Central Nervous System Tuberculosis Rakesh K. Gupta, MD*, Sunil Kumar, MD Approximately one-third of the world’s population is currently infected with tuberculous bacillus, of which approximately 5% to 10% become sick or infectious at some time during their life. People with human immunodeficiency virus (HIV) are more likely to develop tuberculosis (TB). The World Health Organization (WHO) estimates that there were 9.4 million new cases in 2009, including 1.1 million cases among people with HIV. 1 Approxi- mately 1.7 million people died of TB, including 380,000 people with HIV. 1 Most cases were in the south-east Asian, African, and western Pacific regions (35%, 30%, and 13%, respectively). In 2009, the estimated per capita TB incidence was stable or decreasing in all 6 WHO regions. However, the slow decline in incidence rates per capita is offset by population growth. Conse- quently, the number of new cases arising each year is still increasing globally in the WHO regions of Africa, the eastern Mediterranean, and south- east Asia. Neurotuberculosis constitutes 1% of all tuber- culosis and 10% to 15% of the extrapulmonary tuberculosis cases, most (>40%) of which are children. 2 Central nervous system (CNS) tuber- culosis also accounts for 1.5% to 3.2% of all tuberculosis-related deaths. 3 CNS tuberculosis remains common and, despite the availability of effective antituberculous therapy, continues to cause significant morbidity and mortality. TBM constitutes 70% to 80% of all patients with neuro- tuberculosis. 4 CNS tuberculosis is a prominent Key Points: CNS TUBERCULOSIS Central nervous system (CNS) tuberculosis is a major cause of sickness and death, especially in devel- oping countries, and is increasing in developed countries because of the emergence of acquired immunodeficiency syndrome (AIDS). Isolation of Mycobacterium tuberculosis for the definitive diagnosis is possible only in a few patients. Culture has a low yield and needs 6 to 8 weeks. In tuberculous meningitis (TBM), precontrast magnetization transfer (MT) T1 imaging shows abnormal meninges with low MT ratio and is characteristic of the disease. Tuberculomas have solid and/or liquid caseation on noncontrast MT T1 images, a bright rim around T2 hypointensity is a characteristic feature of tuberculoma; the T2 hypointense rim appears bright in tuberculous abscess. When liquefaction of the caseation occurs within tuberculoma as well as abscess, it shows restriction on diffusion-weighted (DW) imaging with low apparent diffusion coefficient (ADC). Advanced imaging methods such as perfusion imaging and diffusion tensor imaging (DTI) may be of value in objective assessment of therapy in tuberculoma. The authors have nothing to disclose. Department of Radiodiagnosis, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Rae Bareli Road, Lucknow 226014, Uttar Pradesh, India * Corresponding author. E-mail address: [email protected]KEYWORDS CNS tuberculosis Tuberculoma TB meningitis TB spondylitis Neuroimag Clin N Am 21 (2011) 795–814 doi:10.1016/j.nic.2011.07.004 1052-5149/11/$ – see front matter Ó 2011 Elsevier Inc. All rights reserved. neuroimaging.theclinics.com
Transcript
Central NervousSystem Tuberculosis
Rakesh K. Gupta, MD*, Sunil Kumar, MD
Key Points: CNS TUBERCULOSIS
� Central nervous system (CNS) tuberculosis is a major cause of sickness and death, especially in devel-oping countries, and is increasing in developed countries because of the emergence of acquiredimmunodeficiency syndrome (AIDS).
� Isolation ofMycobacterium tuberculosis for the definitive diagnosis is possible only in a few patients.Culture has a low yield and needs 6 to 8 weeks.
� In tuberculousmeningitis (TBM), precontrastmagnetization transfer (MT) T1 imaging shows abnormalmeninges with low MT ratio and is characteristic of the disease.
� Tuberculomas have solid and/or liquid caseation on noncontrast MT T1 images, a bright rim around T2hypointensity is a characteristic feature of tuberculoma; the T2 hypointense rim appears bright intuberculous abscess.
� When liquefaction of the caseation occurs within tuberculoma as well as abscess, it shows restriction ondiffusion-weighted (DW) imaging with low apparent diffusion coefficient (ADC).
� Advanced imaging methods such as perfusion imaging and diffusion tensor imaging (DTI) may be ofvalue in objective assessment of therapy in tuberculoma.
Approximately one-third of the world’s population capita is offset by population growth. Conse-
om
is currently infected with tuberculous bacillus, ofwhich approximately 5% to 10% become sick orinfectious at some time during their life. Peoplewith human immunodeficiency virus (HIV) aremore likely to develop tuberculosis (TB). TheWorldHealth Organization (WHO) estimates that therewere 9.4 million new cases in 2009, including 1.1million cases among people with HIV.1 Approxi-mately 1.7 million people died of TB, including380,000 people with HIV.1 Most cases were inthe south-east Asian, African, and western Pacificregions (35%, 30%, and 13%, respectively). In2009, the estimated per capita TB incidence wasstable or decreasing in all 6 WHO regions.However, the slow decline in incidence rates per
The authors have nothing to disclose.Department of Radiodiagnosis, Sanjay Gandhi PostgradLucknow 226014, Uttar Pradesh, India* Corresponding author.E-mail address: [email protected]
Neuroimag Clin N Am 21 (2011) 795–814doi:10.1016/j.nic.2011.07.0041052-5149/11/$ – see front matter � 2011 Elsevier Inc. All
quently, the number of new cases arising eachyear is still increasing globally in the WHO regionsof Africa, the eastern Mediterranean, and south-east Asia.
