ORIGINAL ARTICLE

Central Nervous System Tuberculosis Carlos Torres, MD,* Roy Riascos, MD,† Ramon Figueroa, MD,‡ and Rakesh K. Gupta, MD§ Abstract: Tuberculosis (TB) has shown a resurgence in nonendemic populations in recent years and accounts for 8 million deaths annually in the world. Central nervous system involvement is one of the most serious forms of this infection, acting as a prominent cause of morbidity and mortality in developing countries. The rising number of cases in developed countries is mostly attributed to factors such as the pandemic of acquired immunodeficiency syndrome and increased migration in a globalized world. Mycobacterium TB is responsible for almost all cases of tubercular infection in the central nervous system. It can manifest in a variety of forms as tuberculous meningitis, tuberculoma, and tubercular abscess. Spinal infection may result in spondylitis, arachnoiditis, and/or focal intramedullary tuberculomas. Timely diagnosis of central nervous system TB is paramount for the early institution of appropriate therapy, because delayed treatment is associated with severe morbidity and mortality. It is therefore important that physicians and radiologists understand the characteristic patterns, distribution, and imaging manifestations of TB in the central nervous system. Magnetic resonance imaging is considered the imaging modality of choice for the study of patients with suspected TB. Advanced imaging techniques including magnetic resonance perfusion and diffusion tensor imaging may be of value in the objective assessment of therapy and to guide the physician in the modulation of therapy in these patients. Key Words: MRI, CNS tuberculosis, TB meningitis, tuberculoma, TB spondylitis (Top Magn Reson Imaging 2014;23: 173–189)

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uberculosis (TB) accounts for 8 million deaths annually in the world. Central nervous system (CNS) involvement is one of the most serious forms of this infection, acting as a prominent cause of morbidity and mortality in developing countries. There have been a rising number of CNS TB cases in developed countries, mostly attributed to the pandemic of acquired immunodeficiency syndrome (AIDS). Mycobacterium TB is responsible for almost all cases of the tubercular infection in CNS. It can manifest in a variety of forms as tuberculous meningitis and its complications (including hydrocephalus), focal infarction and parenchymal atrophy, or tuberculoma and tubercular abscess. Spinal infection may result in spondylitis, arachnoiditis, and/or focal intramedullary tuberculomas. Early diagnosis of CNS TB is necessary for the early institution of appropriate therapy to reduce the morbidity and mortality. Noninvasive imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) are routinely used in the diagnosis of CNS TB; however, MRI is considered superior to CT. In this review, we will discuss the various forms of CNS TB, including its complications along with imaging features.

From the *Department of Radiology, The Ottawa Hospital Civic and General Campus, University of Ottawa, Ottawa, Ontario, Canada; †Department of Radiology, The University of Texas Medical Branch, Galveston, TX; ‡Medical College of Georgia, Georgia Regents University, Martinez, GA; and §Department of Radiology, Fortis Memorial Research Institute, Gurgaon, Haryana, India. Reprints: Carlos Torres MD, 1053 Carling Ave, Ottawa, Ontario K1Y 4E9, Canada (e‐mail: [email protected]). The authors declare no conflict of interest. Copyright © 2014 by Lippincott Williams & Wilkins

PATHOGENESIS Central nervous system tuberculosis occurs as a result of hematogenous spread of the disease from a distant active site, usually from the lung. However, it can also spread from active sites in the bone, lymph nodes, and gastrointestinal or genitourinary tract. Direct spread can infrequently occur from paranasal cavities, orbits, or mastoids. The bacilli lodge in the richly vascularized cortical and subcortical regions of the brain and/or meninges.1 Rich and McCordock2 proposed a 2-step model for the pathogenesis of CNS TB. The mycobacteria can initially enter the systemic circulation from pulmonary infection to reach the oxygen-rich CNS, establishing an inflammatory focus (“Rich focus”), which may be located in the meninges, the subpial or subependymal brain regions, or the spinal cord. This Rich focus may rupture into the subarachnoid space or into the ventricular system leading to meningitis.3 An initial nonspecific inflammatory reaction (tuberculous cerebritis) occurs at the beginning. Once sensitized, new inflammatory exposures will result in granulomas. Granulomas may erode into the subarachnoid space causing basal leptomeningitis, which may lead to communicating hydrocephalus. Obstructive hydrocephalus can be secondary to blockage of the foramina of Luschka and Magendie.4 In advanced cases, involvement of the leptomeninges can reach the cerebral convexities, and extension into the ventricular system can cause ependymitis and choroid plexitis. A tuberculous focus within the parenchyma may develop into a tuberculoma or a brain abscess in the absence of adequate host immunity or in the presence of a large tuberculous focus.1,5–8 Vasculitis involving the lenticulostriate and thalamoperforating arteries can occur. The lumen of the vessel may become completely occluded by reactive cellular proliferation and lead to small infarcts in the basal ganglia, thalami, and deep white matter.1,9

IMAGING PROTOCOL The ideal MR protocol for CNS TB should include a sagittal T1-Weighted (T1), axial T1, axial T2-Weighted (T2), axial fluid-attenuated inversion recovery (FLAIR), magnetization transfer (MT) T1, gradient echo or susceptibility-weighted imaging, and diffusion-weighted imaging (DWI), as well as postcontrast axial and coronal T1-weighted sequences. 1H proton spectroscopy could be obtained in lesions that are larger than 2 cm.

