神经型布氏杆菌病

NeurobrucellosisOsman Kizilkilic,MD a,*,Cem Calli,MD bBrucellosis is a multisystem infection that can involve any organ system and may present with a broad spectrum of clinical presentations.Nervous system involvement of brucellosis is known as neurobrucellosis (NB).The nervous system may be one of several systems involved in chronic diffuse brucellosis 1or,rarely,neurologic findings may be the only signs of brucellosis.1–4NB has neither a typical clinical picture nor specific CSF findings.In endemic areas,NB must be considered in the differential diagnosis of patients presented with neurologic symptoms and concomitant fever.PHYSIOPATHOLOGY OF NEUROBRUCELLOSIS The exact mechanism by which the organism rea-ches nervous system is uncertain but,after gaining entry into the body,it invades the reticuloendo-thelial system from where it reaches the blood stream,causing bacteremia,and later reaches the meninges.When host immunity declines,the or-ganism proliferates and invades other nervous system structures.5,6The occurrence of NB during the acute phase of illness may be due to direct deleterious effects oforganisms invading nervous tissues,to the releaseof circulating endotoxins,or to the immunologic and inflammatory reactions of the host to the presence of these organisms within the nervous system or within other tissues of the body.1Brucella bacteria may affect the nervous system directly or indirectly as a result of cytokine or endotoxin on the neural tissue.Cytotoxic lympho-cytes and microglia activation play an immunopatho-logic role in this disease.A depressed immune status is believed to be a risk factor for developing NB.1Nervous system involvement in brucellosis might be due to the persisting intracellular micro-organisms or,perhaps,the infection triggers an immune mechanism leading to neuropathology.7,8In an experimental animal model,the ganglioside-like molecules expressed on the surface of Brucella melitensis were found to induce anti-ganglioside membrane 1(GM1)ganglioside antibodies,result-ing in flaccid limb weakness and ataxia-like symptoms.7,9Involvement of the CNS in brucellosis has been reported with the incidence varying between 0.5%and 25%in different series.10–16Neurologiccomplications of Brucella are rarely seen in chil-dren 17–22;the rate of neurologic complications is0.8%of children affected with systemic brucel-losis.22NB is categorized according to the clinical manifestation,which is CNS or peripheral nervous system involvement,or a combination.23Some immunologic mechanisms operate to produce the demyelinating lesions in the cerebral and spinal cord white matter.13,20,24Although the NB is not very common,it has marked clinical importance for its severity and morbidity.CLINICAL PRESENTATION OFNEUROBRUCELLOSISClinical presentations of NB vary widely because Brucella exhibits a great affinity for the meninges.Brucella enters the CNS during the first stage of the disease by hematogenous spread;then,latent or clinical meningitis occur,from which microor-ganisms may eventually invade the neighboring nervous structures.17The early manifestations appear during the course of the septicemia or a Department of Radiology,Cerrahpasa Medical Faculty,University of Istanbul,34300Kocamustafapasa,Istanbulb Department of Radiology,Medical Faculty,Ege University,35100Bornova,Izmir,Turkey*Corresponding author.E-mail address:ebos90@KEYWORDSNeurobrucellosis Brucellosis NeuropathologyNeuroimag Clin N Am 21(2011)927–937doi:10.1016/j.nic.2011.07.0081052-5149/11/$–see front matter Ó2011Elsevier Inc.All rights reserved.ne u r o i m a g i n g .t h e c l i n i c s .c o mshortly after its termination,whereas the late ones, which are more frequent,may last months or years after having occurred in the septicemic period, which many times are subclinical.17NB can present at any stage of systemic brucel-losis and several clinical forms,such as meningi-tis,meningoencephalitis,brain abscess,epidural abscess,myelitis,radiculoneuritis,cranial nerve involvement,or demyelinating or vascular disease, may be seen.10,13,15,25The clinical manifestation in this group included fever,headache,sweating, weight loss,and neurologic manifestations,such as papilledema,seizures,confusion,polyradicul-opathy,and lymphocytic meningitis.7,26Headache and psychiatric symptoms may develop owing to the toxic effect of NB.20The most common clinical form is meningitis or meningoencephalitis,occurring in50%of the cases(Figs.1and2).Development of basal menin-gitis may lead to lymphocytic pleocytosis,cranial nerve enhancement,and intracranial hypertension. It is characterized by CSF pleocytosis and high protein levels.1,12,27In cases with brucellosis,other possible causes of infection of inflammatory dis-ease such as tuberculosis,fungal infection,or sarcoidosis can be ruled out by the negative culture of CSF or granuloma,and the high index of suspi-cion of brucellosis with positive Brucella titers and marked improvement with