case with Neuro-Behcet showing anteriorly located midbrain hyperintenselesions in the presumed anatomical position of the cortico-spinal tract.

The following clinico-radiological signs must be emphasized and highlighted in neuro-Behçet syndrome:

1. In general the observed pathology in these cases represents demyelination andedema along the cortico-spinal tract fibers (in fact the pyramidal tract is actuallyanatomically mapped by the MRI signal changes of vasogenic edema and contrastenhancement) and is found to be located mainly in the midbrain/thalamus (whichprobably constitutes the primary site of involvement) with upward extension to theposterior limb of the internal capsule and downward extension to the basis pontis.The upward and downward extension of the primary midbrain/thalamic lesionsmight be explained by wallerian degeneration or vasogenic edema (whichcharacteristically spreads along the myelinated fibers of long tracts) and this wasnoted in some pathologic studies as well (20, 43, 44)

2. The selective involvement of the corticospinal tract would explain the clinicalpicture of these patients which is dominated by pyramidal tract involvement andpseudo-bulbar palsy with absence of sensory changes. In fact the clinical picture andthe MRI findings in neuro-Behçet syndrome closely resemble those of motor neurondisease with pseudo-bulbar palsy (they both shared common topographicdistribution and spatial extension of the corticospinal tract lesions), however thecorticospinal tract lesion in motor neuron disease does not show contrast

enhancement. (70). The corticospinal tract linear lesion appeared larger in size inacute neuro-Behçet syndrome compared with that of motor neuron disease probablydue to the contribution of edema in neuro-Behçet syndrome. The corticospinal tractlesion is reversible in the acute neuro-Behçet syndrome, however it is irreversible inmotor neuron disease. In general the lesion in acute neuro-Behçet syndrome has anacute onset and a regressive course, while that of motor neuron disease has achronic progressive course. The MRI signal changes along the course of thecorticospinal tract are mainly due to reversible vasogenic edema in acute neuro-Behçet syndrome, while the MRI signal changes along the course of thecorticospinal tract in motor neuron disease are mainly due to walleriandegeneration. See table 4

3. Neuro-Behcet cases share common clinical (purely motor clinical presentation) andcommon MRI findings (selective pyramidal tract involvement). However sinusthrombosis (vascular Behcet) is much less common and is rarely associated withneuro-Behcet. Which simply means that the parenchymal lesion demonstrated inneuro-Behçet syndrome is a primary neuronal lesion and not secondary to sinusthrombosis (Behcet's disease is a relapsing and remitting, but often progressive,focal meningoencephalitis that most often affects the brain stem). Sinus thrombosisis probably a product of the primary pathology. In general the midbrain lesionscharacteristic of the primary neural type of Behçet disease can associated withcerebral sinus thrombosis and both the primary parenchymal neural type and thevascular type of Behçet disease can coexist in a single patient, but this uncommon.Vascular Behçet is rarely associated with neuro-Behçet. See fig. 5,6,7,8,9 Thepredominant histopathological features in the inflamed tissues in Behcet's diseaseare infiltration of lymphocytes and monocytes, and sometimes polymorph nuclearleukocytes, through small veins without microscopic changes in the vessel walls.Thrombophilia or thrombophlebitis involving small and large veins is also common,whereas arteritis is rare. In these regards, Behçet's disease is unique compared withother vasculitides.

4. The existence of meningeal enhancement in Neuro-Behcet is simply a reflection of ameningitic process that is occasionally present in Behcet disease. The meninges aretypically thickened and adherent to the brain surface in neuro-Behçet syndrome,and acutely there may be considerable meningeal inflammation; hence the commonreference to neuro-Behcet's disease as a meningoencephalitis. (70).