CRANIAL TB Tuberculosis remains a major cause of morbidity and mortality in the developing countries as well as the developed countries,10 due to the surge of AIDS11 and to the ease of migration in a globalized world. The tuberculous bacillus can induce a granulomatous inflammatory reaction in the meninges, the brain, and the skull bones.

Tuberculous Meningitis Meningeal involvement can occur by hematogenous spread or by direct extension from the infected skull base. During the early stage of the disease, routine MRI seems unremarkable, with no evidence of significant meningeal abnormality.4 The MT T1 imaging is considered superior to conventional

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spin-echo sequences for imaging abnormal meninges, because it shows increased signal intensity on the precontrast T1W MT sequence4,12(Fig. 1). As the disease progresses, there is evidence of postgadolinium enhancement in the T1W sequences. Characteristically, there is involvement of the basal meninges within the perimesencephalic cisterns, suprasellar cistern, and prepontine cistern and along the sylvian fissures (Fig. 2); however, there could be involvement of the meninges along the cerebral convexities (Fig. 3). One of the usual complications from meningeal TB is communicating hydrocephalus, resulting from blockage of the basal cisterns by the inflammatory exudates (Fig. 1). Noncommunicating hydrocephalus may infrequently occur, secondary to a parenchymal tuberculoma with ventricular entrapment from mass effect or ventriculitis/ependymitis4 (Fig. 4). There could be choroid plexitis with prominent contrast enhancement, usually in association with ependymitis, ventriculitis, and meningitis.4

Tuberculosis can involve the dura matter causing focal or diffuse pachymeningitis, usually as a result of hematogenous spread.4,13,14 It can also occur in association with leptomeningeal and parenchymal disease. The typical MRI findings are thickening of the dura (which is best seen in the FLAIR sequence) and avid postgadolinium enhancement (Fig. 5). It is important to recognize, however, that focal and diffuse pachymeningitis on MR is not pathognomonic for TB, because it can be seen in multiple inflammatory and noninflammatory entities.4 Ischemic cerebral infarcts could be seen in patients with CNS TB, often resulting from vasculitis involving the smalland medium-sized vessels. There is a preferential involvement of the lenticulostriate arteries, with common infarcts in the basal ganglia; however, large vascular territory infarcts can also be seen.4,15,16 The DWI sequence will confirm the presence of acute or subacute infarcts16 (Fig. 6). The MR angiogram may show areas of segmental narrowing or beading appearance typical of

FIGURE 1. Tuberculous meningitis. A and B, Axial T2 (A) and axial T1 (B) images at the level of the cerebral peduncles show narrow cisternal spaces and dilated ventricular system, suggesting communicating hydrocephalus. C and D, Axial MT T1 (C) shows hyperintense signal in the perimesencephalic cisterns and along some of the cerebral sulci in both occipital lobes with associated intense enhancement in the axial MT T1 postgadolinium (D).

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FIGURE 2. Tuberculous leptomeningitis: 43-year-old man with progressive headaches for 2 weeks, neck stiffness, fever, night sweats, and polyuria. A, Axial FLAIR image at the level of the medulla shows diffuse increased CSF signal of the basal cisterns (*). B, Axial FLAIR image at the pontomedullary junction shows high signal of cisternal subarachnoid spaces and midbrain surface (arrows). C-F, Axial (C and D), sagittal (E), and coronal (F) T1 gadolinium-enhanced images show diffuse leptomeningeal enhancement around the midbrain, medial aspect of the sylvian fissures, and sella structures (arrows) as well as intense enhancement of the suprasellar cistern, hypothalamus, and infundibulum (D and E, arrows). Notice interpeduncular cistern leptomeningeal enhancement (D, arrowheads). Sagittal (E) and coronal (F) images best show the inflammatory confluent suprasellar mass effect and enhancement (arrow). Notice pontine surface leptomeningeal enhancement (E, arrowheads) and leptomeningeal enhancement along the middle cerebral artery fissures (F, arrowheads). Courtesy of S. Chakraborty MD, University of Ottawa, Canada.