adequate treatment. Various chronic manifestations are perhaps best divided into those presenting with peripheral neuropathy or radiculopathy and those presenting with more diffuse CNS involvement including myelitis with cranial nerve involvement and a syn-drome of parenchymatous dysfunction.1,2,15 Symptoms of peripheral neuropathy and radi-culopathy include back pain,areflexia,and para-paresis with involvement of the proximal nerve radicals.In patients with diffuse CNS involvement, myelitis is evidenced by back pain,spastic para-paresis,and demyelination and can also occur with cerebellar dysfunction.The syndrome of parenchymatous dysfunction can occur at any point in the CNS but it most commonly affects the cerebellum,spinal cord and cerebral white matter.Meningovascular complica-tions,in particular mycotic aneurysms,ischemic strokes,and subarachnoid hemorrhage are relatively common.1–3NB can present with other rare neuro-logic manifestations including isolated intracranial hypertension,Guillain-Barre syndrome,solitary ex-traaxial posterior fossa abscess,cerebral venous thrombosis,and subdural hemorrhage.1,28–31Both pseudotumor cerebri and papillitis(optic neuritis)have been implicated in the pathophysi-ology of papilledema.11,32,33Pseudotumor cerebri is characterized by increased CSF pressure,papilledema,but with generally preserved vision, and pupillary reflexes.Papillitis(optic neuritis) presents as pain on movement of the eyes,papil-ledema,rapidly occurring visual loss and relative afferent pupillary defect.32Spinal granuloma or abscess because of brucel-losis may cause an upper motor neuron-type lesion,whereas brucellar spinal root involvement may cause a lower motor neuron-type lesion.34 All these manifestations can lead to confusion and delay in diagnosis.It may also lead to difficulty in differentiating NB from other chronic infections, especially tuberculosis and syphilis.35 DIAGNOSIS OF NEUROBRUCELLOSISNB has neither a typical clinical picture nor specific CSF findings.36The diagnosis of NB is based on the existence of a neurologic picture not explained by any other neurologic disease,evidenced by systemic brucellar infection,and the presence of inflammatory alteration in CSF.37Examination of CSF typically reveals an elevated protein concentration,a depressed glucose con-centration,and a moderate leukocytosis composed mainly of lymphocytes.2,15,38The exception is the cerebellar syndrome,in which the protein concen-tration is elevated but there is no leukocytosis.1,39 Blood culture is not an ideal test for diagnosis of NB because of low yield and long time it req-uires.1,40As a result of low rate of Brucella isolation from CSF(<20%),the diagnosis of NB mainly depends on the detection of specific antibodies in CSF.1,15,41Although the positive culture is the gold standard for diagnosis,it has been thought to be suboptimal.37,42Neuroimaging and neurophysiologic evaluation combined with the microbiological diagnostic tools is useful for both diagnosis and detection of complications.Accurate diagnosis and proper management of central nervous system brucel-losis appears to be fundamental since it is a very subtle disease.7IMAGING OF NEUROBRUCELLOSISMagnetic resonance imaging(MRI)is the imaging modality with capability to show both parenchymal lesions,and cranial nerve involvement;contrast administration is mandatory for the evaluation of leptomeningeal involvement.Although the imaging methods are important for the diagnosis of neurobrucellosis,the test results must be in accordance with the patient’s clin-ical condition to have diagnostic value.A focal cortical cerebral lesion with nodular enhancement and surrounding edema,increase in perivascularKizilkilic&Calli 928Fig.1.MR images of a51-year-old female with NB(A)Axial T2weighted and T1weighted(B)images show supra-sellar cistern located extraaxial lesion,hypointense on both sequences.Contrast enhanced T1weighted image(C) shows slight leptomeningeal contrast enhancement consistent with inflammation.Axial T2weighted superior section image(D)shows diffuse increased white matter intensity,secondary to white matter involvement3 months post medication MR images obtained show:(E)Axial T2weighted image,contrast enhanced T1weighted image(F)show resolution of suprasellar cistern lesion and leptomeningeal contrast enhancement.929vascularization and generalized inflammation of the white matter can be seen on CT and MRI.17Imaging abnormalities in NB are variable and may mimic other infectious or inflammatory conditions.Imaging appearance reflects inflam-matory or demyelinating processes or vascular insult and does not always correlate with clinical situation.1,26According to the Al Sous and colleagues 26imaging findings of NB are divided into 4categories:normal,inflammation (recog-nized by granulomas,abnormal enhancement of the meninges,perivascular space,or lumbar nerve roots),white matter changes and vascular changes.INFLAMMATION AND IMAGING FEATURES