Neurotuberculosis constitutes 1% of all tuber-culosis and 10% to 15% of the extrapulmonarytuberculosis cases, most (>40%) of which arechildren.2 Central nervous system (CNS) tuber-culosis also accounts for 1.5% to 3.2% of alltuberculosis-related deaths.3 CNS tuberculosisremains common and, despite the availability ofeffective antituberculous therapy, continues tocause significant morbidity and mortality. TBMconstitutes 70% to 80% of all patients with neuro-tuberculosis.4 CNS tuberculosis is a prominent
uate Institute of Medical Sciences, Rae Bareli Road,
cause of sickness and death in developing coun-tries.5 In developed countries, there has been anincrease in the number of CNS TB cases, possiblyrelated to the pandemic of AIDS.6M tuberculosis isresponsible for almost all cases of tubercularinfection in CNS.5 Tubercular bacilli initiate a gran-ulomatous inflammatory reaction involving differenttissue types of the CNS such as meninges, brain,spinal cord, and covering bones. The CNS mani-festation is in a variety of forms, such as TBMand its complications, focal cerebritis, tuberculo-ma, and tubercular abscess. Spinal cord infectionis less common and causes either arachnoiditisand/or intramedullary tuberculomas.Early diagnosis and treatment of CNS tuber-
culosis is necessary to reduce the morbidity andmortality. Noninvasive imaging modalities suchas computed tomography (CT) and magnetic re-sonance (MR) imaging are routinely used in thediagnosis of CNS TB; however, MR imaging ispreferred because it offers greater inherent sensi-tivity and specificity than CT. This article reviewsthe various forms of CNS tuberculosis, includingits complications and imaging features.
PATHOPHYSIOLOGYTBM
Tuberculosis is most often a primary infection inchildren and a postprimary infection in adults.CNS tuberculosis transpires hematogenously froma distant active site such as lung, bone, lymph no-des, or gastrointestinal or genitourinary tract. Inthebrain, thebacilli lodge in thecortical andsubcor-tical regions and/or meninges, which are richly vas-cularized.7 Rarely, there is a direct spread fromadjacent infected paranasal sinuses or mastoid aircells.8 Infection typically begins in a subpial or sub-ependymal cortical location called the Rich focus.The site of this focus determines the type of CNSinvolvement.9 Initially, a nonspecific inflammatoryreaction, tuberculous cerebritis, develops. Oncesensitized, the inflammatory response results ina granuloma. This granuloma may erode into thesubarachnoid space and cerebrospinal fluid (CSF),causing basal leptomeningitis. Subsequently, thisleads to communicating hydrocephalus, and occa-sionally obstructive hydrocephalus caused byobstruction of the foramina of Luschka andMagen-die. Vasculitis involving the lenticulostriate and tha-lamoperforating arteriesmay occur. The adventitiallayer of these vessels develop changes similar tothose of the adjacent tuberculous exudates fol-lowed by the intima, which may eventually beinvolved or be eroded by a fibrinoid-hyaline dege-neration. In later stages, the lumen of the vesselmay become completely occluded by reactive
subendothelial cellular proliferation and causesmall infarcts in the deep gray matter nuclei anddeep white matter.7,10
Tuberculoma
The initial lesion, a tubercle, consists of a central areaof incipient or frank necrosis surrounded by inflam-matory cells, lymphocytes, epithelioid and Langer-hans giant cells, with an encircling rich vascularzone.11 These lesionsbegin asaconglomerateofmi-crogranulomata that join to form a noncaseating tu-berculoma.12 Following the initial infection, mostsuch lesions resolveand reactivationor further evolu-tion of these lesions manifests as caseation withinthe center of this tuberculoma. Rarely, the lesionmay continue to grow by successive addition oflayers of granulation tissue and form growth rings.13
Subsequently, central caseous necrosis deve-lops in most cases, which is initially solid sur-rounded by a capsule comprising collagenoustissue, epithelioid cells, multinucleated giant cells,and mononuclear inflammatory cells. The centralcore of solid caseation consists of a cheesymaterial high in lipid contents, with macrophageinfiltration, regional fibrosis/gliosis, macrophageby-products (free radicals), and perilesional cell-ular infiltrates. A few bacilli may be present in thecenter. The caseation then usually liquefies, begin-ning from the center. The capsule consists of gran-ulation tissue and compressed glial tissue.10 Ifabscess formation occurs, this shows central cavi-tation with chronic inflammatory reaction withfibrosis in the wall and the aspirate from the pusstains positive for acid-fast bacilli. All these lesionsare usually accompanied by perilesional edemawith some proliferation of astrocytes in thesurrounding brain parenchyma.9
Spine
M tuberculosis infection in the spine can involveany compartment in the spinal region: vertebrae,intervertebral disk, spinal cord, and its meninges.Meningeal involvement causes spinal meningitisand spinal arachnoiditis.14 The pathophysiologyof spinal meningitis is the same as describedearlier in TBM: during primary infection a sub-meningeal tubercle forms that ruptures into thesubarachnoid space.14 It causes granulomatousinflammation, areas of caseation, and tubercles,with development of fibrous tissue in chronic ortreated cases.
CLINICAL FEATURES
Children and older persons are more vulnerable todevelop CNS tuberculosis because their immune
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systems are less robust. TBM is also common inimmune-suppressed patients (those with HIV ordiabetes, and patients taking steroids or cytotoxicdrugs). The onset of TBM is insidious and may becharacterized by persistent low-grade fever,malaise, headache, and confusion. Typical clinicalfeatures of TBM include fever with nausea, vomit-ing, headache, neck stiffness, and photophobia.15
Cranial nerve palsies, especially of third, fourth,and sixth nerves, may also be present. The intra-cranial tuberculomas manifest with features ofa space-occupying lesion of the brain and thepatients can present with features of increasedintracranial tension, focal or generalized seizures,and focal neurologic deficit. Isolation of M tuber-culosis for the definitive diagnosis from the tissueon smear or culture is possible only in a fewpatients. Culture takes 6 to 8 weeks for the resultand has a low yield. Thus the index of suspicionis mostly indirect; that is, concomitant tubercularinvolvement elsewhere (only 10% of cases mayshow disease elsewhere in the body), malaise,low-grade fever, loss of weight, positive tuberculintest, increased sedimentation rate, history ofcontact,16 and so forth.