vasculitis.4,17 Interestingly, vascular complications could be seen after effective TB therapy, which could be due to healing and fibrosis of the meninges resulting in occlusion of embedded vessels.4 Clinical involvement of the cranial nerves in 17.4% to 40% of patients with CNS TB results from vascular compromise, which leads to ischemia of the affected cranial nerve or © 2014 Lippincott Williams & Wilkins

caused by entrapment of the cranial nerves by the tuberculous exudates.4,17

Parenchymal TB The most common parenchymal form of CNS TB is the tuberculoma. Other presentations of parenchymal involvement www.topicsinmri.com

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FIGURE 3. Lateral tuberculous leptomeningitis. A and B, Sagittal (A) and coronal (B) T1 gadolinium-enhanced images show intense asymmetric nodular enhancement in the right sylvian fissure and lateral leptomeninges (arrows). Nodular leptomeningeal enhancement is also noted in the left hemisphere (arrowheads).

include tuberculous brain abscess, focal cerebritis, and tuberculous encephalopathy. Parenchymal TB is more common in patients with the human immunodeficiency virus and can occur with or without meningitis.6,18

Parenchymal Tuberculomas Tuberculomas are the most common manifestation of parenchymal TB, solitary or multiple, and can occur anywhere in

the brain parenchyma. Tuberculomas can occur at any age but show a predilection for children,19 with predominant infratentorial location. Tuberculomas in adults are more commonly found supratentorially.6,20,21 Patients usually present with headache, seizures, focal neurological deficit, and signs of increased intracranial pressure. Infratentorial compartment lesions can lead to brainstem and cerebellar syndromes as well as to multiple cranial nerve palsies.1,7 Fever may be present.7,22 Cerebrospinal fluid

FIGURE 4. Right basal ganglia tuberculoma with obstructive hydrocephalus. A, Axial T1-weighted image shows a large tuberculoma in the right basal ganglia obstructing the ventricles at the foramen of Monro (arrows). B, Axial T2-weighted image shows dilatation of the lateral ventricles and signs of transependymal CSF flow (arrows). C and D, Axial and coronal gadolinium-enhanced T1-weighted images show intense capsular enhancement of the tuberculoma (arrows). Notice right-to-left shift in reference to midline (white reference line). Courtesy of Dr. S. Jaggi and Dr. I. Talwar, India.

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FIGURE 5. Pachymeningeal TB. A, Axial gadolinium-enhanced T1-weighted image shows tentorial tuberculous pachymeningitis as asymmetric thickening and intense enhancement (arrows). B, Coronal head CT with contrast in another patient shows pachymeningeal enhancement with associated cranial bone erosion (arrows). Courtesy of M. Castillo, MD, UNC-Chapel Hill.

FIGURE 6. Middle-aged man with leptomeningeal TB presenting with acute infarct in the right lenticulostriate arteries. A, Axial FLAIR image at the level of the basal ganglia shows signal abnormality in portions of the right lenticulate nucleus (arrows) with mild mass effect. B, Corresponding DWI shows a matching pattern of diffusion restriction (arrows). C, Apparent diffusion coefficient map confirms cytotoxic edema with low diffusion (arrows). Courtesy of P. Hanagandi, MD, University of Ottawa, Canada.

FIGURE 7. Solid noncaseating parenchymal tuberculoma. A, Sagittal T1-weighted image shows a lobulated left occipital intra-axial lesion (arrows) isointense to the white matter, with surrounding edema and mass effect. B, Corresponding T2 image shows the intra-axial mass (arrows) outlined by vasogenic edema pattern. C, Axial gadolinium-enhanced T1 image shows intense solid enhancement of the lesion (arrows). © 2014 Lippincott Williams & Wilkins

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(CSF) findings could be unremarkable or show a mild nonspecific increase in protein content. Because CSF culture is usually negative, the diagnosis usually rests on the basis of neuroimaging findings, protein-purified derivative reactivity, and response to antituberculous therapy.5,6,18 Early recognition on the imaging and treatment of this condition plays an important role in patient management. Most tuberculomas occur at the corticomedullary junction, which supports the pathogenesis of hematogenous spread.7,21 Some tuberculomas may develop from the extension of CSF infection to the adjacent brain parenchyma through VirchowRobin perivascular spaces or via cortical veins.7,18,23 Tuberculomas originate as a conglomerate of microgranulomata within a region of focal cerebritis, which coalesce into a mature noncaseating tuberculoma. Subsequently, there is usually a solid central caseous necrosis, which in turn, can liquefy.24 Pathologically, tuberculomas show a typical granulomatous reaction consisting of epithelioid cells, multinucleated giant cells, and mononuclear inflammatory cells, predominantly lymphocytes.

