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(i) Tuberculosis of the spine: current views in diagnosis, management, and setting a global standard
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(i) Tuberculosis of the spine: current views in diagnosis, management, and setting a global standard*
The emergence of HIV/AIDS has significantly increased the incidence of disseminated Mycobacterium avium complex infection, which now occurs almost exclusively in patients with CD4 T-lymphocyte counts below 100 cells per mm.2,3,5,6 Apart from the spread of HIV/AIDS, the recent resurgence of chemoresistant variants of Mycobacterium tuberculosis poses a further problem and has raised great concerns worldwide. Overall the prevalence of osteoarticular TB is likely to rise, indicating the need to prepare for a re-emergence in the coming years.2,6 Osteoarticular TB occurs in approximately 20% of all extrapulmonary cases, and the spine is involved in 50% of these patients.14 However, in HIV-positive patients with TB, approximately 60% develop skeletal disease compared with 3e5% of HIV-negative patients.1 Spinal TB is the most dangerous form of osteoarticular TB causing bone destruction of the vertebral body, spinal deformity, and possible paraplegia and pulmonary insufficiency secondary to deformity of the thoracic cage.1,2,5,6 When the body of the spine and the neural arch are involved, particularly in children, translational instability of the affected spine with anterior or lateral vertebral translation may occur and the resultant kyphoscoliotic deformity poses a risk of spinal cord compression to the patient.12e19 Despite recent advances in the diagnosis and management of spinal TB there remains a number of unaddressed issues of significant clinical importance.5 For example, surgical treatment is currently indicated only for the complicated form of spinal TB; however non-complicated and complicated classifications of spinal TB have not yet been clearly defined. This paper seeks to address these issues, which include newer diagnostic techniques, non-culture laboratory methods, immunosuppressant drug use,19,20,24e30 surgical options for spinal deformity and associated neural involvement. Furthermore, a treatment algorithm is suggested, which may help to improve treatment outcomes and reduce complications (Figure 1).
Myung-Sang Moon Sung-Soo Kim Hanlim Moon
Abstract Spinal tuberculosis (TB) is the most common form of osteoarticular TB occurring in approximately half of all cases. It is also the most dangerous form, potentially causing paralysis, permanent neurological deficits and severe deformity. There has been a resurgence of TB over the last decade. This is mostly due to increased host susceptibility from the growing number of immunocompromised patients secondary to human immunodeficiency virus and acquired immunodeficiency syndrome, the wider use of immunosuppressant agents, the ageing population, and an increasing number of chronically debilitated patients. Although a minor factor, the recent reemergence of multi-drug resistant variants of Mycobacterium tuberculosis hints at a possible further resurgence of TB in the coming years. Individualized treatment according to broad-spectrum management is essential for recovery. This article discusses the immunology, clinical manifestations, diagnosis, and medical and surgical treatments of spinal TB.
Keywords diagnosis; management; spine; tuberculosis
Introduction Immunity and tuberculosis
Tuberculosis (TB) remains an urgent global health problem. In 2009, approximately 9.4 million new cases of TB were identified worldwide resulting in 1.7 million deaths in that year. Ninety-five percent of these patients are in the developing world. According to the World Health Organization, each year 1.3 million new cases of TB are diagnosed in China.1e6 In sub-Saharan African countries, the number of reported TB cases has more than doubled because of the spread of human immunodeficiency virus and acquired immunodeficiency syndrome (HIV/AIDS).7e13
Following exposure to M. tuberculosis, some individuals (approximately 10%) develop active TB, while most do not. It is unclear what factors determine the development of active disease, though the condition of the patient’s immune system is thought to be closely related.6,7 Many patients are predisposed to osteoarticular TB, such as the elderly and malnourished, those with agammaglobulinaema, diabetes mellitus, HIV infection, malignancy, renal failure, substance abuse and those undergoing longterm treatment with chemotherapeutic and antirheumatic agents (e.g., corticosteroids, methotrexate, tumour necrosis factor [TNF]a blocking agents, and B-cell depleting therapeutic agents).23e25 The immune response to M. tuberculosis is a lymphoproliferative defence response to antigen or mitogen stimulation, and T-cell mediated cellular immunity is an important factor. In fact, it has been widely used as an in vitro correlate of cell-mediated immunity. There is an imbalance between helper (H) and suppressor (S) T cells in the pathogenesis of TB in humans. The H/S ratio in extrapulmonary TB is lower than in pulmonary TB (1.06 0.44 vs 1.64 0.92).6 Most antirheumatic agents exert their effects through humoral and cellular levels of immune system and marrow suppression and the TNF-a blocking agents inhibit lymphocyte and macrophage activity.6,7,20
*
No benefits in any form have been received from a commercial party related directly or indirectly to the subject of this article. Myung-Sang Moon MD PhD FACS Professor, Department of Orthopedic Surgery, Cheju Halla General Hospital, Jeju, Korea; Director, Moon-Kim’s Institute of Orthopedic Research, Seoul, Korea. Conflicts of interest: none. Sung-Soo Kim MD PhD Orthopaedicc Consultant, Department of Orthopedic Surgery, Cheju Halla General Hospital, Jeju, Korea. Conflicts of interest: none. Hanlim Moon MD PhD CEO Senior Medical Director, CURENCARE Research, Seoul, Korea. Conflicts of interest: none.
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Figure 1 Treatment algorithm for spinal tuberculosis.
Behavioural characteristics of M. tuberculosis
viewpoints and the patient’s neurological state and do not address the effect of residual deformity upon the remaining mobile segments. Thus, terms such as d early and late; early, moderate, and advanced; kyphotic and non-kyphotic; and stage I, II, and III d have been used in staging the severity of disease, as has the percentage of vertebral body loss (Table 1). A satisfactory staging system to include all of these characteristics is still awaited.
Understanding the nature and growth of M. tuberculosis and its response to chemotherapy and biomaterial implants is vital before determining any treatment plan.33,34 M. tuberculosis presents in a free-floating planktonic form, producing minimal adhesion molecules and slime and occasionally becoming dormant. Because of its relatively slow replication rate, antituberculous chemotherapy given intermittently is as effective as daily administration.1,2,6 There has been concern that the use of the biomaterials (titanium cage, screws and rods, polymethylmethacrylate bone cements and stainless steel or ceramic cups) in the tuberculous lesions may cause biomaterial-centred infection and would hinder healing or that the use of such implants would cause the arrested or quiescent infection to flare up.36e40 However, M. tuberculosis has shown little tendency to adhere to implants and they can be safely used in tuberculous lesions.31,32,34,35 In HIV-positive patients, however, the use of biomaterials in such infected foci is inappropriate because mixed infection with pyogenic bacteria is inevitable.6,17,19e22
Clinical manifestations Common symptoms of TB of the spine are malaise, loss of appetite, weight loss and night sweats. Rarely, neurological deficits will present as the first symptom. The involved spine is usually stiff and painful with movement, and back muscle spasms may be present as well as a localized humpback. Relaxation of muscle spasms at night allow for movement between inflamed surfaces of the spine, and patients occasionally cry out in pain (night cries) during sleep. A cold abscess and/or sinus may be present, and a small gibbus may be detected on palpation. The symptoms of TB are often insidious even during the active stage; therefore many of these signs and symptoms may be absent in early stages.
