Most cases of osteomyelitis secondary to Mycobacterium tuberculosis are hematogenous in origin, often from a pulmonary source; however, contiguous spread from adjacent structures is possible.1 After seeding by the organism of the vertebral end plate, the host’s immune response initiates the process of granuloma and caseous abscess formation. The initial step in this process is the local migration of polymorphonuclear leukocytes, followed by macrophages to the site of infection. Phagocytosis of the causative organism by the macrophages transforms them into epithelioid cells—large, pale cells with a sizable vesicular nucleus, plentiful cytoplasm, and indistinct cell margins. When multiple epithelioid cells fuse together, they form giant cells that are characteristic of this infection. Approximately 1 week after inoculation, lymphocytes migrate to the peripheral aspects of the infection to “wall off” the infected tissue. Subsequently, coagulation necrosis caused by the protein fraction of the tubercle bacilli takes place in the center of the lesion, leading to a soft, liquefied center—a caseating granuloma.2 However, if the infection is the result of an atypical causative organism such as Brucella, central necrosis often will not occur.2,3
Three major patterns of vertebral involvement have been described: peridiscal, central, and anterior.4 The peridiscal form, the most common type, begins adjacent to a single vertebral end plate and spreads peripherally to the adjacent intervertebral disk (Figure 1). Contiguous spread to an adjacent vertebra occurs as the infectious material tracks deep to the anterior longitudinal ligament. Because M tuberculosis does not produce proteolytic enzymes, the intervertebral disk is often less severely affected than it is with pyogenic infections. This sparing of the intervertebral disk space prevents the process of autofusion, which often occurs in pyogenic vertebral osteomyelitis.
The central variant type involves abscess formation in the middle of the vertebral body (Figure 2). These infections typically lead to significant vertebral body collapse, resulting in subsequent spinal deformity.
The anterior variant starts with a nidus of infection anterior to the vertebral body and posterior to the anterior longitudinal ligament (Figure 3). It then spreads underneath the anterior longitudinal ligament, leading to scalloping along the anterior aspect of multiple vertebral bodies and may result in an abscess that spans multiple vertebral levels.
Identification of at-risk patients is the first step in the evaluation of those with a suspected tuberculous infection. These patients include those who are immunocompromised (eg, patients with AIDS or a history of organ transplant); those with a history of travel to Asia, Africa, or South America; the homeless population; and those with known exposure to another person with a tuberculous infection, such as hospital, nursing, and homeless shelter employees. Specific symptoms of tuberculous spondylitis are variable; the most common symptom is back pain, which is most frequently located in the thoracic spine.1,5,6 In general, the symptoms associated with this type of infection are less severe and more insidious than those with a pyogenic infection (Table 1).6 Patients commonly experience malaise, night sweats, weight loss, and fevers; however, in severe or chronic untreated infections, patients may develop a kyphotic or gibbus deformity, cutaneous sinuses, and neurologic deficits.1,5,6 Although the exact prevalence of neurologic symptoms with tuberculous spondylitis is variable (10% to 61%),5 elderly patients are at an increased risk for neurologic deficits. Neurologic deficits may be caused by a worsening kyphotic deformity or by direct compression on the neural elements from an extension of the infectious material into the spinal canal.7
Serum testing for erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, and leukocyte count is frequently nonspecific in the case of tuberculous spondylitis. The white blood cell count is not necessarily elevated, and the ESR is normal in up to 25% of patients.4 Kim et al6 reported a white blood cell count >10,000/mm3 in 41.8% of patients with pyogenic vertebral osteomyelitis compared with 19.1% of patients with tuberculous infections. Similarly, a CRP level >5 mg/dL (58.2% versus 27.7%; P < 0.01) and ESR >40 mm/h (84.4% versus 66.0%; P = 0.01) were more common in pyogenic than tuberculous infections, respectively.6