Surrounding the capsule, there is parenchymal edema and astrocytic proliferation.5,6,23–27

MRI Features The imaging findings will depend on the stage of the tuberculoma, whether it is noncaseating, caseating with a solid center, or caseating with a liquid center.24 The degree of surrounding edema varies, usually inversely proportional to the maturity of the lesion.18 On CT, solid noncaseating tuberculomas are isodense or slightly hypodense to brain parenchyma and demonstrate homogeneous postcontrast enhancement. On MRI, these tuberculomas are isointense to hypointense in the T1-Weighted (T1W) and T2Weighted (T2W), sequences, showing homogeneous enhancement after administration of contrast (Fig. 7). Noncaseating tuberculomas also demonstrate hypersignal on MT T1 sequences.4 Caseating granulomas are isointense to hypointense on the T1W and T2W sequences with a T2 isointense-to-hyperintense

FIGURE 8. Left thalamic-basal ganglia caseating tuberculoma. A, Axial T2-weighted image shows a mass in the left basal ganglia/ thalamus with compressive deformity of the third ventricle. Notice the surrounding hypointense capsule due to high deposit of collagen and free radicals (arrows). B, Axial T1 MT image shows hyperintense capsule (arrows) and marked hypointensity of the solid central component. C, Matching axial gadolinium-enhanced T1 image shows intense thick capsular enhancement (arrows), whereas the center of the lesion does not enhance. D, Proton magnetic resonance spectroscopy shows a dominant lipid peak.

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FIGURE 9. Left cerebellar caseating tuberculoma. A, Axial T1 image shows a left cerebellar isointense mass (arrows). B, Axial FLAIR image shows better definition of lesion borders (arrows). C, Axial T2 image shows faint surrounding edema around the lesion (arrows). D, Axial T1 gadolinium-enhanced image shows capsular enhancement and no enhancement of the solid central component of the lesion (arrows). E, Proton MR spectroscopy shows a characteristic large lipid peak at 1.3 ppm with near-complete suppression of N-acetylaspartate, creatine, and choline.

rim. Characteristically, the rim shows hyperintensity on the MT T1 noncontrast images, whereas the solid component remains hypointense. The solid component does not demonstrate restriction on DWI. On postcontrast images, there is peripheral rim enhancement, whereas the solid central component does not enhance (Fig. 8). Of note, the degree of central hypointensity on the T2W sequence is the result of a complex relationship between solid caseation, fibrosis, gliosis, and macrophage by-products (free radicals).4,17 Gupta and colleagues28 demonstrated on1 H MR spectroscopy that, in tuberculomas with a T2 hypointense center, there is a prominent lipid peak at 1.3 ppm (Fig. 9). When the solid center liquefies, it becomes hypodense on CT and hyperintense on the T2W sequence, with a peripheral rim of low T2 signal that shows postgadolinium enhancement1,20,26,29,30 (Fig. 10). Tuberculomas with liquid caseation will show restricted diffusion on DWI. © 2014 Lippincott Williams & Wilkins

The lesion imaging findings of T2 hyperintensity with a peripheral hypointense rim could be seen in other entities, such as pyogenic abscess, neurocysticercosis in a colloidal phase, toxoplasmosis, or metastases. However, the use of conventional sequences, MR spectroscopy, and a thorough clinical history are often useful in differentiating tuberculomas from the other processes. In particular, in neurocysticercosis, the scolex of the parasite appears as a mural hypointense nodule in the T2W sequence. On CT, it has been shown that the “target sign” or central calcification surrounded by ring enhancement in postcontrast images is pathognomonic of tuberculoma.31 Certain tuberculomas can show heterogeneous signal intensity on the T1 and T2W sequences, a slightly T1 hyperintense rim, and heterogeneous postgadolinium enhancement. As demonstrated by Gupta et al,28 on MR spectroscopy, these lesions demonstrate a choline peak at 3.32 ppm, in addition to the lipid peak (Fig. 11). It has been suggested that the choline peak is the result www.topicsinmri.com

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of the presence of high cellular component in this type of tuberculoma.32

Miliary TB Miliary TB of the brain is secondary to hematogenous spread from a primary pulmonary infection focus, often associated with meningitis.7,24,29 Miliary tuberculomas are usually small T2 hyperintense lesions, less than 2 to 5 mm, with homogeneous postgadolinium enhancement. They may not be visible on conventional spin-echo sequences. These same lesions are clearly seen on MT T1-weighted imaging, with MT imaging helping to define the disease load12 (Fig. 12).