CSF analysis in TBM normally shows a lympho-cytic pleocytosis, increased CSF protein level,and decreased CSF sugar concentration.17 CSFculture for acid-fast bacilli and CSF polymerasechain reaction (PCR) examination are confirmatorytests for the diagnosis of TBM. The sensitivity ofCSF culture for detection of acid-fast bacilli hasbeen reported to be approximately18 50%. CSFPCR examination is a new technique, and is moresensitive than the combination of microscopicexamination and culture forM tuberculosis.19
IMAGING
Imaging features of tubercular infections of theCNS, which may involve the meninges, brain,spinal cord, bones covering the brain and spinalcord, are as follows.
Imaging Protocol
The MR imaging protocol for CNS tuberculo-sis includes T2, T1, fluid-attenuating inversionrecovery (FLAIR), magnetization transfer (MT) T1,susceptibility-weighted, DW imaging, and post-contrast T1-weighted images. In addition, inclusionof 1H MR spectroscopy for lesions more than 2 cmis helpful. The closest differential diagnosis of braintuberculomas is neurocysticercosis (NCC) in theregions endemic for NCC. If lesions around 2 cmappear hyperintense on T2-weighted imaging andshowing ring enhancement on postcontrast T1-weighted imaging, isotropic fast imaging excitation
with steady state acquisition (FIESTA) should alsobe performed to show the scolex within a cyst,which is pathognomonic of NCC.
Cranial Tuberculosis
TBMTBM is still a common problem in some parts ofthe world. The meninges are involved either byhematogenous seeding or by local spread fromadjoining infected areas.
During the early stages of disease, conventionalnoncontrast MR imaging studies usually show littleor no evidence of any meningeal abnormality. MTT1 imaging is considered superior to conventionalspin-echo sequences for imaging the abnormalmeninges, which are seen as hyperintense on pre-contrast T1-weightedMT images.20 As the diseaseprogresses,mild shortening of T1 and T2 relaxationtimes may be seen compared with normal CSF.Postcontrast T1-weighted images show abnormalmeningeal enhancement (Figs. 1–3). The commonsites are interpeduncular fossa, pontine cistern,perimesencephalic cistern, suprasellar cistern,and sylvian fissures, with occasional involvementof sulci over the convexities (see Fig. 1).21–23
MT ratio (MTR) quantification helps in identifyingthe cause of chronic meningitis; low MTR sugg-ests TBM.20,24 Ex vivo MR spectroscopy of theCSF shows lactate, acetate, and sugar signalsalong with cyclopropyl rings (�0.5 to 10.5 ppm)and phenolic glycolipids (7.1 and 7.4 ppm), whichare not seen in pyogenic meningitis.25 The combi-nation of ex vivo MR spectroscopy with MT MRimaging may be helpful in diagnosing TBM.
The secondary complications of TBM maydevelop as the disease progresses or even whilethe patient is on treatment. The sequelae associ-ated with TBM are as follows.
Hydrocephalus Hydrocephalus develops comm-only as a result of blockage of the basal cisternsby the inflammatory exudates (communicatingtype) (see Fig. 2), or occasionally due to masseffect of a focal parenchymal lesion or entrapmentof the ventricle by granulomatous ependymitis26
(obstructive type). Periventricular hyperintensityon T2-weighted or FLAIR images usually suggestsseepage of the CSF fluid across the white matter.Atrophy of brain parenchyma may be a latesequela of chronic hydrocephalus. The choroidplexus may serve as an entry point for the patho-gens into the CNS. Its involvement, choroid plexi-tis, presents as prominent contrast enhancementof the choroid plexus and is usually associatedwith ependymitis, ventriculitis, and meningitis.
Fig. 1. TBM without hydrocephalus in a young patient. T2 (A, E) and T1 (B) images at the level of the frontal hornand at the level of the quadrigeminal cistern are unremarkable. MT T1 images at the corresponding levels showbright meninges (C, F) that enhance diffusely on postcontrast T1 images (D) and (G).
Fig. 2. TBM with hydrocephalus. Axial T2-weighted (A) and T1-weighted (B) images show hydrocephalus. Notethe hyperintense lesion in the left anterior temporal lobe (arrow), which is hypointense on the T1-weightedimage. Precontrast MT T1 image (C) shows hyperintensity around the pons as well as tuberculomas (small arrow)that show enhancement on postcontrast T1-weighted images (D). ADC map shows low ADC in the left anteriortemporal lobe tuberculoma (E). The CSF findings and CSF PCR were consistent with TBM.
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Fig. 3. TBMwith vasculitis.Axial T2-weighted (A–C) images showa largeareaof cortical and subcortical hyperinten-sity in the right frontal-parietal and occipital regions, left basal ganglia, and in the periventricular regionwithmildventricular dilatation. DW images (D–F) show a large area of restricted diffusion in the right middle cerebral arteryand posterior cerebral artery territory and left basal ganglia. Axial MT T1 (G) image shows basal exudates andabnormal meninges, which appear bright. Postcontrast T1 (H) image shows abnormal meningeal enhancementin the MT T1 bright regions (G). MR angiogram (I) of the circle of Willis shows segmental narrowing involving thesupraclinoid portion of the right internal carotid artery, middle cerebral artery, and right posterior cerebral artery.
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Vasculitis Vasculitis is another common complica-tion seen at autopsy in cranial TBM involving smalland medium-sized vessels and causing ischemiccerebral infarction.26 Most of the infarcts are inthe basal ganglia and internal capsule regionsbecause of the involvement of the lenticulostriatearteries; however, involvement of the largevascular territory such as the middle cerebralartery may also be encountered.10,21,27 MR angi-ography may help in the detection of vascularinvolvement (see Fig. 3). Intracerebral inflamma-tory aneurysms may also be seen in CNS tubercu-losis.28 MR angiography can reveal this rarevascular complication.25 DW imaging helps inearly detection of infarcts.27 Vascular complica-tions are usually seen following initiation of speci-fic therapy, possibly due to the healing and fibrosisof meninges resulting in the occlusion of em-bedded vasculature.