Tests specific for tuberculosis, such as the tuberculin skin test, allow physicians to rapidly identify patients who have been exposed to tuberculosis. The tuberculin skin test involves injecting 0.1 mL of tuberculin purified protein derivative intradermally, generally on the forearm. The test is read between 48 and 72 hours after placement of the purified protein derivative. A positive test presents as erythema and an area of induration >5 to 15 mm, depending on the patient’s level of immune function and risk for exposure to tuberculosis. However, interpretation of the test is affected by significant inter-reader variability, false-positive results secondary to certain vaccinations, and false-negative results in immunocompromised hosts.5,8 Consequently, the interferon gamma release assay (IGRA) is used frequently.8 This blood test identifies interferon-γ, which is released by monocytes once specific antigens of M tuberculosis are encountered. This test has multiple advantages, including availability of results within 24 hours and the need for only a single patient visit to conduct the test. Additionally, because no antigen is injected into the body, the IGRA does not boost the response to subsequent tests. The IGRA also has been shown to be more specific than, and equally as sensitive as, a tuberculin skin test.9,10
Thoracolumbar and chest radiographs are used in the initial evaluation of a granulomatous spine infection. Chest radiographs of patients with active tuberculosis may demonstrate segmental or lobar infiltrates with ipsilateral hilar or mediastinal lymphadenopathy. Patients may also demonstrate a pleural effusion. The pattern of spinal involvement on radiographs may demonstrate osteolytic changes in affected vertebrae with or without involvement of the disk space. Although the disk is typically spared in M tuberculosis infections, in late stages of the disease, the disk may eventually lose structural integrity because of end plate collapse, leading to a kyphotic spinal deformity (Figure 4).
MRI is frequently used in the diagnosis of tuberculous spondylitis. T1-weighted images may show homogenous low signal intensity in the affected vertebral bodies with possible visualization of subligamentous spread between the vertebrae. T2-weighted images are likely to demonstrate heterogeneous high signal intensity in a subligamentous distribution. Occasionally, associated intraspinal and paraspinal masses may be seen adjacent to the affected vertebral bodies. Frequently, intravenous gadolinium contrast is added to assist in the diagnosis of infectious processes of the spine. In particular, tuberculous infections may demonstrate thin-walled abscesses with peripheral enhancement following the administration of gadolinium. Distinguishing between a bacterial and tuberculous infection is challenging from MRI alone. However, multiple MRI findings have been shown to correlate more consistently with a tuberculous infection, including a well-defined abnormal paraspinal signal, thin and smooth abscess walls, and the presence of paraspinal or intraspinal abscesses on T2-weighted and fat-suppressed T1-weighted axial and sagittal images.11
Despite extensive laboratory work and advanced imaging, differentiating a tuberculous spondylitis from a pyogenic or neoplastic process may still prove to be difficult. Because treatment can vary drastically depending on the etiology of the lesion, an accurate diagnosis is paramount. Consequently, in the case of an uncertain diagnosis, it is necessary to biopsy the lesion, preferably with CT-guided aspiration.12,13 The diagnostic yield for a percutaneous aspiration or biopsy is reported to be between 42% and 76%.8 In the case of a nondiagnostic CT-guided aspiration, open biopsy may be considered. When tuberculous spondylitis is in the differential diagnosis, the biopsied sample should undergo microscopic and pathologic evaluation, including aerobic, anaerobic, and tuberculous-specific culture, acid-fast bacillus (AFB) smear microscopy, polymerase chain reaction (PCR) testing, and routine pathology.8,13 Microscopy using acid-fast staining is time consuming and should be considered positive only when 5 × 103 AFB/mL are identified.14 Diagnosis of Mycobacterium by culture has traditionally been performed on a solid Lowenstein-Jensen medium (requiring 8 weeks for final result), but this has been greatly improved with the advent of broth cultures, such as the Middlebrook medium, which has decreased the time to diagnosis (average, 9.5 ± 4.4 days).8,15 More recently, PCR testing has been used that can provide a diagnosis within as little as 6 hours, with a sensitivity of 75% and a specificity >99%.16,17 The presence of caseating granulomas on histologic analysis also leads to a diagnosis of Mycobacterium.8
Because of the difficulty in establishing a definitive diagnosis from symptoms early in the disease process, patients are often started on anti-inflammatory medications, physical therapy, and/or a lumbar brace before a definitive diagnosis is made.18-20 A high level of clinical suspicion is paramount in establishing a timely diagnosis, which is essential for effective management of tuberculous spondylitis.