Classification of tuberculosis There is currently no universally accepted staging system for TB, although several have been introduced.6,8,26,27 These classification systems have been based upon the stage of disease, and do not help clinicians in the selection of the most appropriate management protocol. They are mostly related to aesthetic
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Diagnosis To ensure proper treatment and improve prognosis, an accurate diagnosis of TB should be made at the patient’s initial
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Staging summary of spinal tuberculosis6,29,47 Disease progress
Size of lesion
Deformity
Disease advancement (stages) Stage I: minimally (very early) Stage II: early Stage III: relatively (moderately) Stage IV: far advanced
Degree of body destructive Loss <20% (2/10) 20e50% 51e100% 101e200%
Degree of kyphosisa 12.2 12.2e22.25 22.26e39.0 39.1e72.5
a
Percentage and degree of kyphosis in cases of conservative treatment are calculated by Rajasekaran’s formula (Y ¼ 5.5 þ 30.5 degree of body destruction).11,37
Table 1
bacilli, lymphocytes secrete IFN-g making the extracorporeal IFN-g test particularly useful for latent TB. There are reports that T-SPOT is more sensitive than TST in immunocompromised patients. However, a disadvantage of these 23assays is that they can detect TB infection, but they cannot differentiate latent TB from active TB. The molecular diagnostic test, PCR, amplifies the DNA of M. tuberculosis and the results can be available within hours. This is an advantage, allowing effective and prompt treatment. PCR DNA amplification of M. Tuberculosis has been used as a marker to monitor response to treatment and been shown to provide rapid information on drug resistance and clonality in epidemiological investigation of outbreaks.
presentation. Therefore, physicians and surgeons must exercise a high index of suspicion in light of the increasing incidence of TB worldwide.6 Clinicians typically rely on a battery of tests for diagnosis. These include investigation of clinical signs and symptoms, tuberculin skin test (TST), laboratory tests such as smear and/or culture, metabolic product detection by interferon (IFN)-g test, polymerase chain reaction (PCR), and the use of various imaging techniques and histological studies. Diagnosis may take days to weeks and may involve expensive, invasive and complex procedures.1,2,5,6 The TST is commonly used but has inherent sensitivity and specificity limitations. Even in areas with a high burden of tuberculosis about 20% of individuals have a negative response throughout their lifetime, despite repeated exposure to the tubercle bacilli. Sensitivity to the TST is also decreased in immunocompromised patients, and false-positive results occur in patients after bacille Calmette-Guerin vaccination and non-tuberculous mycobacterial infections.2,6 Imaging techniques such as simple radiographs, computed tomography, bone scan and magnetic resonance imaging are helpful in identifying TB, but are not diagnostic. When disc and/or end-plate destruction with surrounding soft tissue swelling is observed on imaging tests, spine infection should be suspected. Laboratory aids for diagnosis include full blood counts, including total lymphocytes and CD4 lymphocyte (helper-inducer T-cell) counts, erythrocyte sedimentation rate and C-reactive protein, histology, and the patient’s antibody response.5,6,11,20,23e25 The diagnostic gold standard has been the isolation of M. tuberculosis by smear and/or culture from clinical samples such as aspirates (needle or trochar) and tissue specimens (open or percutaneous biopsy). However, the tubercle bacillus is difficult to culture because it has fastidious growth requirements. Hence the development of various laboratory methods is essential. There are three nonculture diagnostic laboratory tests: (1) immunological tests (antigen and antibody); (2) metabolic product detection, such as extracorporeal IFN-g test; and (3) amplification of DNA of M. tuberculosis by PCR.25 The immunochromatographic TB test [AMRAD-ICT Diagnostics, Sydney, Australia] is an in vitro immunological tool for the detection of antibodies to M. tuberculosis in white blood cells and reliably detects TB in whole blood, enabling rapid and accurate diagnosis at the point of care.2,6 Two ex-vivo IFN-g assay kits have been marketed; Quanti-FERON* TB Gold [Cellestis limited, Carnegie Victoria, Australia, QFT-G] and T-SPOT, TB [Oxford Immunotec, Oxford, UK, T-SPOT].2,6 When T-lymphocytes are exposed to tubercle
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Management The primary treatment goal of spinal TB is to save life through eradication of the infection. Secondary goals are to maintain stability of the affected spinal segments, meet the patients’ aesthetic needs by preventing and/or correcting the spinal deformities, prevent and/or treat paralysis, maintain pulmonary function, and reduce parafusion segment disease. Management decisions must be based on the individual treatment goals of the patient, which consist of supportive care, chemotherapy, and surgery. When a patient presents in the early stages of disease with minimal bone involvement and no noticeable deformity, good general supportive care and chemotherapy alone can be given on an ambulatory basis without bracing.37,38 Studies have shown that early conservative treatment is beneficial in preventing residual kyphosis.13 Historically, selection of adult patients for conservative treatment was based on predictive residual kyphosis, though this is not always a reliable marker.11,39 Nutritional support is an important part of therapy for those who are physically debilitated. These patients may even need hyperalimentation prior to starting treatment to restore premorbid nutritional status. The goals of nutritional therapy should be to achieve a serum albumin level >3 g/dL, an absolute lymphocyte count >800/mm3, and a 24-h urine creatinine excretion >10.5 mg in men and >5.8 mg in women.6,8
Drug therapy The advantages of chemotherapy without surgery include the following: effective ambulatory treatment, spontaneous correction of deformity in early TB in children, the avoidance of surgeryrelated complications, and low cost. However, disadvantages of
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chemotherapy alone include a longer duration of treatment, failure to meet the patients’ aesthetic demands and delayed neurological recovery in Pott’s paralysis (Figure 2). First-line chemotherapy should include a combination of isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin (Table 2). Patients who are HIV-negative should start treatment with at least three agents (isoniazid, rifampicin, and pyrazinamide) or, if resistance is suspected, four (the above three drugs plus ethambutol) or more.6 Recommendations for managing resistant TB are listed in Table 3. Susceptibility testing should be conducted in all isolates and the regimen adjusted accordingly, to include at least two agents to which the isolate is sensitive. For patients with hepatic and renal dysfunction, doses of each drug should be adjusted according to the patient’s liver and renal function. Nonsteroidal anti-inflammatory drugs may also be useful in early disease to prevent lesions caused by nonspecific synovial inflammation and to inhibit or minimize bone resorption caused by prostaglandinmediated inflammation.1,2,6,13 Patients who are HIV-positive, despite diminished cellmediated immunity, usually respond to standard antituberculous
chemotherapy. This is especially the case when it is started early, the patient is compliant and the organism is susceptible. Isoniazid chemoprophylaxis is recommended for HIV-positive patients with a positive TST and for those with a history of exposure to an individual with active TB, regardless of TST results.2,4,5,15,18 There is, as yet, no standard duration of antituberculosis chemotherapy treatment, though several guidelines have been proposed (Table 4).1,2,21,26,40e45,47,50 Some clinicians support the use of 9 months of short-term triple chemotherapy, while others advocate three or four-drug regimens for 12 months.2,6,40,47,48 In some cases, slow or doubtful responders are prescribed chemotherapy for 12e18 months.1,2,5,6 There are also no clear definitions of good (rapid), poor (slow), and non-responders to treatment. The recommended observation period for drug response is based on symptomatic improvement, normalization of inflammatory markers, arrest of the destructive process, signs of reformation on images and recovery (or not) from paralysis. This time frame has been arbitrarily assigned and not well studied. Thus, the common practice of labelling a patient a non-responder by these guidelines may not be accurate. Nevertheless, a 6- to 8-week observation period is recommended for
Figure 2 Radiographs of a 29-year-old man with tuberculous kyphosis. (a) Radiographs prior to 12 months of triple chemotherapy showing tuberculosis kyphosis at C2-4 with a substantial prevertebral abscess that displaced the trachea and oesophagus anteriorly. (b) Radiograph of the area of kyphosis after it was corrected by traction, showing that the abscess had been completely absorbed. (c) A radiograph showing the Minerva cast that was applied 2 months after traction and chemotherapy. (d) Twelve months after treatment, there was spontaneous anterior fusion without residual kyphosis.