Table 4. Differences between motor neuron disease and acute neuro-Behçet syndrome, withregard to the corticospinal tract affection

The corticospinal tract lesion in neuro-Behçetsyndrome

The corticospinal tract lesion in motorneuron disease

The corticospinal tract linear lesion appearedlarger in size probably due to the contribution ofedema

Smaller in size

Reversible IrreversibleShow contrast enhancement Does not show contrast enhancementHas an acute onset and a regressive course Has a chronic progressive courseMRI signal changes are mainly due to reversiblevasogenic edema

MRI signal changes are mainly due toWallerian degeneration

Figure 4. A case with vascular Behcet showing multi-sinus thrombosis

Sometimes an asymmetric subcortical and deep periventricular white matter involvement(involving mainly the posterior limb of the internal capsule) without cortical involvement isobserved in neuro-Behcet. In the majority of reported cases with hemispheric involvement,the lesions were located subcortically, particularly within temporal and occipital regions(7–11, 34, 39, 45, 46). In the acute stage the periventricular white matter changes are due toedema, while in the chronic stage these white matter changes are due to walleriandegeneration, gliosis, and demyelination (4, 20, 21, 43, 44, 47, 48).

Vasculitis is regarded as the key feature in neuro-Behçet syndrome (3, 26), as biopsyspecimens from mucous and cutaneous lesions show those changes (54, 55). Arterial andvenous large vessel involvement, such as narrowing, occlusion, and aneurysmal formation,has been reported in up to 27% to 35% of cases, with 12% arterial and 88% venous (52).An even greater proportion of patients with neuro-Behçet syndrome may have small vesselvasculitis, and recently this has been validated as the pathologic basis of various histologicchanges observed in different organ systems (26).

Lesions of arterial origin may be observed in some patients, in whom these lesions, forexample, may lie within the pons without crossing the midline, consistent with involvementof the penetrating arteries. Although such lesions, resulting from small or medium-sizedintracranial arteries, have been reported either microscopically or radiologically in neuro-Behçet syndrome, they are not as common as the arterial lesions observed with theinvolvement of other systems (20, 21, 40, 43, 47, 48, 50–52). There are also a fewpublications concerning the involvement of large intracranial arteries (40, 51–53).Hemorrhagic lesions seen in some patients most likely resulted from "diapedesis of redcells around veins," as already reported, and are not of arterial origin (21).

Autopsy studies and biopsy specimens of the CNS lesions are consistent with vasculitis aswell, and they show a clear venous predominance (20, 21, 49). Radiologic studies supportthis finding that lesions seen in neuro-Behçet syndrome are not compatible with arterialterritories. Furthermore, significant perilesional edema with a tendency to disappear or toleave disproportionally small residua on follow-up studies has been reported. This featureis consistent with venous infarction, since not all signal intensity changes seen in venousocclusive disease necessarily represent infarction, but rather an accumulation of waterwithin interstitial spaces (56, 57). This information, together with our observations,supports the probable inflammatory-venous pathogenesis for the CNS lesions seen inBehcet's disease.

Table 5. Factors that support the probable inflammatory-venous pathogenesis for the CNSlesions seen in neuro-Behçet syndromeArterial lesions are unilateral and do not cross the middle line, while lesions observed inneuro-Behcet syndrome are frequently bilateral with frequent midline crossing.Autopsy studies and biopsy specimens of the CNS lesions are consistent with vasculitis witha clear venous predominance (20, 21, 49).Significant perilesional edema with a tendency to disappear or to leave disproportionallysmall residua on follow-up studies has been reported. This feature is consistent with venousinfarction, since not all signal intensity changes seen in venous occlusive disease necessarilyrepresent infarction, but rather an accumulation of water within interstitial spaces (56, 57).