Once the diagnosis of tuberculous spondylitis is made, the initial treatment regimen in industrialized nations for patients without neurologic injury or spinal instability is an aggressive pharmacologic treatment with rifampin, isoniazid, ethambutol, and pyrazinamide for 6 to 18 months.5,21 The response to medical treatment is monitored during the treatment period with serial clinical and radiographic evaluations.
Although pharmacologic treatment is often the first line of therapy for tuberculous spondylitis, antibiotic resistance is an emerging problem, with up to 25% of patients developing multidrug-resistant (MDR) tuberculosis secondary to inappropriate drug therapy (either insufficient length of treatment or an insufficient pharmacologic regimen).22 At present, there is a paucity of literature to guide treatment of MDR tuberculosis in the spine. Rajasekaran and Khandelwal21 proposed five principles of management of MDR tuberculous spondylitis: (1) every patient with suspected MDR tuberculosis should be cultured to establish the antibiotic sensitivities; (2) if there is concern that the infection is not responding to initial medical management, adding just one additional antibiotic medication should be avoided; (3) a minimum of four previously unused medications should be added, such as streptomycin, pyrazinamide, ethambutol, rifampicin, cycloserine, isonicotinyl, hydrazine, and linezolid; (4) an injectable aminoglycoside should be used for at least 2 months; and (5) the entire course of pharmacotherapy should last at least 24 months.
In the largest study on MDR tuberculous spondylitis, Pawar et al23 reported on the treatment of 25 patients; the average patient received six different medications for at least 2 years, and 50% experienced adverse effects from the pharmacologic therapy. Despite aggressive medical treatment, 16% required surgical intervention for mechanical instability, and 24% required continued pharmacologic treatment 2 years after diagnosis. By comparison, 6 to 9 months of pharmacotherapy can lead to resolution of the infection in up to 93% of patients with non-MDR tuberculous spondylitis.5 Despite the emergence of MDR strains, the aggressive and efficacious medical management of tuberculosis has resulted in a worldwide decrease in the mortality rate by 40% since 1990 and an annual incidence of 1.3% since 2002.24
Although pharmacotherapy is the first line of treatment in patients with tuberculous spondylitis, a recent meta-analysis concluded that patients with neurologic deficit, those who fail medical management, and patients with instability/deformity of the spine may benefit from surgical intervention.25 The exact role for surgery in patients with minor neurologic change is unclear, but patients with a significant neurologic deficit have improved outcomes with surgery.26 Lifeso et al26 reported that 94% of patients undergoing anterior decompression and fusion experienced resolved neurologic deficits, compared with 79% of patients treated without surgery.
In a systematic review of 124 publications, Jain and Dhammi27 further clarified the issue by identifying three circumstances in which surgery was clearly indicated: with (1) an MRI displaying compression of neural structures by granulation tissue with cord edema or myelomalacia; (2) progressive neurologic deficit; and (3) an unstable spine, which was defined as involvement of both the anterior and posterior column, a pathologic fracture through the lesion, or “severe” or increasing kyphosis.
In patients who require surgical intervention for neurologic decline or spinal cord compression, the decompression should involve débridement of all purulent material, granulation tissue, caseous tissue, sequestered bone fragments, and any bone that is compressing neural elements. Inflamed and demineralized bone that is not compressing the neural elements does not need to be débrided because it will reconstitute following treatment with antitubercular medications.27
One of the challenges facing surgeons who treat patients with tuberculous spondylitis is the management of spinal instability. These patients require treatment that involves not only eradication of the infection but also correction/prevention of angular deformity. To our knowledge, risk factors for the development of kyphosis have been elucidated only in children <10 years of age. These factors were clarified by Rajasekaran28,29 and include pretreatment kyphosis >30°, a junctional segment (cervicothoracic or thoracolumbar) lesion, and the presence of “spine at risk” signs—that is, separation of the facet joints, retropulsion, lateral translation, or toppling. Toppling is identified when a line drawn along the anterior surface of the normal caudal vertebra intersects above the middle of the anterior wall of the cranial vertebral body (Figure 5). Consequently, consideration should be given to surgical intervention early in the disease process in patients at risk for the development of a kyphotic deformity.