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First-line and second-line antituberculosis drugs and recommended doses Antituberculosis agent
First line agents Isoniazid Rifampin Pyrazinamide Ethambutol Second line agents P-aminosalicylic acid Streptomycin Cycloserine Ethionamide Rifabutic Amikacin Capreomycin
Daily dosage in mg/kg (maximum total dose) Children
Adults
10e20 10e20 15e30 15e25
5 (300 mg) 19 (600 mg) 15e30 (2 g) 15e25 (1.5 g)
(300 mg) (600 mg) (2 g) (>12 years)*
200e300 mg/kg/day 20e40 (1 g)
Remarks
10e12 gm 15 (1 g) 1e2 g/day
Urinary tuberculosis
15 mg/kg/day (1.5 g) 1g/day, IM (not to exceed 20 mg/kg/day)
Used for streptomycin resistant strains
Table 2
Surgical treatment
patients without paralysis. A maximum of 3 months is suggested because accurate assessment of drug efficacy is difficult after this time. For patients with paralysis, assessment is done 3e4 weeks after the start of drug therapy.1,6 Priority has been given to the paralytic condition rather than the non-paralytic variety because studies have shown that recovery from paralysis after longer than 1 month on drug therapy is associated with a less favourable outcome.1,5,13,59,60 The failure of medical treatment is defined as lack of improvement of inflammatory markers after 6e8 weeks of adequate chemotherapy despite directly observed therapy, progression of neurological deficit, and progressive spinal deformity on radiological imaging.6 Most TB cases diagnosed after a patient has received biological therapy for rheumatoid diseases represent reactivation rather than new onset infection. To avoid such a relapse, it is critical to screen for TB prior to initiating TNF-a blocking therapy. Also, if postoperative rigor or fever develops during anti-TNF a therapy other bacterial infections must be excluded.6
Chemotherapy alone cannot solve the problems arising from bone and joint destruction. Therefore, surgical procedures still assume an important role in the management of spinal TB (Figure 3).51e57 Over the past four decades various surgical procedures have been developed to treat spinal TB and its complications and have been used with great success. The goal of surgery is to cure the disease and leave no residual deformity. Therefore, it is important to choose the appropriate surgical procedure for each patient based upon his or her overall condition, disease state, and aesthetic needs.6 Surgery is indicated only for disease-related complications such as segmental instability, deformity, and neurological deficit. The following are some of the advantages of using surgery for the management of TB: early cure of the disease by extirpation of the infected focus histological confirmation of diagnosis shortening of the duration of chemotherapy
Suggested regimens for drug-resistant tuberculosis Resistant drug regimen
Suggested regimen
Duration of therapy
Comments
HSZ
RZE, AMK
6e9 mo
HE (S)
RZ, OFL/CIP, AMK
6e9 mo
HR (S) HRE (S) HRZ (S) HRZE (S)
ZE, OFL/CIP, AMK Z, OFL/CIP, AMK, Plus 2 E, OFL/CIP, AMK, Plus 2 OFL/CIP, AMK, Plus 3
18e24 mo 24 mo after conversion 24 mo after conversion 24 mo after conversion
Estimated 100% response rate and <5% relapse rate Efficacy should be comparable to the above regimen Consider surgery Consider surgery Consider surgery Surgery, if possible
AMK, amikacin; CIP, ciprofloxacin; E, ethambutol; H, isoniazid; OFL, ofloxacin; R, rifampin; S, streptomycin; Z, pyrazinamide.
Table 3
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Antituberculous standard regimens and duration of therapy1,2,21,26,40e44,47,50 Standard TB regimens Three drug regimens HRZ, 2 moa; HR, 10 mo RHE (Z), 12 mo HPaS, 3 mo; HPa, 3 mo HPaS, 3 mo; HPa, 6 mo Four drug regimens SRHZ, 2 mo; RH, 7 mo RHEZ, 2 mo; RHE, 4 mo; RH, 6 mo RHZE, 12 mo RHE, 12 mo (at least) RHEZ, 4 mo; RHE, 14 mo
Duration of therapy (mo)
Author
12 12 6 9
Davies PC (1996) Moon et al. (1987, 1995, 1997, 2004) Upadhyay et al. (1996) Upadhyay et al. (1996)
9 12 12 12 18
Yilmaz C et al. (1999) Mehta JS et al. (2001) Govender and Kumor (2003) Hassan (2003) Sundaranaj et al. (2003)
E, Ethambutol; H, INH; Pa, P-aminosalicylic acid; R, Rifampin; S, Streptomycin; Z, Pyrazinamide. a Drug r esistant cases S(E)HRZ, 2 mo.
Table 4
reduction of late recurrence rates possible correction and/or prevention of deformity early effective neurological recovery patients’ satisfaction for aesthetically restored spinal alignment.
We would like to see the use of surgery for advanced cases and severe deformities as a thing of the past. Therefore, residual disease such as deformity, neurological deficit, and deformityrelated late adjacent joint disease must be minimized by every therapeutic effort.51e57
Figure 3 Radiographs in a 47-year-old paraparetic woman with tuberculous kyphosis of T12-L2. A preoperative radiograph (a) and preoperative myelogram (b) show 60 initial kyphosis. Myelography demonstrates the obliterated spinal canal from T10 level down. (c) Postoperative day 0 showing 30 kyphosis (c). Three months after surgery showing 42 kyphosis (d). Six months after surgery showing 43 kyphosis (e). Eighteen months after surgery showing kyphosis stable at 43 (f ). Total loss after the correction of kyphosis was 13 .