Tuberculous Cerebritis Tuberculous cerebritis is a less frequent clinicoradiological pattern, mostly reported in patients without AIDS, characterized by intense gyral enhancement and associated edema 18,33 (Fig. 12C). Microscopically, it is characterized by microgranulomata, lymphocytic infiltrate, Langerhans giant cells, epithelioid cells, and variable evidence of scarce tubercle bacilli.5

Tuberculous Encephalopathy Tuberculous encephalopathy is a condition that preferentially occurs in infants and young children with pulmonary TB caused by a delayed type 4 hypersensitivity reaction related to tuberculous protein. It leads to extensive damage to the white matter along with the infrequent onset of perivascular demyelination. The CT and MRI studies reveal severe brain edema that could affect only 1 cerebral hemisphere. Despite the use of antituberculous medication, death usually occurs within 1 to 2 months after disease onset.1,20,34

Tuberculous Abscess Tuberculous abscess is an infrequent complication that occurs in less than 10% of all patients with CNS TB.18,35 A tuberculous abscess can arise in patients with TB meningitis from the spread of tuberculous foci into the brain parenchyma or from tuberculous granulomas already within the brain parenchyma.7 This encapsulated collection of pus with abundant viable tubercle bacilli demonstrates a thicker wall than a pyogenic abscess.20,36 Clinically, patients with TB abscesses present acutely with fever, headache, and focal neurologic signs, deteriorating more rapidly

FIGURE 10. Liquefying tuberculoma. A, Superior vermis liquefying tuberculoma shows T2 hyperintensity in its central area with a peripheral hypointense rim. B, Axial T1 image shows increased signal relative to CSF from increased protein content. C, Axial FLAIR image shows increased signal intensity within the lesion compared with CSF within the dilated temporal horns. D, T1 MT shows a hyperintense rim, which demonstrates intense enhancement after gadolinium administration (E). Note the additional lesion in the left middle cerebral fissure.

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in comparison with patients with tuberculomas.7,20 The Whitener36 criteria for the diagnosis of tuberculous abscess include macroscopic evidence of abscess formation within the brain

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parenchyma and histologic demonstration of vascular granulation tissue in the abscess wall, containing acute and chronic inflammatory cells and tuberculous bacilli.4,20,37 The MRI findings are

FIGURE 11. Heterogeneous tuberculomas. A, Axial T2 shows a multicystic right frontal lobe tuberculoma with heterogeneous T2 signal within its components (long and short arrows). B, Axial T1 shows variable signal from isointense to hyperintense behavior (long and short arrows). C, DWI shows restricted diffusion on all tuberculoma components (long and short arrows). D, T1 MT axial image shows hyperintense rim on both types of lesion components (long and short arrows), whereas gadolinium T1 sagittal image (E) shows multiple cystic and solid components with intense capsule enhancement (long arrows). F, Proton MR spectroscopy demonstrates a choline peak at 3.32 ppm, in addition to the lipid peak, suggesting high cellular components in this type of tuberculoma. © 2014 Lippincott Williams & Wilkins

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usually nonspecific. Tuberculous abscesses usually present as large (usually >3 cm), frequently multiloculated, ring-enhancing lesions with perilesional edema and mass effect.37 On DWI, the abscess shows restricted diffusion with low apparent diffusion coefficient values secondary to the presence of pus with inflammatory cells38–40 (Fig. 13). MR spectroscopy demonstrates lipid, lactate, and phosphoserine signals without evidence of cytosolic amino acids, in contrast to pyogenic abscesses. This helps to differentiate a tuberculous abscess from a pyogenic or fungal abscess. In addition, MT imaging can help in differentiating tuberculous from pyogenic abscesses, as the rim of tuberculous abscesses (19.89 ± 1.55) shows lower magnetization transfer ratio values in comparison with pyogenic abscesses (24.81 ± 0.03). The high lipid-containing myobacterium TB bacilli are responsible for this low magnetization transfer ratio.40–42

SPINAL TB Incidence Tuberculous spondylitis was initially described by Percivall Pott, an English surgeon in 1779,43 hence known as Pott disease. The musculoskeletal system is typically involved secondarily in the tuberculous process (1%-2%), with the spine being the most common site of osseous TB (50%), followed by the pelvis, hip, and knee.44 The lower thoracic spine is involved in half of the cases, followed by the lumbar spine, whereas the cervical spine and the sacrum are rarely involved.6,45–47 Isolated spinal involvement is seen in half of the cases of Pott disease.48 Early diagnosis is crucial to avoid complications. Delays in establishing the correct diagnosis and initiating treatment can lead to irreversible deformity of the vertebral bodies or severe narrowing of the central spinal canal, which can lead to

FIGURE 12. Miliary TB and tuberculous cerebritis. A, Axial T2 image at the level of the basal ganglia shows left external capsule and right occipital white matter edema (arrowheads) and a focal area of low signal in the lateral left putamen (arrow). More subtle lesions are noted in the right internal capsule and bilateral thalami. B, Axial T1 image shows a subtle nodular lesion in the left parietal cortico-subcortical region without significant mass effect (arrow). C, Axial FLAIR image at the same level shows better the cortico-subcortical lesion as well as additional nodular lesions (arrows). Notice the pattern of edema and mass effect in the left external capsule, which resulted in tuberculous cerebritis. D, Axial T1 MT image shows a large number of lesions, difficult to recognize on previous images, which helps to define the disease load. E, Axial gadolinium-enhanced T1 image shows multiple additional nodular enhancing lesions in the brain parenchyma in keeping with miliary TB (arrows).