Appropriate surgical planning and technique for granulomatous lesions is critical for optimal long-term stability and outcome. When the infection compromises the anterior column of the spine, the surgical plan should involve direct resection of the lesion and reconstruction of the spine. Following surgical débridement, placement of a structural graft is recommended. Graft sources may include iliac crest or rib autograft; femoral, humeral, or fibular allograft; or titanium cages filled with autogenous or allogeneic cancellous bone. Surgeons should avoid isolated posterior decompressions in this situation because a laminectomy may destabilize the only structurally sound portion of the spinal column at that level, leading to a kyphotic deformity.30
These principles were incorporated into the “Hong Kong technique,” which was the first widely accepted and successful technique used for the surgical treatment of tuberculous spondylitis.31 Through an anterior approach, débridement of infected bone and decompression of the spinal canal is performed; this is followed by correction of the kyphotic deformity using structural grafting. Upadhyay et al32 followed 112 patients for 15 years after each underwent an isolated débridement or a débridement and structural grafting (ie, the Hong Kong technique). Although there was no difference in neurologic function between the two groups, alignment was significantly improved in the patients who underwent structural grafting. All patients who had undergone structural grafting for a lumbar infection had normal lordosis at 15 years, compared with only 63% of patients who had undergone an isolated débridement.32
In addition to anterior decompression and structural grafting, adding a posterior spinal fusion with instrumentation is safe and efficacious in the treatment of tuberculous spondylitis. Oga et al33 demonstrated that Mycobacteria have a limited ability to colonize a stainless steel disk. Furthermore, in a review of more than 100 case series involving >1,000 patients who underwent instrumentation in the setting of a tuberculous spondylitis,34 the use of instrumentation was critical in preventing complications that are common in patients after an extensive débridement.
More recently, some surgeons have advocated for a posterior-only approach using newer surgical techniques and instrumentation.35-37 Wang et al35 compared clinical outcomes in 55 patients who underwent an anterior débridement with posterior stabilization and 60 who had a circumferential decompression and fusion through an isolated posterior approach. There was no difference in the rate of new neurologic deficit or neurologic recovery; however, there was a significant (P < 0.05) improvement in postoperative kyphosis in the anterior débridement group compared with the all-posterior group in the thoracolumbar region (4.1° of kyphosis postoperatively versus 14.7°, respectively) as well as the lumbar region (3.8° of postoperative kyphosis versus 7.8°, respectively). The posterior-only group did have a significant (P < 0.05) decrease in surgical time, estimated blood loss, and length of hospital stay (Figure 6). Using either an all-posterior approach to address the anterior and posterior columns of the spine versus separate anterior and posterior approaches appears to be acceptable for obtaining the consistent surgical goals of adequate decompression, excision of the pathologic lesion, and reconstruction and stabilization of the spine.
In addition to M tuberculosis, many other organisms have the ability to form granulomatous infections of the spine (Table 2). These organisms are frequently classified as atypical organisms and include bacterial, fungal, and parasitic organisms. Bacterial organisms include Brucella, Actinomyces, and Nocardia. Fungal infections may include candidiasis, aspergillosis, coccidioidomycosis, blastomycosis, and cryptococcosis. Parasitic organisms include Echinococcus and Taenia solium, (the causative organism in neurocysticercosis).