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The four conditions of spinal TB that can be managed by various surgical procedures are cold abscess, tuberculous lesions, paraplegia, and spinal deformity. In most cases, small and medium-size cold abscesses rapidly resolve spontaneously with chemotherapy alone. Surgical abscess drainage does not alter the patients’ general condition. Emergency decompression drainage should be carried out for the sudden onset of respiratory difficulty due to prevertebral abscess compressing the trachea or spinal cord compression above C4.6,32 Focal debridement of the lesion is rarely indicated because evidence suggests it does not improve healing or prevent progressive kyphosis.31 Radical debridement may also damage the uninvolved growth plates in children.1,2,6,47 Anterior radical surgery was once advocated as the treatment of choice for spinal TB; however there were problems with frequent graft failure, prevention of the progression of kyphosis and/or correcting pre-existing kyphosis.6 Posterior or anterior instrumentation surgery have since contributed greatly to the treatment of TB of spine. Early neurological recovery from paralysis can be achieved from these procedures as well as prevention and correction of deformity. Instrumentation has hastened intercoporeal fusion by maintaining stability of the graft and the diseased segment preventing graft slip out and fracture. Consequently, the patient’s quality of life has been greatly enhanced. A topic of great controversy is the degree of acceptable residual kyphosis, which is related to both aesthetic and biomechanical considerations. Deformity prevention and/or correction are currently based on the predictive value of residual kyphosis.12,39,61,62 The value can be calculated using the following formula12:
involvement, and vertebral body remnant shape. Dislocation of facets, posterior retropulsion of the diseased small remnant body fragment and toppling of the cephalad vertebra suggest a worse prognosis for kyphosis.1,5,6,12 Buckling (invaginating angulatory) collapse of the spine is unique to advanced paediatric TB at the lower dorsal and dorsolumbar spine. Fortunately, the above risk factors have not been seen in early TB. The deformity in children could correct spontaneously due to bone reformation from the growth plates.6 However, in most children with advanced disease, despite disease healing, there is a gradual increase of deformity as a consequence of growth plate destruction. When the affected unfused segment is not stabilized, the deformity progresses more rapidly than when the block vertebrae are fused.6,12,65 Therefore, prophylactic instrumentaided stabilization and/or corrective procedures should be considered to prevent further progression of kyphosis.6 There are contradicting views on the effect of a small wedged-single vertebral body remnant and the fused wedge block vertebrae on the development of kyphosis during growth. Upadhyay et al. concluded that there was no disproportionate posterior spinal growth that worsened the deformity after anterior intercorporeal fusion.46 On the contrary, Schulitz et al. observed progressive kyphosis in children with fused block vertebrae.10 Rajasekaran reported a posterior longitudinal overgrowth in cases of unfused tuberculous kyphosis after healing of TB that eventually caused facet joint subluxation with a great risk of spinal deformity, which was supported by the current authors.12,63 In children, posterior tether instrumentation is expected to be a successful procedure for growth correction of the kyphotic spine. Spontaneous intercorporeal fusion rarely occurs during chemotherapy in children.1,2,6,12,40,49,63 This phenomenon has not been satisfactorily explained. A study of bone morphogenetic protein (BMP), anti-BMP factors and other inflammatory cytokines in the tissue around the tuberculous lesion may clarify the cause.13,32
Final kyphosis ¼ 5:5 þ 30:5 degree of vertebral body destruction in 10 gradesð0:1 1:0Þ The predictive value of this formula was initially reported by Rajasekaran et al. to be around 90%, though when reassessed by Jain et al. this value was reported to be around 78%.12,39 The current authors’ view is that the discrepancy arose because of the inaccurate estimation of initial vertebral body loss, since perfect estimation of vertebral body loss at pre-chemotherapy is impossible. The numerical discrepancy of final kyphosis can reach 6.1 (30.5 0.2) because of 10% over- or underestimation of vertebral body destruction. In 2008, Oguz et al. presented a new classification and guideline for surgical treatment; however it did not address several important issues such as consideration of the patients’ aesthetic demands associated with long-term outcome, posterior element TB, adjacent segment disease and compensatory hyperlordosis above and below the residual kyphotic segment. It also did not include information in children and subsequently has not been widely advocated.27,64
Tuberculosis in the elderly The ageing body’s weakened immune system may contribute to the re-emergence of TB in previously infected individuals as they grow older. Indeed, the increased rates of TB, both endogenous reactivation and exogenous infection, may be associated with recently observed increases in life expectancy.20,24 Three and four drug regimens are well tolerated and effective. However, elderly patients frequently have co-morbidities, and the presence of concomitant diseases such as liver or renal failure may necessitate dosage adjustment of some of the treatment regimens.6,20,25 For example, streptomycin is excreted exclusively, and ethambutol predominantly, by the kidney. The dose of these drugs should be adjusted accordingly if prescribed for patients with renal insufficiency. The serum concentration of streptomycin should not exceed 5 mg/ml. If the patient is on dialysis, the dose should be given 5 h beforehand. Ethambutol should be given in a dose of 25 mg/kg three times weekly if the creatinine clearance is between 30 and 50 ml/min. Most of the other antituberculous medicines can be hepatotoxic. In patients with alcoholism or those who are hepatitis B antigen carriers, isoniazid, rifampicin, and one non-hepatotoxic drug should be given
Tuberculous kyphosis in children The risk of late kyphosis in children with Pott’s disease depends on age (greatest <5 years), level of involvement (thoracic most likely to occur), extent of the disease (>2 vertebrae make kyphosis most likely), growth plate damage, the patterns of
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to ensure that the duration of treatment does not need to be prolonged. 5
Pott’s paraplegia 6
Many factors affect recovery from Pott’s paraplegia.6,65,69,70 There are two treatment approaches: conservative (medical) and surgical decompression.6,64e68 The time-frame for surgery clearly depends on the intensity of the neurological deficit; dense and progressive deficits need much earlier surgical management because paraplegia usually resolves rapidly after adequate decompression6,65e67 The more severe the kyphosis, the worse the prognosis. In 1995, Tuli stated that a 60 kyphosis seems to be the watershed for possible neurological recovery after decompression surgery.16,39 He found that better neurological recovery was achieved in the early paralysis of the conservatively treated group, and in children.58,66 If neurological function in an adult with severe kyphosis worsens during chemotherapy, decompressive surgery alone is recommended in an attempt to restore normal neurology, though some surgeons have recommended combined decompression and corrective surgery.6 Our experience has been that posterior instrument-aided stabilization alone under the cover of antitubercular chemotherapy, regardless of the disease stage and/or severity of deformity, can hasten neurological recovery without direct decompression surgery.6,65,66,71 Historically, spinal cord tuberculoma has been excised surgically because there was no other therapeutic choice. However, we recommend combined antitubercular and degranulating agent therapy (anti-TNFa blocker treatment; subcutaneous injection of etanercept, 25 mg twice weekly up to 6e8 weeks) or steroids after the diagnostic biopsy.6 This therapy can obviate the need for total excisional surgery for tuberculoma.