If one considers the possible venous territories in which brain stem lesions have occurred inneuro-Behçet syndrome, it is clear that the affected venous structures are indeed smallintraaxial veins of the brain stem (58). That particular predilection of occurrence raises thequestion of why these veins are affected or why occlusion of them causes symptoms. Theliterature on autopsy studies states no apparent tendency toward these venous channels,and brain stem veins and cerebral hemispherical veins are equally affected, although thereis a clear-cut predominance of lesions in the brain stem. The question can also be addressedaccording to regional hemodynamic properties. It is well known that cerebralhemispherical structures are drained by superficial and deep venous systems, both ofwhich anastomose via medullary veins. They interconnect superficial pial veins to theinternal cerebral vein and the basal vein of Rosenthal, the former being more commonthan the latter (59), whereas in the brain stem, intraparenchymal radial and longitudinalanastomotic channels are nearly absent (58). In the spinal cord, intraaxial anastomoses are

claimed to be prominent at the thoracic level (60). The particular arrangement of veins inthe cerebral hemisphere permits them to flow in both directions via medullary veins, asseen with certain disorders, such as deep arteriovenous malformations, Sturge-Weberdisease, and the developmental venous anomalies (60), possibly explaining the smalldiameter and unimportance of parenchymal lesions when such a vein is thrombosed. At themesencephalic, diencephalic, and pontine levels, thrombosis of small veins might beaccompanied by a very large, sometimes hemorrhagic lesion, since there is nearly nocollateral venous pathway. The same anatomic arrangement might also explain thevulnerability of the cervical spinal cord (7, 44). It appears, therefore, that the variability ofvenous anatomic arrangements at different levels of the CNS might explain the predilectionof lesions for different regions.

Vasculitis, like inflammation in other tissues, is caused by many different agents andpathogenic mechanisms; however, these different causes produce only a limited number ofhistologic expressions of injury. The major type of injury to nervous tissue in vasculitis isischemia. Therefore, the same clinical manifestations can result from etiologically andpathogenetically different vasculitic diseases. In vasculitic processes, location, extension,and distribution of vascular involvement might point to a specific diagnosis, such asTakayasu or temporal arteritis (26, 61–65). In neuro-Behçet syndrome, lesions thereforeappear secondary to the small vessel venous vasculitis, and the anatomy of those intraaxialvenous structures explains the dominant involvement of the upper brain stem anddiencephalic structures.

Pathologically proved small vessel arteritis, either alone or with venous inflammation, hasalso been reported in conjunction with neuro-Behçet syndrome, and it is probable thatsome of the cerebral hemisphere and midbrain lesions might result from small vesselarteritis (62, 63). In this case, there appeared to be at least one lesion that occurred within aprobable pontine arterial territory, and the hemispheric lesions seen in neuro-Behçetsyndrome were not significantly different from the CNS lesions of other vasculopathies ofaccepted arteritic origin.

It is possible to explain the selective involvement of the corticospinal fibers observed in thispatient. If the primary pathology in Behcet disease is inflammatory vascular process withsecondary demyelination, then the myelinated fibers in the long tracts will suffer more. Theposterior part of the brain stem is mainly reticular while the anterior part is compact andis occupied mainly by the pyramid in the cerebral peduncle, crus cerebral and basis pontis.It is quite illogical to see inflammatory demyelination in the reticular posterior parts of thebrain stem. The inflammatory demyelinating process will affect the anteriorly located longmyelinated fibers in the corticospinal tract.

Vasogenic edema is the most common type of edema associated with brain tumors, venouscongestion and other causes and results from local disruption of the blood brain barrier.This leads to extravasation of protein-rich filtrate of plasma into the interstitial space, withsubsequent accumulation of vascular fluid. This disruption results from loosening of thetight junctions between endothelial cells, and the neoformation of pinocytic vesicles. Oncethe barrier is breached, hydrostatic and osmotic forces work together to extravasate

intravascular fluid. Once extravasated, fluid is retained outside the vasculature, mostly inthe white matter of the brain, and within the bundles of myelinated axons of long tractsand commissural fibers. This is because axons run in parallel bundles of fibres with looseextracellular space (that offer low resistance and facilitates the extension of vasogenicedema along myelinated axons which are spreaded apart by the edema) as opposed to graymatter, which has high cell density and is enmeshed in an interwoven network ofconnecting fibres that offer high resistance to the formation and spread of edema. Bydefinition, this type of edema is confined to the extracellular space. (70) In neuro-Behcetcase reports of diffusion weighted imaging (DWI) of the T2 hyperintense lesions revealedelevated ADC values compared to normal subjects, indicating restricted diffusion and thepresence of vasogenic edema (71,72). Contrast enhancement of the corticospinal tract inthis case is due to break down of the blood brain barrier along the course of thecorticospinal tract and it is a good sign of vasogenic edema which is mainly due to breakdown of the blood brain barrier. (70)