Focal or diffuse pachymeningitis CNS TB mayinvolve the dura mater, causing pachymeningitis,which may occur either in isolation or with pial orparenchymal disease. Pachymeningitis maypresent as focal or diffuse involvement of thedura mater and occur secondary to hematoge-nous spread.29,30 Thickened dura mater may beevident on precontrast studies but is detectedusually as abnormal enhancement on postcontrastimages. However, the appearance of focal anddiffuse pachymeningitis on MR imaging is nonspe-cific and may be seen in a large number of inflam-matory and noninflammatory conditions.
Cranial nerve neuropathy Clinical involvement ofthe cranial nerves is seen in 17.4% to 40% ofpatients with TBM caused by vascular compro-mise resulting in ischemia of the nerve or causedby entrapment of the nerves by the exudates.25
Intracranial tuberculomaBrain tuberculoma is a space-occupying mass ofgranulomatous tissue that is encountered morefrequently in developing countries and is respon-sible for high morbidity and mortality.5 The inci-dence of tuberculoma is higher in the developingworld (15%–50% of all intracranial lesions),compared with developed countries where theincidence is about 0.2% of all biopsied brainlesions.13 Early recognition and treatment of thiscondition on imaging plays an important role inpatient management. Intracranial tuberculomasmay be solitary or multiple and variable in size.These tuberculomas are found across all agegroups; however, a predilection for children hasbeen reported.13 The common sites include cere-bral hemispheres, basal ganglia, cerebellum, and
brainstem. Rarely, ventricular system and men-inges are also involved.13,31
Extra-axial tuberculomas may also occur, whichmay cause widening of the basal foramen oradjacent bone destruction.32 Tuberculoma in thehypophyseal region is rare and it is frequentlyassociated with thickening of the pituitary stalk.33
MR features From the appearance on T2-weighted imaging, the intra-axial tuberculomasmay be classified as:
1. T2 hyperintense lesion2. T2 hypointense lesion3. T2 hyperintense center with peripheral hypoin-
tense rim4. Lesion with mixed/heterogeneous signal
intensity.
T2 hyperintense lesion Noncaseating tuberculo-mas, typically less than 1.5 cm in diameter, appearhyperintense on T2-weighted images, isointenseto hypointense on T1, hyperintense on MT T1,and FLAIR, and show nodular or ring enhancementon postcontrast studies. On DW imaging, theselesions may show hyperintensity with lowADC.20,25 These tuberculomas may be part ofmiliary tuberculosis or TBM (Fig. 4). This appear-ance may resemble metastases, lymphomas,demyelinating plaques, and other infective granu-lomas. The presence of a bright rim on noncon-trast MT T1 along with low MTR may help in itsdifferentiation from other lesions.
T2 hypointense lesion Tuberculomas with solidcaseation are usually isointense to hypointenseon both T2-weighted and T1-weighted images.These lesions are surrounded by a rim of variablethickness that may appear hyperintense on T1-weighted and T2-weighted images. On DWimages, there is no restriction seen in the solidcaseation of the tuberculoma with a high ADC.On noncontrast MT T1 images, this rim shows hy-perintensity, a characteristic feature seen in tuber-culomas, and the solid caseation remainshypointense (Figs. 5–7). The rim comprises inflam-matory cells, some of which may contain frag-mented portions of the lipid-rich cell wall of Mtuberculosis. Lipids are known to have no MTeffect; the rim has a lower MT ratio than the coreand appears bright on MT. Biochemically, thecore contains necrotic tissue and macromoleculesthat are responsible for the higher MT ratiocompared with the rim.34 The rim shows enhance-ment on postcontrast T1 images, whereas solidcaseation does not enhance. The solid caseationcontains cheesy material high in lipid contents,withmacrophage infiltration, regional fibrosis/gliosis,
Fig. 4. Miliary tuberculomas. Multiple areas of focal hyperintensity are seen on T2-weighted axial image (A). Theseareas are seen as slight hypointensities on a T1-weighted image (B). DW image (C) does not reveal any abnormality.MT T1 (D) shows multiple small lesions with bright rims in the regions of hyperintensity noted on T2 (A).Susceptibility-weighted imaging (E) does not show any blooming that would indicate calcification or bleeding.Contrast-enhanced T1-weighted image (F) confirms the presence of multiple small lesions with rim enhancementin the areas of MT T1 (D) and T2 hyperintensities (A). Chest skiagram of the patient showed miliary tuberculosis.
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and macrophage by-products (free radicals),components that are possibly responsible for thehypointensity seen on T2-weighted images.25
These MT T1 visible constituents of tuberculomaclosely match the histologic appearances.34 TheMT ratio of the core has been shown to be muchlower than similar-appearing cysticerci lesions.20
In vivo MR spectroscopy of these tuberculomasreveals the presence of lipid peaks.35 The pres-ence of serine at 3.7 to 3.9 ppm on ex vivo/in vitroMR spectroscopy of the tuberculoma samplesuggest the presence of M tuberculosis becauseserine is found in abundance in the wall ofthis bacterium.25 T2 hypointensity is seen insome lymphomas, glioblastoma, metastasesfrom colonic carcinoma or melanoma, fungalgranulomas, or cysticerci lesions. Hemorrhage,hemorrhagic tumor, occult cerebrovascular mal-formation, and calcification may also appear as
T2 hypointense lesions. Susceptibility-weightedsequences such as SWAN may differentiatehemorrhage and calcification from other T2 hypo-intense lesions.