7 8
9
10
11
12
13
14 15
16
Conclusions
17
Spinal TB is a curable disease with currently available chemotherapeutic agents. Due to the early detection and initiation of chemotherapy, and to improved surgical techniques, patients with kyphosis are nowadays rare. Selection of the correct therapeutic measures to minimize residual kyphosis in the highly mobile spinal segments after disease healing is important for the restoration of sagittal alignment. Even paraplegic patients can be well managed, with minimal residual effects, if early diagnosis and effective treatment are achieved. The development of posterior instrumentation has hastened neural recovery without the need for direct decompression. Spinal cord tuberculoma can be effectively treated without radical excision by combining the antituberculous medication and anti-TNFa blocker therapy with minimal residual disease. A
18 19
20
21 22
23
REFERENCES 1 Moon MS. Tuberculosis of the spine: controversies and a new challenges: spine update. Spine 1997; 22: 1791e7. 2 Moon MS. Managing tuberculosis of spine. Med Pr 2004; 593e602. 3 China Tuberculosis Control Collaboration. The effect of tuberculosis control in China. Lancet 2004; 364: 417e22. 4 World Health Organization. Global tuberculosis control, 2010. http://www.who.int/tb/publications/global_report/2010/en/
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index.html. Published November 2010. (accessed 15 August 2011). Moon MS. Development in the management of tuberculosis of the spine. Curr Orthop 2006; 20: 132e40. Moon MS. Tuberculosis of spine e contemporary thoughts on current issues and perspective views. Curr Orthop 2007; 21: 364e79. Kwon OJ. The role of nitric oxide in the immune response of tuberculosis. J Korea Med Sci 1997; 12: 481e7. Kumar K. Tuberculosis of spine: natural history of disease and its judicious management. J West. Pacif Orthop Assoc 1988; 15: 1e8. Moon MS. Treatment of spinal infections. Commemorative issue. 3rd Spinal Section Congress, WPOA. J West. Pacif Orthop Assoc 1983; 7e11. Schulitz K, Kothe R, Leong J, Wehling P. Growth changes of solidly fused kyphotic bloc after surgery for tuberculosis; comparison of four procedures. Spine 1997; 22: 1150e5. Jeong GY, Yang YS, Oh WI. Peripheral lymphocyte subsets in patients with pulmonary and extrapulmonary tuberculosis. Korea J Clin Pathol 1999; 19: 696e701. Rajasekaran S, Shammugasundaram TK. Prediction of the angle of gibbus deformity in tuberculosis of the spine. J Bone Joint Surg Am 1987; 69: 503e9. Moon MS, Moon YW, Moon JL, Kim SS, Sun DH. Conservative treatment of tuberculosis of the lumbar and lumbosacral spine. Clin Orthop 2002; 398: 40e9. Polley P, Dunn R. Noncontiguous spinal tuberculosis: incidence and management. Eur Spine J 2009; 18: 1091e101. Tuli SM. Tuberculosis of the skeletal system (bone, joints, spine and bursal sheath). 3rd edn. New Delhi: Jaypee Brother Medical publishers Pvt. Ltd., 2004. Tuli SM. Severe kyphotic deformity in tuberculosis of the spine. Int Orthop (SICOT) 1995; 19: 327e31. Arora A. Basic science of host immunity in osteoarticular tuberculosis. Indian J Orthop 2006; 40: 1e15. Maeda Y, Izawa K, Nabeshima T, Yonenobu K. Tuberculous spondylitis in elderly Japanese patients. Int Orthop 2008; 13: 16e20. Cunningham ME, Girardi F, Papadopulos EC, Cammisa FP. Spinal infections in patients with compromised immune systems. Clin Orthop 2006; 444: 73e82. Govender S, Parbhoo AH, Kumar KPS, Annamalai K. Anterior spinal decompression in HIV-positive patients with tuberculosis. J Bone Joint Surg 2001; 83-B: 864e7. Davies PDO. Tuberculosis in the elderly: d epidemiolagy and optimal management. Med Pr Sept 1996; 25e8. Kim HA, Yoo CD, Back HJ, et al. Mycobacterium tuberculosis infection in a corticosteroid-treated rheumatic disease patient. Clin Exp Rheumatol 1998; 16: 9e13. Genestier L, Paillet R, Fournel S, Ferrero C, Miossec P, Revillard J. Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated peripheral T cells. J Clin Invest 1998; 102: 322e8. Cole RA, Lu HM, Shi YZ, et al. Clinical evaluation of a rapid immunochromatographic assay based on the 38 KDa antigen of Mycobacterium tuberculosis on patients with pulmonary tuberculosis in China. Tuber Lung Dis 1996; 77: 363e8. Brisson-Noel A, gicqual B, Lecossier D, et al. Rapid diagnosis of tuberculosis by amplification of mycobacterial DNA in clinical samples. Lancet 1989; 334: 1069e71.
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26 Mehta JS, Bhojraj SY. Tuberculosis of the thoracic spine. A classification based on the selection of surgical strategies. J Bone Joint Surg 2001; 83-B: 859e63. 27 Oguz E, Sehirlioglu A, Altinmakas M, et al. A new classification and guide for surgical treatment of spinal tuberculosis. Int Orthop 2008; 32: 127e33. 28 Hodgson AR, Stock FE. Anterior spine fusion for the treatment of tuberculosis of the spine: the operative findings and results of treatment in the first 100 cases. J Bone Joint Surg 1960; 42A: 295e310. 29 Moon MS. Combined posterior instrumentation and anterior interbody fusion for active tuberculous kyphosis of the thoracolumbar spine. Curr Orthop 1991; 5: 177e9. 30 Zhao J, Lian XF, Hou TS, Ma H, Chen ZM. Anterior debridement and bone grafting of spinal tuberculosis with one-stage instrumentation anteriorly or posteriorly. Int Orthop 2007; 31: 859e63. 31 Nagariya S, Patgaonkar P, Chhabra S, Agrawal V, Franke J. Single stage anterior decompression and instrumentation for spinal tuberculosis. J Spinal Surg 2010; 2: 373e82. 32 Moon MS, Moon JL, Kim SS, Moon YW. Treatment of tuberculosis of the cervical spine. Clin Orthop 2007; 460: 67e77. 33 Oga W, Arizono T, Takasita M, et al. Evaluation of the risk of instrumentation as a foreign body in spinal tuberculosis: clinical and biologic study. Spine 1993; 18: 1890e4. 34 Ha KY, Chung YG, Ryoo SJ. Adherence and biofilm formation of staphylococcus epidermis and mycobacterium tuberculosis on various spinal infections. Spine 2004; 29: 1e6. 35 An YH, Stuart GW, McDowell CJ, McDaniel SE, Kang O, Friedman RJ. Prevention of bacterial adherence to implant surfaces with a crosslinked albumin coating in vitro. J Orthop Res 1996; 14: 846e9. 36 Kim YY, Yoon YS. Replacement arthroplasty using Charnley prosthesis in old tuberculosis of the hip. Int Orthop 1979; 3: 81. 37 Medical Research Council Working Party on Tuberculosis of Spine. Results at three years of a study in Korea. J Bone Joint Surg 1993; 75B: 240e8. 38 Griffith DLI. Short-course chemotherapy in the treatment of spinal tuberculosis. J Bone Joint Surg 1986; 68B: 158. 39 Jain AK, Aggarval PK, Arora A, Singh S. Behavior of the kyphotic angle in spinal tuberculosis. Int Orthop 2004; 28: 110e4. 40 Upadhyay SS, Saji MJ, Yau CMC. Duration of antituberculous chemotherapy in conjunction with radical surgery in the management of spinal tuberculosis. Spine 1996; 21: 1898e903. 41 Yilmaz C, Selck HY, Gunkan I, Erdemli B, Korkusuz. Anterior instrumentation for the treatment of spinal tuberculosis. J Bone Joint Surg 1999; 81A: 1261e9. 42 Govender S, Kumar RP. Cortical allograft in spinal tuberculosis. Int Orthop 2003; 27: 244e8. 43 Hassan MG. Anterior plating for lower cervical spine tuberculosis. Int Orthop 2003; 27: 73e7. 44 Sundararaj GD, Behera S, Ravi V, Venkatesh K, Cherian VM, Lee V. Role of posterior stabilization in the management of tuberculosis of the dorsal and lumbar spine. J Bone Joint Surg 2003; 85B: 100e6. 45 Moulding T, Dutt AK, Reichman LB. Fixed-dose combinations of antituberculous medications to prevent drug resistance. Ann Intern Med 1995; Jun; 122: 951e4. 46 Upadhyay SS, Sell P, Saji MJ, Sell B, Yau ACMC, Leong JCY. 17-year prospective study of surgical management of spinal tuberculosis in children. Spine 1993; 18: 1704e11.