Involvement of one or more cranial nerves is seen in more than 50%of the cases with NB,this is mostly a result of basal meningitis.In cases with Brucellosis the causes of cranial nerve involve-ment include extension of meningeal infection,possible vasculitic processes,pseudotumor cere-bri and side effect of tetracycline which is com-monly used for the treatment of Brucellosis (see Figs.1and 2;Fig.3).Cranial nerve paralyses are seen more frequently during the acute/subacute disease course associated with CNS involve-ment.2,20,22The vestibulocochlear nerve is the most common affected cranial nerve in NB.On the other hand isolated involvement of cranial nerve is a very rare.23,27,33,43Brucellar cranial nerve palsies usually resolve completely with the administration of antibiotics,whereas those withchronic CNS infections often have permanentneurologic deficits.7,8,20,44The abducens nerve has the longest intracranialcourse and is therefore susceptible to direct and indirect insults like microvascular infarction or direct compression.7,45Fig.2.MR images of 24-year-old female presented with headache andfever,CSF examination revealed neurobrucellosis.(A )Axial T2weighted,(B )FLAIR,and (C )T1weighted images,show leptomeningeal thickeningin the right half of prepontine cistern that shows leptomeningeal thick-ening and contrast enhancement in the same location on postcontrastT1weighted image (D ).Kizilkilic &Calli930The pathogenesis of optic neuritis and abdu-cens nerve palsy is speculative.Possible mecha-nisms include extension of meningeal infection secondary to an inflammation of the meninges in the subarachnoid cistern and microorganism reaching the neuroaxis via the bloodstream or lym-phatic system.It attacks the Schwann cells and leads to demyelination.Another theory is a vas-culitic process.The bacterial antigen,antibody,and complement complex are deposited in the vasa nervosum with vascular and perivascular infiltrates.23,46,47Although formation of the granulomas results from inflammation that is relevant to infection,it is a rare manifestation in NB.Brucella meningitis may behave as an exclusively neurologic disease mimicking vascular accidents that are frequently paroxysmal and recurrent.3Computed tomography and MR studies in uncomplicated meningitis are usually normal or some enhancement of the meninges is seen on post contrast images.In granulomatous menin-gitis,enhancement is typically seen in basal meninges,whereas bacterial meningitistypically Fig.3.MR images of a 18-year-old female presented with malasia,fever and headcahe.Physical examination re-vealed nuchal rigidity,microbiological examinations were consistent with NB and meningitis.(A )Axial T2weighted,(B )T1weighted images,show subdural collection on the left side and leptomeningeal thickening.Post contrast Axial (C )and Coronal (D )T1weighted image shows diffuse leptomeningeal thickening,contrast enhancement and subdural effusion (empyema).Neurobrucellosis931shows enhancement over the cerebral convexi-ties.In all types of meningitis contrast MR ismore sensitive than CT.Contrast enhanced FLAIR sequence may be even more sensitive in detecting enhancement.Extension of enhancing subarach-noid exudates deep into the sulci can be seen in severe cases.Imaging of the affected patients is not per-formed routinely other than to ensure the absence of hydrocephalus or abscess before a lumbar puncture is performed.Neuroimaging is indicated if the clinical diagnosis is unclear,if neurologic deterioration occurs secondary to increased intra-cranial pressure or if patients’recovery from the disease is slow.Cortical lesions with surrounding edema show a characteristic enhancement consisting of a cen-tral nodular intense enhancement and a faint peripheral enhancement (target sign)that might reflect diverse stages of brain inflammation,similar to those reported in chronic brain abscess,such as tuberculosis.17,47Early stage of the parenchymal infection is the cerebritis stage.In the cerebritis stage,an ill-defined subcortical hyperintense lesion can be seen in T2W images.During the late stage the central necrotic area is hyperintense on T2W images and show restricted diffusion on diffusion weighted imaging.The thick,somewhat irregularly marginated rim appears iso to mildly hyperintense on T1W images and enhances after administration of contrast media.Peripheral vasogenic edema is always present.Despite its rareness,brucellosis should be consid-ered in the differential diagnosis of focal brain lesionsor leptomeningeal enhancing lesions,especially in the patients with a history of contact with domestic animals,consumption of non-pasteurized lactic pro-ducts or previous brucellosis.17WHITE MATTER INVOLVEMENTThree patterns of white matter involvement that manifests as hyperintense lesions on T2weigh-ted images have been noted.The first pattern is a diffuse appearance affecting the arcuate fibers region,the second pattern is periventricular,and the