Another explanation for the selective involvement of the corticospinal tract in neuro-Behcetis that the signal changes observed in the MRI study is due to vasogenic edema secondaryto venous congestion, vasogenic interstitial edema spreads in the white matter alongmyelinated fibers of long tracts and commissural fibers (This is because axons of longtracts run in parallel bundles of fibres with loose extracellular space that offer lowresistance to the formation and spread of edema as opposed to grey matter). The longtracts are anteriorly located within the brain stem in the crus cerebra, cerebral peduncle,and basis pontis. Subsequently brain stem interstitial or vasogenic edema is much morelikely to be concentrated anteriorly within the corticospinal tract as vasogenic edemaspreads the myelinated fibers apart and extends along them. In the presented case the MRIsignal changes were maximum in the upper midbrain and internal capsule, present to alesser extent in the pons and to a much less extent in the medulla. Anatomically thecorticospinal tract remains abundant, compact and in a single bundle as it transverses inthe posterior limb of the internal capsule down to the cerebral peduncle (crus cerebri) inthe midbrain. The corticospinal and corticobulbar fibers gradually decreases in number asthey descend down to the pons, and through the medulla to the spinal cord. Also startingfrom the level of pons and downward the corticospinal tract starts to fragment intoscattered, irregular and isolated bundles. The corticospinal fibers, being more abundantand more compact at the internal capsule and midbrain levels, compared withcorticospinal fibers at the level of pons and medulla, would explain why MRI signalchanges were maximum in the internal capsule and upper midbrain. However selectiveinvolvement of the corticospinal tract in Behcet disease still needs further explanation.

Concerning the differential diagnosis, hemispheric white matter lesions are not common inneuro-Behçet syndrome, and when they are present, they are more likely to be subcorticalthan periventricular. Furthermore, these are generally associated with brain stem–diencephalic lesions. That combination is unlikely in systemic lupus erythematosus (SLE)and non-Behçet vasculitides. CNS involvement due to SLE and other systemic vasculitistends to involve arterial territories, and as a result, cortical involvement is frequentlyobserved (34, 66, 67). We have not observed cortical involvement in neuro-Behçetsyndrome, despite pathologic studies in which such involvement has been reported (21).

These changes, however, are minor in neuro-Behçet syndrome, which may explain theradiologic-pathologic discrepancy. Periventricular and ovoid lesions suggestive of MS arenot expected to be seen in neuro-Behçet syndrome.

Figure 5. Precontrast MRI T1 images showingfocal signal hypointensity in the left basis pontis,left crus cerebri (cerebral peduncle) and theposterior limb of the internal capsule. The focalhypointense lesions has no or very mild masseffect and they are apparently continuoscephalocaudally. Contralaterally, the pontinebasis is showing ? a very small hypointense lesionin the right side. The lesions are located in thepresumed anatomical area of the corticospinal(pyramidal) tract.

Figure 6. Postcontrast MRI T1images showing enhancement of thehypointense lesions shown in figure 5(same patient). The lesion in the rightanterior pontine zone is more definitenow and is better delineated bycontrast enhancement. All enhancedareas are surrounded by ahypointense edema area with mildmass effect. Also notice contrastenhancement of the meningealcovering of the pons and midbrainwhich indicates the existence of ameningitic element.

Figure 7. Postcontrast coronal MRI T1 images showing that the pontine, midbrain andcapsular lesions described in figure 5,6 (same patient) are continuous cephalocaudally as alinear long lesion, the lesion is surrounded by a hypointense edema area and is located inthe presumed anatomical area of the corticospinal (pyramidal) tract. The corticospinaltract was actually mapped by contrast enhancement. The contralateral side is involved to alessor degree. Notice meningeal enhancement which reflects a meningitic element. Contrastenhancement of the corticospinal tract in this case is due to break down of the blood brainbarrier along the course of the corticospinal tract and it is a good sign of vasogenic edemawhich is mainly due to break down of the blood brain barrier (70). Notice middle linecrossing of the lesions suggesting its venous rather that arterial origin. Also notice the mildmass effect induced by the pyramidal tract lesion in the left side which could be due toedema.