T2 hyperintense center with peripheral
hypointense rim When liquefaction of the case-ation occurs within a tuberculoma, it appears asa T2 hyperintense lesion with peripheral hypoin-tense rim. On T1-weighted and MT T1-weightedimages, the centers of these lesions are hypoin-tense. Tuberculomas with liquid caseation showrestriction on DW images (see Figs. 2, 5, and 8).There is rim enhancement on postcontrast studies.The MTR remains significantly lower in tuberculo-ma compared with other conditions such asNCC. This appearance of a T2 hyperintense centerwith peripheral hypointense rim may also be seenin other conditions such as pyogenic or tubercular
Fig. 5. Multiple tuberculomas in a 32-year-old woman. T2-weighted (A) and T1-weighted (B) axial images showmultiple lesions with mixed intensity on T2-weighted as well as T1-weighted images in the right frontal regionwith perilesional edema. DW image (C) shows bright intensity in one of the lesions, suggesting liquefied caseationwith restricted diffusion. SWAN image (D) does not reveal any blooming, eliminating the possibility of calcificationor hemorrhage. MT T1-weighted (E) and contrast-enhanced T1-weighted images (F) show rim of hyperintensityaround the lesions (E) that enhances on contrast. 1H MR spectroscopy (G) reveals the prominent lipid peak withslightly increased choline and reduced N-acetyl aspartate (NAA) and creatine. Minimal increase in choline is seenfrom the cellular component of the tuberculoma; reducedNAAand creatine are causedby the partial volumeeffectand lipids represent the caseation. Thepatienthadpulmonary tuberculosis andwason treatment. She responded toantituberculous therapy and lesions regressed in a period of 18 months.
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abscesses, degenerating NCC, toxoplasmosis,and metastases. In NCC, the scolex appears asan eccentrically placed hypointense nodule onT2-weighted imaging that differentiates it fromtuberculoma. The susceptibility-weighted andisotropic T2-weighted imaging techniques arehelpful in differentiating these lesions from neu-rocysticercosis. MR spectroscopy may differen-tiate this stage of tuberculomas from pyogenicabscesses by showing cytosolic amino acidsresonances in the latter.
Lesion with mixed/heterogeneous signal
intensity At times, tubercular lesions show mixedintensity on spin-echo imaging with a rim of variablethickness that may appear minimally hyperintenseon T1 and show variegated enhancement (Fig. 9).Similar-appearing lesions include lymphomas, gli-oblastoma, metastases, fungal granulomas, andtoxoplasmosis. 1H MR spectroscopy may benonspecific in its differentiation. This type of
tubercular lesions show large choline and lipid reso-nances with variable creatine resonance and corre-late with predominantly cellular infiltrate along withsmall areas of solid caseation on histopathology.36
It is suggested that thepresenceof choline iscausedby the contribution from the cellular component inthis type of tuberculoma.36 On MT images, the rimshows hyperintensity, whereas the caseous regionsare heterogeneously hypointense.
Miliary tuberculosis Miliary brain tuberculosis isa result of hematogenous spread of infection inwhich multiple, small miliary tubercles of lessthan 2 mm are seen. It is usually associated withTBM. These lesions may not be visible on conven-tional spin-echo MR images or show only tinyfoci of hyperintensity on T2-weighted images.The spin-echo invisible lesions are clearlyvisible on MT T1-weighted imaging. T1-weightedimages after gadolinium administration shownumerous small, homogeneous enhancing lesions
Fig. 6. Vermian tuberculoma in a 17-year-old boy. T2-weighted axial image (A) shows a hypointense mass withsmall central hyperintensity in the vermis that appears isointense with central hypointensity on the T1-weightedimage (B)withobstructivehydrocephalus. The rimof the lesion is hyperintenseon theMTT1 image (C). Nodiffusionrestriction is noted on the DW image (D). Postcontrast BRAVO axial (E), and sagittal (F) images show rim enhance-ment. 1H MR spectroscopy (G) shows prominent lipid peaks. Histology confirmed it as tuberculoma.
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(see Fig. 4). MT T1 imaging helps in defining thetrue disease load in these patients.20
Role of advanced imaging In a recent study,Guptaand colleagues performed dynamic contrastenhancementMR (DCE-MR) imaging in 13 patientswith brain tuberculoma and showed that theregional cerebral blood volume (rCBV) of thecellular portion significantly correlated with thecellular fraction volume, microvascular density(MVD), and vascular endothelial growth factor(VEGF) of the excised tuberculomas. MVD alsocorrelated significantly with VEGF. Correlationbetween rCBV, MVD, and VEGF confirms thatrCBV is a measure of angiogenesis in the cellularfraction of the brain tuberculoma.37,38 In anotherrecent DCE-MR imaging study in brain tuberculo-ma, the investigators reported a significant positivecorrelation between physiologic indices (Ktrans andve) and matrix metalloproteinase-9 (MMP-9)expression (a marker of blood-brain barrier disrup-tion) in excised tuberculoma. However, a weakcorrelation between physiologic indices and
VEGF expression in excised tuberculoma suggestsa limited role of VEGF in opening of the blood-brainbarrier. Correlation between Ktrans and MMP-9suggests that Ktrans can be used as a surrogatemarker of blood-brain barrier disruption. Theseparameters may be useful in assessment of thera-peutic response in tuberculomas.
Diffusion tensor MR imaging (DTI) has beenwidely used for the detection of white matterabnormality in various clinical conditions.39–41 Arecent serial DTI study showed strong negativecorrelation of MMP-9 expression in excised tuber-culoma with fractional anisotropy (FA), linearanisotropy (CL), and planar anisotropy (CP), andsignificant direct correlation with spherical anisot-ropy (CS). The investigators also reported signifi-cant increase in FA, CL, and CP along withsignificantly decreased CS with time in patientswho were serially followed up with antituber-cular therapy42 (ATT). These methods may be ofvalue in objective assessment of therapy in tu-berculoma and guide the clinician in modulationof treatment.