third pattern is a focal demyelinating appearance.Brain MRI shows extensive bilateral high signal abnormalities in the periventricular white matter on T2-weighted and FLAIR images.MR angiog-raphy could be normal (see Fig.1;Fig.4).Imaging of multifocal white matter hyperintensities on T2W and FLAIR MR Images are nonspecific,and the differential diagnosis of these lesions is very broad.The nature and cause of white matter abnormali-ties are not known,but they may be due to an auto-immune reaction.The white matter involvement may mimic other inflammatory or infectious disease,such as multiple sclerosis,acute disseminated encephalomyelitis,or Lyme disease.11,26,36,48–51In contrast multiple sclerosis these white matter lesions do no tend to locate in the callosomarginal region and they do not enhance.MRI features consisting of high-intensity con-fluent areas in the white matter of the brain around the lateral ventricles are in favor of a demyelinating process.In the presence of any posterior fossa or brain stem lesion highly probable diagnosis will be multiple sclerosis.VASCULAR INVOLVEMENTBrucella infection by itself triggers the immune mechanism leading to a demyelinating state.As the disease gets more chronic,theimmune Fig.4.MR images of a 37-year-old female.(A )Coronal FLAIR,Axial T2(B )weighted images show millimetric hyperintense lesion in the periventricular white matter in both cerebral hemispheres.Axial post contrast T1weighted image (C )shows lack of enhancement of periventricular lesions.Kizilkilic &Calli932mechanism processes increase.20,24This disease does not show predilection of size or location of vascular structure.20The vascular insult is likely due to one of the following two mechanisms.In the first,an inflam-matory process of the small vessels or venous sys-tem causes lacunar infarcts,small hemorrhages,or venous thrombosis.2,26,52–55Brucella can cause vasculitis;it has no predilection of size or location of vascular structure.Arterial and/or venous struc-tures may be affected.56,57Vascular involvement may result in lacunar infarcts,small hemorrhages or venous thrombosis.10The second possible mechanism is hemorrhagic stroke caused by rupture of a mycotic aneurysm,a likely sequel of embolic stroke from brucellar endocarditis.2,26,58,59 The pathogenesis of TIA and ischemic stroke in brucellosis still remains uncertain.Transient cerebral ischemic attacks can be seen secondary to the vascular-perivascular inflammatory reaction or vascular rge vessel involvement is rare in NB.1,7,10Most likely,ischemic stroke in NB is a consequence of an accompanying vascu-litis.2,25Various degrees of vascular inflammation ranging from acute to chronic with the possibility of necrosis and aneurysmal formation have been described in NB.25,60It has been proposed that TIA in brucellosis may be related to infectious vasculitis,cerebral vasospasm or cardioembo-lism.11,60,61Vessel involvement in Brucella may also develop secondary to cardiac embolization leading to necrosis of the occluded vessel and formation of mycotic aneurysm that may rupture and lead to subarachnoid or cerebral hemorrhage.55 Carotid angiograms may disclose diffuse vas-cular spasm in the territory of the affected artery. Most of the patients with ischemic cerebral symp-toms in the literature have normal cerebral angio-grams.61Normal appearance of cerebral vessels in DSA is considered consistent with vasculitis of deep penetrating arteries.11Diffusion weighted imaging is useful in the setting of acute ischemia,as it will detect infarc-tions earlier than conventional MR sequences or FLAIR sequence.Frequently multiple lacunar type infarcts are seen in the distribution of perforating vessels in the brainstem,basal ganglia,and white matter as a result of involvement of basal cisterns and vessels contained therein.Myelitis is generally evidenced by back pain,ataxia, paresthesia,paraplegia and sphincter abnormalities.7 Since NB mimics peripheral and central nervous system pathologies,differential diagnosis is important in probable patients.MR examination shows thick-ening of the spinal roots and diffuse enhancement along the distal cord and caudaequina.Fig.5.MR images of21-year-male with NB and meningitis(A)Sagittal T2weighted image of cervical regionshows intradural-extramedullary hypointense nodular lesions(consistent with granuloma formation).Sagittal postcontrast T1weighted(B)cervical region image shows peripheral enhancement of the spinal cord,and lackof contrast enhancement of intradural-extramedullary lesions.