Figure 8. Postcontrast sagittal MRI T1 images showing that the pontine, midbrain andcapsular lesions described in figure 5,6,7 (same patient) are continuous cephalocaudally asa linear long lesion in the anterior parts of the pons and midbrain, the lesion is located inthe presumed anatomical area of the corticospinal (pyramidal) tract and is seensurrounded by a hypointense edema area. The corticospinal tract was actually mapped bycontrast enhancement. Also notice meningeal enhancement. Thrombosis of the superficialand deep venous systems is also seen.

Figure 9. MRI T2 image showing the capsular lesion(in the posterior limb of the internal capsule), Thelesion is mainly hyperintense with some hypointensezones probably representing a hemorrhagicelement. (same patient as in figure 5,6,7,8)

Extensive confluent periventricular changes that are seen in MS and occasionally insarcoidosis are not observed in patients with neuro-Behçet syndrome. Posterior fossalesions, particularly those located around the fourth ventricle with or without theassociated supratentorial lesions seen in MS, are not similar to the neuro-Behçet syndromelesions described above. Brain stem lesions in MS are usually small, even in the acute stage,and prominent brain stem and/or cerebellar atrophy without cerebral volume loss, which isobserved in the chronic phase of neuro-Behçet syndrome, is unusual in MS (7, 34). Whenone considers cervical involvement, this rarely extends more than a few vertebral segmentsin MS (68), unlike the more extensive lesions we observed in neuro-Behçet syndrome.Leptomeningeal contrast enhancement is a typical finding of sarcoidosis (69). We did notencounter this finding in patients with neuro-Behçet syndrome. Devlin et al (38) reportedabnormal leptomeningeal enhancement in two of their patients with neuro-Behçetsyndrome. Abnormal meningeal enhancement secondary to dural venous occlusion or tolumber puncture should be excluded before attributing it to the disease itself (70).

Table 6. Differences between neuro-Behçet syndrome. and other similar diseases

Pathology Comment

CNS lupus versusneuro-Behcet

CNS involvement due to SLE and other systemic vasculitis tends toinvolve arterial territories, and as a result, cortical involvement isfrequently observed (34, 66, 67).

MS versus neuro-Behcet

Periventricular and ovoid lesions suggestive of MS are notexpected to be seen in neuro-Behçet syndrome.Extensive confluent periventricular changes that are seen in MSand occasionally in sarcoidosis are not observed in neuro-Behçetsyndrome.Posterior fossa lesions, particularly those located around thefourth ventricle with or without the associated supratentoriallesions seen in MS, are not similar to the neuro-Behçet syndromelesions.When one considers cervical involvement, this rarely extends morethan a few vertebral segments in MS (68), unlike the moreextensive lesions observed in neuro-Behçet syndrome.Brain stem lesions in MS are usually small, even in the acute stage,and prominent brain stem and/or cerebellar atrophy withoutcerebral volume loss, which is observed in the chronic phase ofneuro-Behçet syndrome, is unusual in MS (7, 34)Abnormal meningeal enhancement is unusual in MS and reportedin neuro-Behçet syndrome. (38)

Inflammatory demyelinating diseases, such as MS, and inflammatory vascular disorders(vasculitides), such as neuro-Behçet syndrome and SLE, can affect the CNS primarily orsecondarily, and onset tends to occur in young adulthood. Although the clinicalpresentation of these diseases may be similar, the radiologic findings of neuro-Behçet

syndrome are quite distinct, which may help differentiate it from other disorders, even inthe absence of overt systemic involvement.