Brucellosis spondylitis is the most commonly reported cause of atypical spondylitis. It is a chronic granulomatous infection that is caused by one of four Brucella species (B melitensis, B abortus, B suis, B canis). It is often transmitted through the ingestion of unpasteurized milk products, although airborne transmission is possible through inhalation of contaminated aerosolized particles. Although relatively rare in North America, Brucella is more prevalent in the Mediterranean region, Arabian Peninsula, Near East, and Central and South America.38 Systemic brucellosis often presents with a waxing and waning fever; a pathognomonic malodorous perspiration also may be present. Involvement of the musculoskeletal system is the most common complication, and this can occur as peripheral arthritis, sacroiliitis, or spondylitis.38 Brucellosis spondylitis occurs in up to 15% of patients with brucellosis, and it most commonly affects a single level in the lumbar spine.39-41
Diagnosis of brucellosis spondylitis is often delayed, with an average time to diagnosis of 10 weeks;40 the patient often reports vague, nonspecific symptoms such as back or neck pain, fatigue, fever, weight loss, loss of appetite, sweats, or arthralgia.40 Neurologic symptoms are more common in patients with cervical disease (71%) compared with lumbar disease (21%).42
Compared to patients with brucellosis without spondylitis, patients with spondylitis are significantly (P < 0.05) older (average, 54 years compared with 34 years), have a delay in diagnosis (average, 72 days compared with 39 days), and have an elevated ESR (average, 40.9 compared with 20.3).40 In patients with suspected brucellosis spondylitis, additional laboratory tests are beneficial in confirming the diagnosis, such as a Brucella antibody titer of 1:160 (sensitivity between 68% and 91%),40,41 and the Rose Bengal test (sensitivity of 92.9%).43 Blood cultures are often taken, but they are positive in <50% of patients with brucellosis spondylitis. Because of the specificity of the laboratory evaluation, a biopsy is required in only 5% of patients with suspected brucellosis spondylitis.44 Classic radiographic features of brucellosis spondylitis include involvement of the lower lumbar spine, maintained vertebral structure in spite of diffuse osteomyelitis, involvement of the disk space, and minimal involvement of the paraspinal soft tissue45,46 (Figure 7).
Like tuberculous spondylitis, the first line of treatment in patients with brucellosis spondylitis is antibiotic therapy. No single antibiotic regimen has been established in the literature; proposed treatment regimens range from doxycycline/ciprofloxacin to doxycycline/rifampicin/streptomycin.39 Although the ideal treatment length is uncertain, it is clear that patients treated for 3 months relapse less than do patients treated for 6 weeks.39 Because excellent results have been demonstrated with pharmacologic management, surgical intervention should be reserved only for patients who fail pharmacologic management or who have progressive neurologic deterioration.
Actinomycosis is caused by a number of different species of Actinomyces, a genus of slow-growing, anaerobic, gram-positive bacteria that commonly live in the human oropharynx, gastrointestinal tract, and urogenital tract as normal flora. Although the bacteria are unable to penetrate the intact mucosa, once the mucosa has been damaged, the bacteria can invade the tissue and form an abscess. It may also cause sinus tracts, fistulae, and tissue fibrosis.47 Once this has occurred, spread to the skeletal system is possible and most often occurs as a result of direct extension of the abscess without regard for anatomic barriers.48 Because oral cervicofacial actinomycosis accounts for >50% of all reported cases, and because the spread of the disease is often from direct extension, most spinal infections occur in the cervical and thoracic spine.47,49,50
Because of the rarity of actinomycosis spondylitis, diagnosis is frequently delayed, and there is a paucity of literature available to establish a definitive treatment algorithm; however, multiple case reports of patients with epidural compression secondary to actinomycosis spondylitis have demonstrated that treatment with a prolonged course of intravenous penicillin G can lead to resolution of the infection and improved neurologic function.51,52
Nocardiosis is caused by number of different species of Nocardia, a genus of aerobic, gram-positive bacteria that are found worldwide in soil, decomposing organic matter, and fresh or salt water.53 It is an opportunistic infection, with up to two thirds of infected patients who are immunocompromised.53 Although the infection most often begins in the respiratory system, two or more organ systems are involved in 21% of cases.53 Additionally, the prognosis for nocardiosis is significantly worse than that for other granulomatous infections, with a mortality rate of up to 31%.54
Graat el al55 identified 11 cases of reported vertebral osteomyelitis secondary to nocardiosis; 4 cases were in the lumbar spine, 3 were in the thoracic spine, 2 were in the cervical spine, 1 was in the sacrum, and 1 involved vertebrae in the cervical, thoracic, and lumbar spines. In these cases, symptoms were nonspecific, including back pain, fevers, productive cough, malaise, weight loss, and weakness. However, in contrast to the good results of pharmacologic treatment of actinomycosis, >70% of patients with nocardiosis spondylitis required combined surgical and pharmacologic treatment.