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paraplegia.49 The lack of diagnostic capabilities has been identified by the World Health Organization as a barrier in establishing early therapy. Skin tuberculin tests have shown false negative rates of 14%,50 making biopsy and aspiration necessary for pathologic confirmation and culture confirmation. The advent of CSF polymerase chain reaction tests provides higher sensitivity than microscopic evaluation and cultures.6

Tuberculous Spondylitis Tuberculosis can affect the vertebrae and the meninges of the spinal cord. The typical disease presentation affects the anterior elements of the vertebra. The spinal involvement initiates through hematogenous spread via the epidural and perivertebral Batson plexus, which anastomoses with pleural and intercostal veins.43,51 Three patterns of spinal involvement have been described in the adults, which include paradiscal, anterior, and central granuloma.52 The paradiscal disease is most frequent, with a focus of infection involving the vertebral metaphysis,

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beginning in the anterior vertebral body adjacent to the endplate, resulting in posterior demineralization of the bony endplate. From this original presentation, the disease typically follows 2 pathways, involvement of the intervertebral disk or spread through the anterior longitudinal ligament. If the infection continues posteriorly through the cartilaginous endplate, it can affect the intervertebral disks and spread to the adjacent vertebral bodies. However, this process is less common than with bacterial spondylodiscitis, likely due to the lack of proteolytic enzymes in TB. A second pattern of spread involves an anterior granuloma between the anterior longitudinal ligament and the anterior vertebral body, where infection can spread to the adjacent vertebral bodies sparing the intervertebral disks, with no evidence of reactive sclerosis or local periosteal reaction.51 Anterior granulomas can elevate the periosteum, triggering avascular bone necrosis that can lead to “cold abscess” formation,43 known as such for its lack of the inflammatory response compared with the pyogenic processes.52 The anterior granuloma can also spread to the adjacent paraspinal tissues and the epidural space, presenting as an epidural phlegmon or abscess or extending to the adjacent

FIGURE 13. Left inferior temporal tuberculous abscess. A, Axial T2 image shows a left inferior temporal cystic appearing subcortical lesion (arrow) with thick T2 hypointense capsule, also easily recognizable in the axial T1 (B) and axial T1 MT (C) images. D, Axial gadolinium-enhanced T1 image shows a subcortical abscess (arrow) with thick enhancing capsule. E, Axial DWI shows strong restricted diffusion within the center of the lesion. F, Proton MR spectroscopy shows a dominant lipid peak in an otherwise suppressed metabolic peak pattern. © 2014 Lippincott Williams & Wilkins

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FIGURE 14. Tuberculous spondylitis paradiscal disease. A, Sagittal T1 image shows paradiscal TB involving the vertebral metaphyses of C4 through T1 (arrows) with sparing of the intervertebral disks. Notice the large soft tissue involvement of the paravertebral components. B, Sagittal fat-suppressed T2 image shows the hyperintense behavior of the tuberculous involvement along the anterior epidural space (arrows), the paraspinal cervical soft tissues (short arrows), and the high signal in the bone marrow spaces at C4 to C7 (*). Articular endplates seem maintained. There is associated compression of the cord, which shows increased signal intensity from C3 to T1. C, Sagittal fat-suppressed T1 gadolinium image best outlines the inflammatory masses with caseous compartments (arrows) and the vertebral marrow space involvement (*). Courtesy of Dr. P. Hanagandi, University of Ottawa, Canada.

musculature. The psoas muscle is most frequently involved and can be affected on both sides.53 Other sites of paraspinal involvement include the thigh and the pelvis.54 Once the lesion affects the vertebral body (if left untreated), the infection can evolve into structural weakening and vertebral

collapse, which can be seen as a wedge deformity or a complete collapse, also known as Gibbus deformity.51,55 MR is the imaging modality of choice in spinal TB, showing not only the bony involvement but also the soft tissue extension of the disease, abscess formation, and any compromise of

FIGURE 15. Thoracic spine Pott disease. A, Sagittal T2 image shows prominent phlegmonous changes in the anterior epidural space causing compression of the cord (arrowheads). Note the collapse of one of the midthoracic vertebrae (Gibbus deformity). B, Sagittal T1 gadolinium-enhanced image shows a large septated prevertebral tuberculous abscess (arrows). There is enhancement of the phlegmon in the anterior epidural space (arrowheads). C, Axial T2 image shows the predominant left-sided ventral epidural phlegmon (arrows) extending from the left perivertebral space to the ventral epidural space, with spinal cord (*) compressive deformity.