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47 Moon MS, Kim L, Woo YK, et al. Conservative treatment of tuberculosis of the thoracic and lumbar spine in adults and children. Internat Orthop (SICOT) 1987; 11: 315e22. 48 Moon MS, Rhee SK, Kang YK. Harrington rods in treatment of active spinal tuberculosis with kyphosis. J West. Pacif Orthop Assoc 1986; 23: 53e8. 49 Kloeckner C, Valencia R. Sagittal alignment after anterior debridement and fusion with or without additional posterior instrumentation in the treatment of pyogenic and tuberculous spondylodiscitis. Spine 2003; 28: 1036e42. 50 Moon MS, Yoo YK, Lee KS, et al. Posterior instrumentation and anterior interbody fusion for tuberculosis kyphosis of dorsal and lumbar spine. Spine 1995; 20: 1910e6. 51 Bhojraj S, Patel T, Kalkotwar S, Prasad G. Transpedicular approach: a gateway to the spine. J Spinal Surg 2010; 2: 420e5. 52 Lee S, Sung J, Park Y. Single stage transpedicular decompression and posterior instrumentation in treatment of thoracic and thoracolumbar spinal tuberculosis. J Spinal Disord Tech 2006; 19: 595e602. 53 Benli IT, Maya A, Acaroglu E. Anterior instrumentation in tuberculous spondylitis. Clin Orthop 2007; 460: 108e16. 54 Jain AK, Dhammi IK, Jain S, Mishra P. Kyphosis in spinal tuberculosis prevention and correction. Indian J Orthop 2010; 44: 127e36. 55 Jain AK. Tuberculosis of the spine - a fresh look at an old disease. J Bone Joint Surg 2010; 92B: 905e13. 56 Yau AMC, Hsu LCS, O’Brien JP, et al. Tuberculous kyphosis: correction with spinal osteotomy, halopelvic distraction, and anterior posterior fusion. J Bone Joint Surg 1974; 56A: 1419e34. 57 Lehman SM, Kappler L, Biscup RS, et al. Posterior transvertebral osteotomy for adult thoracolumbar kyphosis. Spine 1994; 19: 2060e7. 58 Shimode M, Kojima T, Sowa K. Spinal wedge osteotomy by a single posterior approach for correction of severe and rigid kyphosis or kyphoscoliosis. Spine 2002; 27: 2260e76. 59 Van Dijk M, Smit TH, Jiya TW, Waisman PI. Polyurethane real-size models used in planning complex spinal surgery. Spine 2001; 26: 1920e6. 60 Kawahara N, Tomita K, Murakami H, Akameru M, Hata T. Spinal Shortening in total enbloc spondylectomy. Jpn Orthop Congress Book 2005. 3A-P9e4. 61 Kobayashi T, Kawahara N, Murakami H, et al. An experimental study on the influence of spinal shortening on the spinal cord. Jpn Orthop Assoc Congress Book 2005. 3A-P9e1. 62 Tanaka Y, Kokubun S, Ozawa K, et al. Shortening spinal osteotomy for tethered cord syndrome. Jpn Orthop Assoc Congress Book 2005. 3A-P9e2. 63 Rajasekaran S. The natural history of post-tubercular kyphosis in children: radiological signs which predict late increase in deformity. J Bone Joint Surg 2001; 83B: 954e62. 64 Jain AK, Sinha S. Evaluation of systems of grading of neurological deficit in tuberculosis. Spinal Cord 2005; 43: 375e80. 65 Moon MS, Ha KY, Sun DH, et al. Pott’s paraplegia: 67 cases. Clin Orthop 1996; 323: 122e8. 66 Moon MS, Moon JL, Moon YW, Kim SS, Sun DH. Pott’s paraplegia in patients with severely deformed dorsal or dorsolumbar spines: treatment and prognosis. Spinal Cord 2003; 41: 164e71. 67 Wong YW, Leong JCY, Luk KDK. Direct internal kyphectomy for severe angular tuberculous kyphosis. Clin Orthop 2007; 480: 124e9.
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68 Laheri VJ, Badhe NP, Dewnany GT. Single stage decompression, anterior interbody fusion and posterior instrumentation for tuberculous kyphosis of the dorsolumbar spine. Spinal Cord 2001; 39: 429e36. 69 Harsha CKS, Shetty AP, Rajasekaran S. Intradural spinal tuberculosis in the absence of vertebral or meningeal tuberculosis: a case report. J Orthop Surg 2006; 14: 71e5. 70 Liu YD, Wang FY, Xu JM, Guan Y, Guan H. Intramedullary thoracic tuberculoma (a case report). Spinal Cord 2010; 48: 80e2.
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71 Kahanovitz N, Arnoczky SP, Levine DB, Otis JP. The effects of internal fixation on the articular cartilage of unfused canine facet joints. Spine 1984; 9: 268e72.
Acknowledgements The authors thank Mr. Seog In Moon for his secretariat work.