Granulomatous infections of the spine often present in an insidious and frequently delayed fashion. However, the key to successful management of these spinal infections is a timely and accurate diagnosis. Symptoms are generally nonspecific, and the treating surgeon must maintain an awareness of the possibility of a granulomatous infection, particularly in at-risk patients. Once suspected, organism-specific tests are indicated (eg, the tuberculin skin test), and a biopsy is sometimes necessary. Once a spinal infection is diagnosed, medical management is an integral part of the treatment of this disease process. Surgery is frequently not necessary and is generally reserved for cases of neurologic compression with associated functional deficit, spinal instability, or spinal deformity.
Evidence-based Medicine: Levels of evidence are described in the table of contents. In this article, reference 32 is a level I study. References 9, 10, 15, 25, 31, 35, and 42 are level II studies. References 1, 11, 14, 16, 17, 27, 39, 43, and 44-46 are level III studies. References 6, 12, 13, 19, 20, 23, 26, 28, 33, 34, 36, 37, 40, 41, 48-52, 54, and 55 are level IV studies. Reference 2-5, 7, 18, 22, 29, 38, 47, and 53 are level V expert opinion.
References printed in bold type are those published within the past 5 years.
1. Fuentes Ferrer M, Gutiérrez Torres L, Ayala Ramírez O, Rumayor Zarzuelo M, del Prado González N: Tuberculosis of the spine: A systematic review of case series. Int Orthop 2012;36(2):221–231.
2. Agrawal V, Patgaonkar PR, Nagariya SP: Tuberculosis of spine. J Craniovertebr Junction Spine 2010;1(2):74–85.
3. Williams GT, Williams WJ: Granulomatous inflammation: A review. J Clin Pathol 1983;36(7):723–733.
4. Tay BK, Deckey J, Hu SS: Spinal infections. J Am Acad Orthop Surg 2002;10(3):188–197.
5. Khoo LT, Mikawa K, Fessler RG: A surgical revisitation of Pott distemper of the spine. Spine J 2003;3(2):130–145.
6. Kim CJ, Song KH, Jeon JH, et al.: A comparative study of pyogenic and tuberculous spondylodiscitis. Spine (Phila Pa 1976) 2010;35(21):E1096–E1100.
7. Boachie-Adjei O, Squillante RG: Tuberculosis of the spine. Orthop Clin North Am 1996;27(1):95–103.
8. Colmenero JD, Ruiz-Mesa JD, Sanjuan-Jimenez R, Sobrino B, Morata P: Establishing the diagnosis of tuberculous vertebral osteomyelitis. Eur Spine J 2013;22(suppl 4):579–586.
9. Rangaka MX, Wilkinson KA, Glynn JR, et al.: Predictive value of interferon-γ release assays for incident active tuberculosis: A systematic review and meta-analysis. Lancet Infect Dis 2012;12(1):45–55.
10. Dosanjh DP, Hinks TS, Innes JA, et al.: Improved diagnostic evaluation of suspected tuberculosis. Ann Intern Med 2008;148(5):325–336.
11. Harada Y, Tokuda O, Matsunaga N: Magnetic resonance imaging characteristics of tuberculous spondylitis vs. pyogenic spondylitis. Clin Imaging 2008;32(4):303–309.
12. al-Mulhim FA, Ibrahim EM, el-Hassan AY, Moharram HM: Magnetic resonance imaging of tuberculous spondylitis. Spine (Phila Pa 1976) 1995;20(21):2287–2292.
13. Jain R, Sawhney S, Berry M: Computed tomography of vertebral tuberculosis: Patterns of bone destruction. Clin Radiol 1993;47(3):196–199.
14. Watterson SA, Drobniewski FA: Modern laboratory diagnosis of mycobacterial infections. J Clin Pathol 2000;53(10):727–732.
15. Queipo-Ortuño MI, Colmenero JD, Bermudez P, Bravo MJ, Morata P: Rapid differential diagnosis between extrapulmonary tuberculosis and focal complications of brucellosis using a multiplex real-time PCR assay. PLoS One 2009;4(2):e4526.