Fig. 7. Right parieto-occipital tuberculoma showing regression with therapy. T2-weighted axial image (A1) showsa hypointense lesion with areas of small hyperintensity and perifocal edema that gradually regressed after 6months (A2) and 14 months (A3) of therapy. Note the corresponding changes on T1 (B1–3), MT T1 (C1–2), postcon-trast T1-weighted images (D1–3). ADC maps (E1–3) show gradual regression in the lesion, whereas FA maps showincrease in FA (F1–3) in the periphery, suggesting disappearance of edema and increase in fibrosis around thelesion. T1 contrast perfusionmaps such as Ktrans (G1–3), corrected CBV (H1–3) and CBF (I1–3) show gradual normal-ization suggesting healing of the lesion. Note the persistence of rim enhancement (D3) in the absence of any sig-nificant Ktrans (G3), suggesting the presence of false disease activity. Single-voxel 1H MR spectroscopy done on thefirst study shows only the presence of lipids (J).
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Tuberculous brain abscessTuberculous brain abscesses constitute approxi-mately 4% to 7%of the total CNS TB in developingcountries. These abscesses are diagnosed frommacroscopic evidence of abscess formation alongwith histologic demonstration of vascular gran-ulation tissue in the wall containing both acuteand chronic inflammatory cells, and isolation ofM tuberculosis.43
On MR imaging, these appear as large, solitary,and frequently multiloculated ring-enhancing les-ions with surrounding edema and mass effect.44
DW imaging in tuberculous abscesses showsrestricted diffusion with low ADC values.45–48
High lipid-containing M tuberculosis bacilli areprobably responsible for significantly lower MTRvalues from the rim of tuberculous abscesses(19.89� 1.55) compared with pyogenic abscesses(24.81 � 0.03).49
In vivo 1H MR spectroscopy in tuberculousabscesses shows only lactate and lipid signals(at 0.9 and 1.3 ppm), without any evidence of cyto-solic amino acids. This pattern may be useful butis not characteristic because a similar patternmay also be seen in staphylococcal abscess.Quantitative MT T1 imaging may be needed tohelp in its differentiation (Fig. 10).
Spinal Tuberculosis
Intraspinal TBThe MR features of spinal meningitis are usuallyvisible on contrast-enhanced images in which attimes a thin, diffuse meningeal enhancementmay be noted. In arachnoiditis, imaging featuresinclude CSF loculation and obliteration of thespinal subarachnoid space with loss of outline ofthe spinal cord and clumping of the nerve roots
Fig. 8. A large tuberculoma in the left temporal region. T2-weighted axial image (A) shows central hyperintensitywith a peripheral hypointense rim and perifocal edema. The lesion appears hypointense in the center with periph-eral isointensity on the T1-weighted (B) image.MTT1 image (C) shows ahyperintense rimbeyond the T2 hypointen-sity, suggesting a cellular rim of the tuberculoma that enhances on the postcontrast T1-weighted image (D).Thelesion does not show restriction of diffusion on the DW image (E) with high ADC (F). 1HMR spectroscopy (G) showsprominent lipid resonance at 1.3 ppm with small resonance of choline. Histology confirmed it as tuberculoma.
Fig. 9. Tuberculoma presenting as a heterogeneous mass in the left temporal lobe in a 40-year-old man. A masslesion with mixed signal intensity appears with surrounding edema on T2-weighted (A), T1-weighted (B), andFLAIR (C) images. Small areas of hyperintensity are seen within this mass on DW images (D), which have low signalon the ADC map (E). MT T1 image shows multiple small hyperintense rings around these hyperintense DWimaging lesions (F), which enhance on the postcontrast T1-weighted image (G). 1H MR spectroscopy (H) of thislesion reveals a large lipid with increase in choline. Histology confirmed it as tuberculoma.
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Fig. 10. Tubercular abscess in the left cerebellar hemisphere. Axial T2-weighted image (A) shows a well-defined,round, heterogeneously hyperintense lesion with peripheral hypointense rim. On the T1-weighted image (B), thelesion is heterogeneously hypointense centrally with a peripheral isointense rim. Axial FLAIR (C) image showsminimal perilesional edema. On the MT T1 images, with MT pulse off (D) and pulse on (E), the T2 hypointenserim appears hyperintense. Axial postcontrast T1-weighted (F) image shows thick nodular rim enhancement.The DW image (G) shows restriction in the dependent part of the cavity with corresponding low ADC (H) suggest-ing cellular debris. FA map (I) and color-coded FA map (J) show high FA in the wall as well as in parts of the cavityof the lesion. 1H MR spectroscopy (K) shows dominant lipid resonances. Histology from the wall was consistentwith tuberculous abscess. Pus culture was positive for M tuberculosis.
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in the lumbar region. Contrast studies may shownodular, thick, linear dural enhancement, oftencompletely filling the subarachnoid space on post-contrast MR images.50–52 In chronic stages ofdisease, there may not be any enhancementeven though unenhanced images show signs ofarachnoiditis.50,51 The spinal cord may be involvedsecondarily and show infarction, syringomyelia,myelitis, and tuberculoma formation. Syringomy-elia is seen as cord cavitation with CSF-like inten-sity that does not show any enhancement onpostcontrast images.50,51
MyelitisTuberculous myelitis is usually associated withtuberculous intracranial involvement of the
meninges or brain parenchyma, or with tuberculousarachnoiditis of the spine (Fig. 11). Intramedullarytuberculomas are uncommon and have similarimaging features to brain tuberculomas.53,54 MRimaging features of spinal tubercular abscess,another rare condition, are similar to cerebral tuber-cular abscess. As the treatment begins, there isreduction in the T2 hyperintensity in the spinal cordand enhancement becomes more clearly definedon postcontrast T1-weighted images.55 Thesurrounding edema continues to be extensive.These findings suggest the beginning of intramedul-lary abscess formationwith imaging features seen inbrain abscesses.55 The abnormalities visible onT2-weighted images subside in weeks, whereascontrast enhancement may persist for months.55
Fig. 11. Tubercular myelitis with arachnoiditis. Midsagittal T2, T1, and fat-suppressed precontrast and postcon-trast T1-weighted images (A–D) of the dorsal spine show nonenhancing CSF-like signal intensity collection ante-rior (arrow) (C6–D2 level) and posterior (D3–D5 level) to the spinal cord. The underlying upper dorsal cord iskinked. The spinal cord from D3 to D9 shows diffuse central hyperintensity (A). The midsagittal fat-saturatedpostcontrast T1-weighted (D) image shows thick continuous meningeal enhancement posteriorly from D5 toD8 with diffuse leptomeningeal enhancement. White arrow denotes the second dorsal vertebra.