The diagnosis of Behcet's disease is clinical. Patients with Behcet's disease and venousthrombosis are often heterozygotes or homozygotes for the factor V Leiden allele. The CSFin patients with neurologic involvement is typically characterized by a pleocytosis (usuallyless than 100/mm3) that is equally likely to be neutrophil or lymphocyte predominant. CSFprotein is only slightly elevated. There have been reports of intrathecal synthesis ofoligoclonal IgA and IgM. An immunofixation electrophoretic pattern of oligoclonal bandshas been reported in 16% of patients. Magnetic resonance imaging in patients with CNSdisease typically reveals multiple 3-10 mm in diameter sharply marginated, irregular, andoften confluent lesions in the spinal cord, brain stem, thalamus, basal ganglia, and deepcerebral white matter. The lesions may be quite extensive. In some cases, they may bedifficult to distinguish from those of multiple sclerosis, but Dawson's fingers are not seen.(70)

High-dose corticosteroids (prednisone 60 mg/day) are effective in suppressing skin,mucosal, and arthritic manifestations of Behcet's disease. Pulse corticosteroids(methylprednisolone I gm/day for 3 days) are often employed effectively for acute flares ofneurologic disease, but the effect of corticosteroid treatment on chronic or recurrentneurologic disease is less satisfactory. Corticosteroids are clearly ineffective in halting theprogression of uveitis and chlorambucil; 0.1-0.2 mg/kk/day has been used withconsiderable success in treating this disabling manifestation. (70) O'Duffy, (3) also inducedremission in eight of nine patients with meningoencephalitis using chlorambucil.Azathioprine (Immuran), cyclosporine A, and colchicine have been shown in prospective,randomized studies to be highly effective in halting or preventing the ocular manifestationsof Behcet's disease; however, cyclosporine A is relatively contraindicated in the presence ofneurologic disease. Acute neurologic symptoms are remarkably reversible and justifyaggressive treatment during flares. Patients with cerebral venous thrombosis respond wellto chronic anticoagulation without significant risk of intracranial hemorrhage. (70)

Thalidomide (Thalomid) is highly effective in suppressing oral and genital manifestationsof Behcet's disease; however, between 6% and 50% of patients develop an axonalsensorimotor polyneuropathy that may be dose related. (70)

Figure 10. Atypical neuro-Behcet lesion in a 30-year-old woman. (a) T1-weighted MRimage (500/10) shows a large area of low signal intensity (arrow) in the left parietotemporallobe. (b) Gadolinium-enhanced T1-weighted MR image (500/10) shows strong enhancementof the masslike lesion, mimicking an abscess. (c) Follow-up MR image obtained aftersteroid treatment shows a marked decrease in the extent of the lesion (arrow).

SUMMARY

The parenchymal distribution of lesions in neuro-Behçet syndrome seems to support thehypothesis of small vessel vasculitis, mainly venular involvement. The known anatomicarrangement of CNS intraaxial veins explains the predominant involvement of the brainstem structures observed in these patients. This pattern of lesion distribution might help todifferentiate neuro-Behçet syndrome from other vasculitides as well as from theinflammatory-demyelinating diseases of the CNS, such as MS. Our experience with neuro-Behçet syndrome has caused us to consider neuro-Behçet syndrome in the differentialdiagnosis of patients who have brain stem and/or diencephalic lesions that extend along thelong tracts and have a tendency to resolve on subsequent imaging studies, whether or notthey are associated with periventricular and subcortical lesions. CNS involvementgenerally manifests several years after the onset of systemic Behcet's disease, butoccasionally it may be an initial feature and even precede other disease manifestations.According to the diagnostic criteria of Behcet's disease of the International Study Group'sclassification (13), it is very difficult to diagnose Behçet disease without oro-genitalulcerations. However and in the author experience, primary parenchymal neuro-Behçet

disease with selective involvement of the corticospinal tract (and with a purely motorclinical presentation) taken together with the characteristic MR imaging findings ofselective pyramidal tract involvement are highly suggestive of Behçet disease even if CNSinvolvement precedes other disease manifestations.

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