16. Shah S, Miller A, Mastellone A, et al.: Rapid diagnosis of tuberculosis in various biopsy and body fluid specimens by the AMPLICOR Mycobacterium tuberculosis polymerase chain reaction test. Chest 1998;113(5):1190–1194.
17. Cheng VC, Yam WC, Hung IF, et al.: Clinical evaluation of the polymerase chain reaction for the rapid diagnosis of tuberculosis. J Clin Pathol 2004;57(3):281–285.
18. McLain RF, Isada C: Spinal tuberculosis deserves a place on the radar screen. Cleve Clin J Med 2004;71(7):537–539, 543-549.
19. Mehta JS, Bhojraj SY: Tuberculosis of the thoracic spine: A classification based on the selection of surgical strategies. J Bone Joint Surg Br 2001;83(6):859–863.
20. Moon MS, Moon YW, Moon JL, Kim SS, Sun DH: Conservative treatment of tuberculosis of the lumbar and lumbosacral spine. Clin Orthop Relat Res 2002;398:40–49.
21. Rajasekaran S, Khandelwal G: Drug therapy in spinal tuberculosis. Eur Spine J 2013;22(suppl 4):587–593.
22. Prasad R: Management of multi-drug resistant tuberculosis: Practitioner’s view point. Indian J Tuberc 2007;54(1):3–11.
23. Pawar UM, Kundnani V, Agashe V, Nene A, Nene A: Multidrug-resistant tuberculosis of the spine: Is it the beginning of the end? A study of twenty-five culture proven multidrug-resistant tuberculosis spine patients. Spine (Phila Pa 1976) 2009;34(22):E806–E810.
24. Suk KS, Kim KT, Lee SH, Park SW: Prevertebral soft tissue swelling after anterior cervical discectomy and fusion with plate fixation. Int Orthop 2006;30(4):290–294.
25. Zhang X, Ji J, Liu B: Management of spinal tuberculosis: A systematic review and meta-analysis. J Int Med Res 2013;41(5):1395–1407.
26. Lifeso RM, Weaver P, Harder EH: Tuberculous spondylitis in adults. J Bone Joint Surg Am 1985;67(9):1405–1413.
27. Jain AK, Dhammi IK: Tuberculosis of the spine: A review. Clin Orthop Relat Res 2007;460(460):39–49.
28. Rajasekaran S: The natural history of post-tubercular kyphosis in children: Radiological signs which predict late increase in deformity. J Bone Joint Surg Br 2001;83(7):954–962.
29. Rajasekaran S: Kyphotic deformity in spinal tuberculosis and its management. Int Orthop 2012;36(2):359–365.
30. Rand C, Smith MA: Anterior spinal tuberculosis: Paraplegia following laminectomy. Ann R Coll Surg Engl 1989;71(2):105–109.
31. A controlled trial of anterior spinal fusion and débridement in the surgical management of tuberculosis of the spine in patients on standard chemotherapy: A study in Hong Kong. Br J Surg 1974;61(11):853–866.
32. Upadhyay SS, Sell P, Saji MJ, Sell B, Hsu LC: Surgical management of spinal tuberculosis in adults: Hong Kong operation compared with debridement surgery for short and long term outcome of deformity. Clin Orthop Relat Res 1994;302:173–182.
33. Oga M, Arizono T, Takasita M, Sugioka Y: Evaluation of the risk of instrumentation as a foreign body in spinal tuberculosis: Clinical and biologic study. Spine (Phila Pa 1976) 1993;18(13):1890–1894.
34. Jain AK, Jain S: Instrumented stabilization in spinal tuberculosis. Int Orthop 2012;36(2):285–292.
35. Wang X, Pang X, Wu P, Luo C, Shen X: One-stage anterior debridement, bone grafting and posterior instrumentation vs. single posterior debridement, bone grafting, and instrumentation for the treatment of thoracic and lumbar spinal tuberculosis. Eur Spine J 2014;23(4):830–837.