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Dural and subdural disordersTuberculous pus formation may occur betweenthe dura and the leptomeninges and appear asa loculation. This appears hyperintense on T2-weighted images and isointense to hypointenseon T1-weighted images. However, the dural gran-ulomas appear hypointense to isointense on T2-weighted images and isointense on T1-weightedimages. Peripheral enhancement can be seen onpostcontrast images.51
Epidural tuberculous abscesses may be seenin isolation or in association with arachnoiditis,myelitis, spondylitis, and intramedullary and duraltuberculomas.51,55 These lesions appear to be iso-intense to the spinal cord on T1-weighted imagesand show mixed intensity on T2-weighted images(Fig. 12). Uniform enhancement is seen if the TBinflammatory process is phlegmonous in natureon postcontrast images, which converts to periph-eral enhancement if epidural abscess formation orcaseation develops.51,55
Tuberculous spondylitisTuberculous spondylitis is a frequent occurrencein developing countries and is an important causeof spine-related morbidity. Early diagnosis and
prompt treatment are required to avoid permanentdamage or deformity in the spine.
Tuberculous spondylitis commonly involvesvertebral bodies; however, disease in other stru-ctures, such as posterior osseous elements,epidural space, paraspinal soft tissue, and in-tervertebral disks, is also seen.56 The mostcommonly involved sites in tuberculous spondy-litis are dorsal and lumbar spine, especially thethoracolumbar junction. Usually more than 1 verte-bral body is affected, but solitary vertebral lesionscan also occur.
MR has the unique ability to detect marrowabnormalities before any bony destruction; henceit has assumed the role of primary imaging modal-ity. The involved vertebrae are hyperintense onT2-weighted images and hypointense on T1-weighted images.56,57 As the disease progresses,diskovertebral involvement may be visible.Features suchas vertebral intraosseousabscesses(Figs. 13–15), paraspinal abscesses, diskitis, skiplesions, and spinal canal encroachment can allbe seen. Reduction in disk height andmorphologicalteration of the paraspinal soft tissue is a lateoccurrence. Enhanced MR studies are valuablefor characterizing tuberculous spondylitis by
Fig. 12. Posterior epidural tuberculous abscess in an HIV-positive patient. Sagittal T2-weighted image (A) showsa curvilinear area of increased signal intensity in the posterior subarachnoid space of the mid-dorsal spinal canal.The corresponding area is hypointense on the T1-weighted image (B). The underlying spinal cord is compressedand shows increased signal intensity with almost complete obliteration of the subarachnoid space (A–C) causedby mass effect. Sagittal (D) and axial (E) postcontrast T1-weighted images show thick peripheral wall enhance-ment with a central nonenhancing area of liquefaction suggesting epidural abscess. No abnormal enhancementis noted in the adjacent vertebral bodies and intervertebral disks.
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showing rim enhancement around intraosseousand paraspinal soft tissue abscesses (see Figs.13–15) and, rarely, in lesionswith solid caseation.57
Therapeutic response is assessed by showingprogressive increase in signal intensity on T1-weighted images (Fig. 16) in the affected vertebraecaused by fatty marrow deposition that indicateshealing.56
Demonstration of bone fragments in the intra-spinal and/or extraspinal soft tissue is consideredcharacteristic of tuberculous spondylitis.56 This is
caused by the lack of proteolytic enzymes thatlyse the bone in the tuberculous inflammatoryexudate. These fragments are best shown on CT;however, T2*-weighted images can also showthese by accentuating the diamagnetic suscepti-bility properties of the calcium salt present in thebone fragments. The presence of bone fragmentis characteristic of tuberculous spondylitis evenin the absence of abscess formation.57
As in brain, diffusion imaging is useful fordemonstrating restriction of diffusion in spinal
Fig. 13. Tuberculous spondylitis involving the craniovertebral junction. Axial T2-weighted (A) image shows areaof heterogeneous signal intensity in the occipital condyle and lateral mass of atlas on the left side. Axial (B) andmidsagittal (E) fat-suppressed postcontrast T1-weighted image shows moderate heterogeneous contrastenhancement of the altered area. (C–D) Extension of the enhancing soft tissue between the anterior arch of atlasand dens on T2 images resulting in atlantoaxial dislocation (AAD) of 4.3 mm with mild basilar invaginationcausing mild narrowing of the foramen magnum. No abnormal cord signal intensity or enhancement is seen.
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infections.58 Tubercular abscesses in soft tissuesas well as within the vertebrae also behave ina similar manner and show restriction of diffusion(see Fig. 15) with low ADC.
TUBERCULOSIS IN HIV/AIDS
Tuberculosis has seen a resurgence in the past2 decades because of the increasing numbersof patients with AIDS.59 A total of 5% to 9% ofpatients with AIDS develop tuberculosis, and, ofthese, 2% to 18% have CNS involvement.23,60,61
CNS tuberculosis may be the initial clinical mani-festation of AIDS and may result from reactivationof a previous infection or from a primary, newlyacquired infection.59 The predominant mechanismof disease spread is hematogenous.