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the central spinal canal.56 It is also helpful in the evaluation of the spinal cord involvement.47 The compromised vertebral bodies show low T1 signal, with increased T2 and short tau inversion recovery signal and postgadolinium enhancement. Phlegmonous processes tend to have a similar appearance. When TB abscess is present, it will demonstrate increased T2 and short tau inversion recovery signal, but the enhancement will be nodular and peripheral (Figs. 14, 15). Bone scintigraphy with Tc-99 or Gallium (Ga-67) studies have separately shown low specificity without good sensitivity for the diagnosis of spinal TB57; however, when used in combination, they result in increased sensitivity.58,59 The atypical presentations of spinal TB include involvement of the posterior elements, vertebra plana, and panvertebral involvement.60 Tuberculous appendicular involvement frequently becomes a diagnostic challenge, selectively affecting the posterior elements with little or no changes of the vertebral bodies. This underdiagnosed presentation tends to present with earlier neurological symptoms due to spinal cord compression.47,61 Another atypical pattern is the isolated vertebral body involvement, which mimics spinal metastasis.62 Although rare, focal vertebral intraosseous abscesses can also be seen (Fig. 16).

TB Myelitis and Arachnoiditis Tuberculous myelitis is most commonly associated with intracranial TB involving the parenchyma and the meninges. Isolated leptomeningeal involvement is rare (1%-2%)47, most frequently affecting the subarachnoid space. On imaging, there could be linear or nodular enhancement in the acute phase. In the chronic phase, the subarachnoid space may not enhance despite imaging findings of arachnoiditis in the unenhanced images. Of note, postgadolinium studies may show thick enhancement, often completely filling the subarachnoid space6 (Fig. 17C). The MRI findings of TB myelitis are nonspecific, with increased T2 signal intensity of the affected cord segment (Figs. 17A, B). Spinal cord tuberculomas are extremely rare, described in less than 1% of the spinal TB cases.47 They are usually preceded

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by brain intraparenchymal disease, having similar imaging features to brain tuberculomas.63 On MRI, noncaseating tuberculomas are hypointense on T1W and T2W sequences, showing homogeneous postcontrast enhancement. Caseating granulomas are isointense to hypointense on T1W and T2W sequences, demonstrating peripheral rim enhancement, whereas the solid central component does not enhance. When present, this finding could be associated with cord edema/myelitis (Fig. 18). The presence of a center of necrosis is not typically seen in this presentation. Pott disease is considered an advanced stage of TB and requires aggressive systemic therapy.56 One of the complications of Pott disease that can be detected through imaging is the presence of syringomyelia. Multiple chemotherapy treatments are used to treat Pott disease, which include regimens that combine streptomycin, rifampicin, isoniazid, and ethambutol.64,65 The disease has a more favorable response to treatment the earlier it is diagnosed.45 Surgical intervention is indicated in patients with spinal instability due to vertebral body collapse and in those presenting with compression-related neurological symptoms.45,56 Imageguided interventional procedures are used in the diagnosis of the lesion and also in the drainage of the abscesses. Although most physicians classify Pott disease simply as early or late; multiple other classifications have been proposed for diagnosis and staging, but none are currently accepted. Oguz et al66 proposed a new classification based on 7 clinical and radiological criteria—abscess formation, disk degeneration, vertebral collapse, kyphosis, sagittal index, instability, and neurological problems, subdividing the disease in 3 types. Type 1A is disease affecting 1 vertebra and 1 level of disk degeneration, without an abscess, collapse, or neurological deficit. These patients should be treated with fine needle biopsy and drug treatment. Type 1B disease is characterized by an abscess formation with 1 or 2 levels of disk degeneration without vertebral collapse or neurological deficit, with the proposed treatment being drainage and debridement. Type 2 disease has vertebral collapse, abscess formation, and kyphosis, with the kyphotic

FIGURE 16. Spinal vertebral abscesses. A, Sagittal T2 image shows multiple round hyperintense intraosseous lesions (arrows) at T12, L3, and L5. These lesions are located in the superior-anterior corners of these vertebrae, under the anterior longitudinal ligament. B, Similar lesions identified at T5 and T8 also show a T2 hyperintense ring (arrows). C, Coronal T1 image shows hypointense lesions in the sacrum and right iliac bone (arrows). D, Round lucent vertebral body lesions on CT (arrows) consistent with bone abscesses. Courtesy of S. Chakraborty, MD, University of Ottawa, Canada. © 2014 Lippincott Williams & Wilkins

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deformity being stable with or without neurological deficit. The proposed treatment is anterior debridement and fusion, with surgical decompression for cases of collapse with neurological deficit. Type 3 cases show severe vertebral collapse and abscess formation, with unstable deformity. The treatment requires surgical decompression, correction of the deformity, and anterior debridement and fusion.