36. Wu P, Luo C, Pang X, Xu Z, Zeng H, Wang X: Surgical treatment of thoracic spinal tuberculosis with adjacent segments lesion via one-stage transpedicular debridement, posterior instrumentation and combined interbody and posterior fusion: A clinical study. Arch Orthop Trauma Surg 2013;133(10):1341–1350.
37. Sun L, Song Y, Liu L, Gong Q, Zhou C: One-stage posterior surgical treatment for lumbosacral tuberculosis with major vertebral body loss and kyphosis. Orthopedics 2013;36(8):e1082–e1090.
38. Pappas G, Akritidis N, Bosilkovski M, Tsianos E: Brucellosis. N Engl J Med 2005;352(22):2325–2336.
39. Pappas G, Seitaridis S, Akritidis N, Tsianos E: Treatment of brucella spondylitis: Lessons from an impossible meta-analysis and initial report of efficacy of a fluoroquinolone-containing regimen. Int J Antimicrob Agents 2004;24(5):502–507.
40. Solera J, Lozano E, Martínez-Alfaro E, Espinosa A, Castillejos ML, Abad L: Brucellar spondylitis: Review of 35 cases and literature survey. Clin Infect Dis 1999;29(6):1440–1449.
41. Yilmaz E, Parlak M, Akalin H, et al.: Brucellar spondylitis: Review of 25 cases. J Clin Rheumatol 2004;10(6):300–307.
42. Colmenero JD, Cisneros JM, Orjuela DL, et al.: Clinical course and prognosis of Brucella spondylitis. Infection 1992;20(1):38–42.
43. Ruiz-Mesa JD, Sánchez-Gonzalez J, Reguera JM, Martín L, Lopez-Palmero S, Colmenero JD: Rose Bengal test: Diagnostic yield and use for the rapid diagnosis of human brucellosis in emergency departments in endemic areas. Clin Microbiol Infect 2005;11(3):221–225.
44. Colmenero JD, Jiménez-Mejías ME, Sánchez-Lora FJ, et al.: Pyogenic, tuberculous, and brucellar vertebral osteomyelitis: A descriptive and comparative study of 219 cases. Ann Rheum Dis 1997;56(12):709–715.
45. al-Shahed MS, Sharif HS, Haddad MC, Aabed MY, Sammak BM, Mutairi MA: Imaging features of musculoskeletal brucellosis. Radiographics 1994;14(2):333–348.
46. Sharif HS, Aideyan OA, Clark DC, et al.: Brucellar and tuberculous spondylitis: Comparative imaging features. Radiology 1989;171(2):419–425.
47. Wong VK, Turmezei TD, Weston VC: Actinomycosis. BMJ 2011;343:d6099.
48. Lewis RP, Sutter VL, Finegold SM: Bone infections involving anaerobic bacteria. Medicine (Baltimore) 1978;57(4):279–305.
49. Honda H, Bankowski MJ, Kajioka EH, Chokrungvaranon N, Kim W, Gallacher ST: Thoracic vertebral actinomycosis: Actinomyces israelii and Fusobacterium nucleatum. J Clin Microbiol 2008;46(6):2009–2014.
50. Cope VZ: Actinomycosis of bone with special reference to infection of vertebral column. J Bone Joint Surg Br 1951;33(2):205–214.
51. Eftekhar B, Ketabchi E, Ghodsi M, Ahmadi A: Cervical epidural actinomycosis: Case report. J Neurosurg 2001;95(suppl 1)132–134.
52. Vernon V, Pranav G, Palande D: Actinomycosis of the neck causing cervical epidural cord compression: ‘A case report and review of literature.’ Spinal Cord 2007;45(12):787–789.
53. Wilson JW: Nocardiosis: Updates and clinical overview. Mayo Clin Proc 2012;87(4):403–407.
54. Torres OH, Domingo P, Pericas R, Boiron P, Montiel JA, Vázquez G: Infection caused by Nocardia farcinica: Case report and review. Eur J Clin Microbiol Infect Dis 2000;19(3):205–212.
55. Graat HC, Van Ooij A, Day GA, McPhee IB: Nocardia farcinica spinal osteomyelitis. Spine (Phila Pa 1976) 2002;27(10):E253–E257.