Pathologic Features
The most common intracranial manifestation oftuberculosis is basal meningitis; however, tuber-culomas, tuberculous abscess, and cerebralinfarction are also seen. HIV infection may alterthe pathologic features of TBM. Fewer basalexudates and greater numbers of acid-fast bacillioccur in the brain parenchyma and meninges inpatients with HIV infection.62
Imaging Features
Imaging features depend on the site of infec-tion. In TBM, hydrocephalus and meningealenhancement are seen.60 The hydrocephalusresults primarily from obstruction of the basal
Fig. 14. Tuberculous spondylitis of the dorsal spine. Midsagittal T2-weighted (A) and fat-saturated T1-weighted(B) images show contiguous involvement with an area of altered signal intensity in D2 and D3 vertebral bodiesand the intervening disk, resulting in wedge collapse and kyphotic deformity. Hyperintense signal intensity thatindicates edema is noted in the underlying cord caused by mass effect. Fat-suppressed postcontrast T1-weighted(C) image shows moderate heterogeneous enhancement of the altered signal area within the vertebral bodies.Axial postcontrast T1-weighted (D, E) images show a thick-walled abscess in the prevertebral and paravertebralregion. Bilateral minimal pleural effusion is also noted.
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cistern by inflammatory exudates. In addition,cerebral abscesses and tuberculomas may beseen.60
Tuberculomas occurred in 24% of patients ina study by Whiteman and colleagues.23 Theappearance of tuberculomas in AIDS is similarto those seen in patients who do not have HIVand was described earlier. On postcontrastimages, noncaseating tuberculomas shownodular homogeneous enhancement. Caseatingtuberculomas have ring enhancement. Tubercu-lous abscesses are more common in HIV-infected patients. Among patients with CNS
tuberculosis, 4% to 8% of those without HIVinfection developed abscesses, compared with20% in the group of patients with HIV.23
Abscesses tend to be larger than tuberculomas,frequently greater than 3 cm. Abscesses arealso more frequently solitary unlike tuberculo-mas. The imaging features of tubercularabscesses are described in an earlier section.9
Cerebral infarction complicates CNS tubercu-losis and was seen in 36% of the patients in thestudy by Whiteman and colleagues.23 Imagingfeatures are similar to those described in patientswithout HIV.
Fig. 15. Tuberculous spondylitis of lumbar spine. Midsagittal T2-weighted (A) and T1-weighted (B) images showareas of abnormal signal intensity which are hyperintense on T2-weighted, and hypointense on T1-weighted,images in D12, L1, L3, and L4 vertebral bodies and intervertebral disks at D12/L1 and L3/4 levels, with partialwedge collapse of L3 vertebra. Fat-suppressed postcontrast sagittal T1-weighted (C) image shows heterogenousenhancement of the altered signal area with central areas of liquefaction. Coronal T2-weighted (D) image showscraniocaudal extent of the right paravertebral abscess. Axial T2-weighted (E) and axial fat-suppressed postcon-trast T1-weighted (F) images show hyperintense prevertebral, bilateral psoas muscles, and left paraspinal collec-tion with peripheral enhancement. DW (G) image shows restriction inside the collection.
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ASSESSMENT OF THERAPEUTIC RESPONSE
Once the diagnosis is made on imaging and otherlaboratory investigations, the patients are givenantitubercular treatment63,64 (ATT). MR imaging isthe modality of choice for following these patients.Serial imaging in responding patients usuallyshows a decrease in lesion size after 3 to 4 monthsand its disappearance by 12 months.64 Rarely,a paradoxic progression of intracranial tuberculo-mas or development of new lesions during thetreatment of CNS tuberculosis has also beenrecognized.65 Advanced imaging techniques suchas perfusion imaging and DTI may be useful in theassessment of response in these patients (seeFig. 7). It has been shown that changes in Ktrans
and ve closely match the therapeutic response inbrain tuberculoma even in the presence of a para-doxic increase in the lesion volume.37
A reduction in the intensity of the meningealenhancement is considered a positive responseto treatment in patients with TBM. In a recent
serial DTI study in TBM, it was shown that thecortical FA values decreased on treatment (0.13� 0.02) compared with baseline values (0.15 �0.03). The investigators also reported a significantpositive correlation between FA and proinflamma-tory molecules (PMs), thereby suggesting that theDTI metrics may be used as noninvasive surrogatemarker of PMs in assessing therapeutic responsein patients with TBM.37
Calcification of the meninges and parenchymaltuberculoma is seen as sequelae of TBM, andusually appear markedly hypointense on all spin-echo sequences. An isointense or hypointensecore with a hyperintense rim on T2-weighted andFLAIR images is the most common imagingappearance.66
SUMMARY
CNS tuberculosis is a major cause of sickness anddeath in developing countries and is beingincreasingly seen in the developed world because
Fig. 16. Follow-up case of healed tuberculous spondylitis. Midsagittal T2-weighted (A) and T1-weighted (B)images show abnormal hyperintensity in the paradiscal area of L4 and 5 vertebral bodies showing suppressionwith no obvious enhancement on a sagittal fat-suppressed postcontrast T1-weighted (C) image, suggesting fattyreplacement. No residual prevertebral or epidural collection is seen. The intervening disk is hypointense andthinned out, suggesting sclerosis.
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of the emergence of AIDS. It spreads hematoge-neously and involves meninges, brain paren-chyma, spinal cord, and covering bones. Thepresenting clinical features vary according to thesite of infection, and are usually nonspecific. Isola-tion ofM tuberculosis for the definitive diagnosis ispossible only in a few patients. MR imaging playsan important role in its early recognition. MT-T1imaging is considered superior to conventionalspin-echo sequences for imaging the abnormalmeninges and tuberculomas. The MT ratio of tu-berculomas remains significantly lower comparedwith other conditions such as cysticercosis. Use of1HMR spectroscopy in combination with other MRimaging techniques may also help in its differenti-ation from similar diseases. Imaging characteris-tics of tuberculomas in HIV remain the same asin patients without HIV. Advanced imagingmethods such as perfusion imaging and DTI maybe of value in objective assessment of therapy intuberculoma and guide the clinician in modulationof treatment.
REFERENCES
1. WHO 2010/2011 tuberculosis global facts. Available