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(i) Tuberculosis of the spine: current views in diagnosis, management, and setting a global standard*
The emergence of HIV/AIDS has significantly increased the incidence of disseminated Mycobacterium avium complex infection, which now occurs almost exclusively in patients with CD4 T-lymphocyte counts below 100 cells per mm.2,3,5,6 Apart from the spread of HIV/AIDS, the recent resurgence of chemoresistant variants of Mycobacterium tuberculosis poses a further problem and has raised great concerns worldwide. Overall the prevalence of osteoarticular TB is likely to rise, indicating the need to prepare for a re-emergence in the coming years.2,6 Osteoarticular TB occurs in approximately 20% of all extrapulmonary cases, and the spine is involved in 50% of these patients.14 However, in HIV-positive patients with TB, approximately 60% develop skeletal disease compared with 3e5% of HIV-negative patients.1 Spinal TB is the most dangerous form of osteoarticular TB causing bone destruction of the vertebral body, spinal deformity, and possible paraplegia and pulmonary insufficiency secondary to deformity of the thoracic cage.1,2,5,6 When the body of the spine and the neural arch are involved, particularly in children, translational instability of the affected spine with anterior or lateral vertebral translation may occur and the resultant kyphoscoliotic deformity poses a risk of spinal cord compression to the patient.12e19 Despite recent advances in the diagnosis and management of spinal TB there remains a number of unaddressed issues of significant clinical importance.5 For example, surgical treatment is currently indicated only for the complicated form of spinal TB; however non-complicated and complicated classifications of spinal TB have not yet been clearly defined. This paper seeks to address these issues, which include newer diagnostic techniques, non-culture laboratory methods, immunosuppressant drug use,19,20,24e30 surgical options for spinal deformity and associated neural involvement. Furthermore, a treatment algorithm is suggested, which may help to improve treatment outcomes and reduce complications (Figure 1).
Myung-Sang Moon Sung-Soo Kim Hanlim Moon
Abstract Spinal tuberculosis (TB) is the most common form of osteoarticular TB occurring in approximately half of all cases. It is also the most dangerous form, potentially causing paralysis, permanent neurological deficits and severe deformity. There has been a resurgence of TB over the last decade. This is mostly due to increased host susceptibility from the growing number of immunocompromised patients secondary to human immunodeficiency virus and acquired immunodeficiency syndrome, the wider use of immunosuppressant agents, the ageing population, and an increasing number of chronically debilitated patients. Although a minor factor, the recent reemergence of multi-drug resistant variants of Mycobacterium tuberculosis hints at a possible further resurgence of TB in the coming years. Individualized treatment according to broad-spectrum management is essential for recovery. This article discusses the immunology, clinical manifestations, diagnosis, and medical and surgical treatments of spinal TB.
Keywords diagnosis; management; spine; tuberculosis
Introduction Immunity and tuberculosis
Tuberculosis (TB) remains an urgent global health problem. In 2009, approximately 9.4 million new cases of TB were identified worldwide resulting in 1.7 million deaths in that year. Ninety-five percent of these patients are in the developing world. According to the World Health Organization, each year 1.3 million new cases of TB are diagnosed in China.1e6 In sub-Saharan African countries, the number of reported TB cases has more than doubled because of the spread of human immunodeficiency virus and acquired immunodeficiency syndrome (HIV/AIDS).7e13
Following exposure to M. tuberculosis, some individuals (approximately 10%) develop active TB, while most do not. It is unclear what factors determine the development of active disease, though the condition of the patient’s immune system is thought to be closely related.6,7 Many patients are predisposed to osteoarticular TB, such as the elderly and malnourished, those with agammaglobulinaema, diabetes mellitus, HIV infection, malignancy, renal failure, substance abuse and those undergoing longterm treatment with chemotherapeutic and antirheumatic agents (e.g., corticosteroids, methotrexate, tumour necrosis factor [TNF]a blocking agents, and B-cell depleting therapeutic agents).23e25 The immune response to M. tuberculosis is a lymphoproliferative defence response to antigen or mitogen stimulation, and T-cell mediated cellular immunity is an important factor. In fact, it has been widely used as an in vitro correlate of cell-mediated immunity. There is an imbalance between helper (H) and suppressor (S) T cells in the pathogenesis of TB in humans. The H/S ratio in extrapulmonary TB is lower than in pulmonary TB (1.06 0.44 vs 1.64 0.92).6 Most antirheumatic agents exert their effects through humoral and cellular levels of immune system and marrow suppression and the TNF-a blocking agents inhibit lymphocyte and macrophage activity.6,7,20
*
No benefits in any form have been received from a commercial party related directly or indirectly to the subject of this article. Myung-Sang Moon MD PhD FACS Professor, Department of Orthopedic Surgery, Cheju Halla General Hospital, Jeju, Korea; Director, Moon-Kim’s Institute of Orthopedic Research, Seoul, Korea. Conflicts of interest: none. Sung-Soo Kim MD PhD Orthopaedicc Consultant, Department of Orthopedic Surgery, Cheju Halla General Hospital, Jeju, Korea. Conflicts of interest: none. Hanlim Moon MD PhD CEO Senior Medical Director, CURENCARE Research, Seoul, Korea. Conflicts of interest: none.
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Figure 1 Treatment algorithm for spinal tuberculosis.
Behavioural characteristics of M. tuberculosis
viewpoints and the patient’s neurological state and do not address the effect of residual deformity upon the remaining mobile segments. Thus, terms such as d early and late; early, moderate, and advanced; kyphotic and non-kyphotic; and stage I, II, and III d have been used in staging the severity of disease, as has the percentage of vertebral body loss (Table 1). A satisfactory staging system to include all of these characteristics is still awaited.
Understanding the nature and growth of M. tuberculosis and its response to chemotherapy and biomaterial implants is vital before determining any treatment plan.33,34 M. tuberculosis presents in a free-floating planktonic form, producing minimal adhesion molecules and slime and occasionally becoming dormant. Because of its relatively slow replication rate, antituberculous chemotherapy given intermittently is as effective as daily administration.1,2,6 There has been concern that the use of the biomaterials (titanium cage, screws and rods, polymethylmethacrylate bone cements and stainless steel or ceramic cups) in the tuberculous lesions may cause biomaterial-centred infection and would hinder healing or that the use of such implants would cause the arrested or quiescent infection to flare up.36e40 However, M. tuberculosis has shown little tendency to adhere to implants and they can be safely used in tuberculous lesions.31,32,34,35 In HIV-positive patients, however, the use of biomaterials in such infected foci is inappropriate because mixed infection with pyogenic bacteria is inevitable.6,17,19e22
Clinical manifestations Common symptoms of TB of the spine are malaise, loss of appetite, weight loss and night sweats. Rarely, neurological deficits will present as the first symptom. The involved spine is usually stiff and painful with movement, and back muscle spasms may be present as well as a localized humpback. Relaxation of muscle spasms at night allow for movement between inflamed surfaces of the spine, and patients occasionally cry out in pain (night cries) during sleep. A cold abscess and/or sinus may be present, and a small gibbus may be detected on palpation. The symptoms of TB are often insidious even during the active stage; therefore many of these signs and symptoms may be absent in early stages.