(C)Sagittal and axial(D)postcontrast T1weightedlumbar images show contrast enhancement of the cauda equina and thickening of the filum terminale roots.Imaging following medical treatment show:(E)Sagittal T2weighted cervical MR image shows resolution of intradural-extramedullary lesions.Sagittal contrast enhanced T1weighted image(F)shows resolution of samelesions and lack of contrast enhancement of cervical spinal cord.Sagittal T1weighted postcontrast MR image(G)of lumbar region shows absence of contrast enhancement of the cauda equina.Neurobrucellosis933MR imaging of focal brain involvement by NB is scant,and no specific reports in pediatric patients has been made to date.MYELOPATY AND SPINAL DISEASE Myelopathy may result from different mecha-nisms.Acute transvers myelitis,spinal cord infarc-tion,adhesive arachnoiditis,compression from epidural abscess or from brucellar spondylitis may occur.Brucella spondylitis affects the lumbo-sacral and lower thoracic region most frequently,causing erosion and vertebral collapse leading tocord or cauda equina compression.35The major role of neuroimaging is to identifytreatable conditions that can mimic myelopathy.These include acute disk herniation,hematoma,epidural abscess,or compressive myelopathy.During the acute phase of the myelopathy,MR images are normal in half of the patientsand Fig.6.MR images of a patient presented with acute neurologic deficit and headache.(A )Axial T2weighted,(B )FLAIR images shows hyperintens lesion in the left half of pons.Diffusion weighted image (C )with b 51000sec/mm 2with corresponding ADC map (D )shows restricted diffusion of the same lesion consistent with acute ischemic lesion.Sagittal T1weighted postcontrast image (E )shows thrombosis of the right transvers sinus (filling defect-empty delta sign).MR angiography,MIP image (F )shows normal intracranial arteries.Imaging of the patient after success full medical treatment clinical recovery shows:(G )Axial T2weighted,(H )FLAIR and (I )T1weighted images show lesion on the left side of the pons with CSF-like signal intensity on all images,consistent with chronic lacune.MR venography MIP image (J )shows patency and recanalizationof the right transvers sinus.Kizilkilic &Calli934nonspecific in the other half.Focal cord expan-sion,poorly delineated increased signal in the spinal cord on T2W images may seen.Varying degree of contrast enhancement occurs in some of the cases(Fig.5).CEREBRAL VENOUS THROMBOSIS AND VENOUS INFARCTCerebral venous thrombosis may occur as a complication of certain infections during preg-nancy or postpartum,with contraceptives,in Beh-cet’s disease or systemic lupus erythematosus, and in several coagulopathies including protein C and S antithrombin III deficiency,and in antiphos-pholipid antibody syndrome.62In the acute phase(when the clot is dense), thrombus can be seen on CT as hyperdense in the sinus on non contrast CT.In the subacute phase of the thrombosis,contrast enhanced images show filling defect within the sinus.MR imaging is very helpful for the diagnosis and is the best method of noninvasive investigation. The acutely thrombosed sinus is isointense to the brain parenchyma on T1W images and hypoin-tense to brain on T2W images.This appearance cannot be distinguished from slow flow.When the thrombus is subacute and hyperintens on T1W images it is very easy to recognize(Fig.6). Advances in MR venography have greatly aided the diagnosis of venous sinus thrombosis by MR imaging.Two-dimensional time-of-flight MR ven-ography or phase contrast MR venography can be used to make the diagnosis.Since time-of-flight MR angiography is acquired using T1W images,both moving blood and subacute thrombus may be seen equivocal.CT venography is also a fast and reliable way of making the diagnosis.The MR differential diagnosis of dural sinus thro-mbosis is primarily imaging artifacts that can mimic intravascular clot.These include contrast enhanced scans with flow compensation meth-ods,unenhanced scans with inflow of fully un-saturated spins into the imaged slice(entry phenomena),incorrect pulse sequence selection or misplaced saturation bands,incorporation of hyperintense clot.On CT,venous infarcts are usually poorly de-limited,hypodense or mixed attenuation areas involving the subcortical white matter and causing a slight mass effect on ventricles.On MR,early venous infarcts may be identified by prolongation of T1and T2W images.Reduced diffusion is not an early sign of venous infarction;diffusion appears to be heterogenous with areas of in-creased,normal and decreased diffusion.Some of the venous infarct may be hemorrhagic or maycause hematoma.SUMMARYNB has neither a typical clinical picture nor specificCSF findings and its diagnosis is based on the existence of a neurologic picture not explainedby any other neurologic disease,evidenced by systemic brucellar infection,and the presence of inflammatory alteration in CSF,especially in patients living in endemic areas for the infection. Neuroimaging and neurophysiologic evaluation combined with the microbiological diagnostictools is useful for both diagnosis and detection of complications.Magnetic resonance imaging isthe imaging modality,which may show both parenchymal lesions,and cranial nerve involve-ment;contrast administration is mandatory forthe evaluation of leptomeningeal involvement. 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