Management Boxer et al67 studied the course of healing of spinal TB in 26 patients and described how soft tissue masses increased in size up to 45 days after installment of the treatment and took approximately a year to resolve. Despite treatment, progressive loss of vertebral height was seen in almost 80% of patients. Half of the patients developed sclerosis in the first 5 months of treatment and took almost 2.5 years to go back to normal. Reduction of the disk space and vertebral fusion can be seen in 75% of the cases. The imaging differential diagnosis with pyogenic spondylitis is challenging. Jung et al68 found MR to help differentiate these 2 processes. Pott disease shows increased paraspinal signal

abnormalities, thin-walled abscess, and subligamentous spread to 3 or more levels. It also shows more involvement than pyogenic spondylodiscits of multiple vertebral bodies, mostly of the thoracic vertebrae. Other granulomatous processes that affect the spine should be taken into consideration; such as brucellosis, which tends to preserve the architecture of the vertebra independent of the involvement, with the development of smaller paraspinal abscesses than TB.69 Fungal diseases such as aspergillosis can also present with similar findings, with common prevertebral abscesses, but the disks will not be hyperintense on the T2-weighted images as in Pott disease.70,71

ROLE OF ADVANCED IMAGING Dynamic contrast-enhanced (DCE) MRI has been used in neoplastic lesions to quantify tumor angiogenesis in vivo. Recently, Gupta et al72,73 have performed DCE-MRI in 13 patients with brain tuberculoma and correlated the relative cerebral blood volume (rCBV) values of cellular and necrotic component with microvascular density (MVD) and vascular endothelial growth factor (VEGF). The rCBV of cellular portion significantly correlated with cellular fraction volume, MVD, and VEGF of the

FIGURE 17. Tuberculous myelitis and meningeal enhancement. A and B, Sagittal (A) and axial (B) T2 images show abnormal increased signal intensity of the midthoracic cord (arrows) in keeping with myelitis. C, Sagittal T1 postgadolinium image with fat saturation shows diffuse cauda equina and thecal sac meningeal and subarachnoid enhancement (arrows) outlining the spinal cord. Courtesy of J. Saini, MD, NIMHANS, Bangalore, India.

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FIGURE 18. Tuberculous myelitis and intramedullary tuberculomas. A, Sagittal T2 image shows diffuse thoracic spinal cord expansion from T1 to the conus and edema with syrinx formation down to T8-9 disk level (small arrows). Notice the hypointense tuberculoma at T9 to T11 (arrows). B, Sagittal midline T1 image of the thoracic spine shows diffuse cord expansion and low signal above the level of the tuberculoma (arrows). C, Sagittal midline thoracic spine gadolinium-enhanced T1 image at the same level demonstrates an intramedullary tuberculoma with peripheral enhancement in the lower thoracic spinal cord at T9 to T11 (lower 3 arrows). An additional enhancing focus is also noted along the posterior cord surface at T5 to T6 (upper arrow). Courtesy P. Hanagandi MD, University of Ottawa, Canada.

excised tuberculomas. Correlation among the rCBV, MVD, and VEGF confirmed that rCBV is a measure of angiogenesis in the cellular fraction of the brain tuberculoma. In a recent DCE-MRI study in brain tuberculoma, authors have reported a significant positive correlation between physiological indices (transfer constant and ve) and matrix metalloproteinase-9 expression (a marker of blood-brain barrier disruption) in excised tuberculoma. These parameters have been shown to help in the assessment of therapeutic response in tuberculoma. Diffusion tensor MRI (DTI) has been widely used for the detection of white matter abnormality in various clinical conditions. A recent serial DTI study has shown a strong negative correlation of matrix metalloproteinase-9 expression in excised tuberculoma with fractional anisotropy, linear anisotropy, and planar anisotropy and a significant direct correlation with spherical anisotropy. They have also reported significant © 2014 Lippincott Williams & Wilkins

increase in fractional anisotropy, linear anisotropy, and planar anisotropy along with significant decreased spherical anisotropy over time in patients who were serially followed-up with antitubercular therapy.74 These methods may be of value in the objective assessment of therapy and guide the physician in the modulation of therapy in these patients.

SUMMARY We have summarized the MRI features of CNS TB, which help in the diagnosis and objective assessment of therapeutic response in this condition and may become fatal if not recognized early. ACKNOWLEDGMENT The authors would like to thank Dr. Mauricio Castillo, Dr. Santanu Chakraborty, Dr. Satya Patro, Dr. Prasad Hanagandi, www.topicsinmri.com

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Central nervous system tuberculosis.

Tuberculosis (TB) has shown a resurgence in nonendemic populations in recent years and accounts for 8 million deaths annually in the world. Central ne...
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