Classification of tuberculosis There is currently no universally accepted staging system for TB, although several have been introduced.6,8,26,27 These classification systems have been based upon the stage of disease, and do not help clinicians in the selection of the most appropriate management protocol. They are mostly related to aesthetic
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Diagnosis To ensure proper treatment and improve prognosis, an accurate diagnosis of TB should be made at the patient’s initial
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Staging summary of spinal tuberculosis6,29,47 Disease progress
Size of lesion
Deformity
Disease advancement (stages) Stage I: minimally (very early) Stage II: early Stage III: relatively (moderately) Stage IV: far advanced
Degree of body destructive Loss <20% (2/10) 20e50% 51e100% 101e200%
Degree of kyphosisa 12.2 12.2e22.25 22.26e39.0 39.1e72.5
a
Percentage and degree of kyphosis in cases of conservative treatment are calculated by Rajasekaran’s formula (Y ¼ 5.5 þ 30.5 degree of body destruction).11,37
Table 1
bacilli, lymphocytes secrete IFN-g making the extracorporeal IFN-g test particularly useful for latent TB. There are reports that T-SPOT is more sensitive than TST in immunocompromised patients. However, a disadvantage of these 23assays is that they can detect TB infection, but they cannot differentiate latent TB from active TB. The molecular diagnostic test, PCR, amplifies the DNA of M. tuberculosis and the results can be available within hours. This is an advantage, allowing effective and prompt treatment. PCR DNA amplification of M. Tuberculosis has been used as a marker to monitor response to treatment and been shown to provide rapid information on drug resistance and clonality in epidemiological investigation of outbreaks.
presentation. Therefore, physicians and surgeons must exercise a high index of suspicion in light of the increasing incidence of TB worldwide.6 Clinicians typically rely on a battery of tests for diagnosis. These include investigation of clinical signs and symptoms, tuberculin skin test (TST), laboratory tests such as smear and/or culture, metabolic product detection by interferon (IFN)-g test, polymerase chain reaction (PCR), and the use of various imaging techniques and histological studies. Diagnosis may take days to weeks and may involve expensive, invasive and complex procedures.1,2,5,6 The TST is commonly used but has inherent sensitivity and specificity limitations. Even in areas with a high burden of tuberculosis about 20% of individuals have a negative response throughout their lifetime, despite repeated exposure to the tubercle bacilli. Sensitivity to the TST is also decreased in immunocompromised patients, and false-positive results occur in patients after bacille Calmette-Guerin vaccination and non-tuberculous mycobacterial infections.2,6 Imaging techniques such as simple radiographs, computed tomography, bone scan and magnetic resonance imaging are helpful in identifying TB, but are not diagnostic. When disc and/or end-plate destruction with surrounding soft tissue swelling is observed on imaging tests, spine infection should be suspected. Laboratory aids for diagnosis include full blood counts, including total lymphocytes and CD4 lymphocyte (helper-inducer T-cell) counts, erythrocyte sedimentation rate and C-reactive protein, histology, and the patient’s antibody response.5,6,11,20,23e25 The diagnostic gold standard has been the isolation of M. tuberculosis by smear and/or culture from clinical samples such as aspirates (needle or trochar) and tissue specimens (open or percutaneous biopsy). However, the tubercle bacillus is difficult to culture because it has fastidious growth requirements. Hence the development of various laboratory methods is essential. There are three nonculture diagnostic laboratory tests: (1) immunological tests (antigen and antibody); (2) metabolic product detection, such as extracorporeal IFN-g test; and (3) amplification of DNA of M. tuberculosis by PCR.25 The immunochromatographic TB test [AMRAD-ICT Diagnostics, Sydney, Australia] is an in vitro immunological tool for the detection of antibodies to M. tuberculosis in white blood cells and reliably detects TB in whole blood, enabling rapid and accurate diagnosis at the point of care.2,6 Two ex-vivo IFN-g assay kits have been marketed; Quanti-FERON* TB Gold [Cellestis limited, Carnegie Victoria, Australia, QFT-G] and T-SPOT, TB [Oxford Immunotec, Oxford, UK, T-SPOT].2,6 When T-lymphocytes are exposed to tubercle
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Management The primary treatment goal of spinal TB is to save life through eradication of the infection. Secondary goals are to maintain stability of the affected spinal segments, meet the patients’ aesthetic needs by preventing and/or correcting the spinal deformities, prevent and/or treat paralysis, maintain pulmonary function, and reduce parafusion segment disease. Management decisions must be based on the individual treatment goals of the patient, which consist of supportive care, chemotherapy, and surgery. When a patient presents in the early stages of disease with minimal bone involvement and no noticeable deformity, good general supportive care and chemotherapy alone can be given on an ambulatory basis without bracing.37,38 Studies have shown that early conservative treatment is beneficial in preventing residual kyphosis.13 Historically, selection of adult patients for conservative treatment was based on predictive residual kyphosis, though this is not always a reliable marker.11,39 Nutritional support is an important part of therapy for those who are physically debilitated. These patients may even need hyperalimentation prior to starting treatment to restore premorbid nutritional status. The goals of nutritional therapy should be to achieve a serum albumin level >3 g/dL, an absolute lymphocyte count >800/mm3, and a 24-h urine creatinine excretion >10.5 mg in men and >5.8 mg in women.6,8
Drug therapy The advantages of chemotherapy without surgery include the following: effective ambulatory treatment, spontaneous correction of deformity in early TB in children, the avoidance of surgeryrelated complications, and low cost. However, disadvantages of
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chemotherapy alone include a longer duration of treatment, failure to meet the patients’ aesthetic demands and delayed neurological recovery in Pott’s paralysis (Figure 2). First-line chemotherapy should include a combination of isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin (Table 2). Patients who are HIV-negative should start treatment with at least three agents (isoniazid, rifampicin, and pyrazinamide) or, if resistance is suspected, four (the above three drugs plus ethambutol) or more.6 Recommendations for managing resistant TB are listed in Table 3. Susceptibility testing should be conducted in all isolates and the regimen adjusted accordingly, to include at least two agents to which the isolate is sensitive. For patients with hepatic and renal dysfunction, doses of each drug should be adjusted according to the patient’s liver and renal function. Nonsteroidal anti-inflammatory drugs may also be useful in early disease to prevent lesions caused by nonspecific synovial inflammation and to inhibit or minimize bone resorption caused by prostaglandinmediated inflammation.1,2,6,13 Patients who are HIV-positive, despite diminished cellmediated immunity, usually respond to standard antituberculous
chemotherapy. This is especially the case when it is started early, the patient is compliant and the organism is susceptible. Isoniazid chemoprophylaxis is recommended for HIV-positive patients with a positive TST and for those with a history of exposure to an individual with active TB, regardless of TST results.2,4,5,15,18 There is, as yet, no standard duration of antituberculosis chemotherapy treatment, though several guidelines have been proposed (Table 4).1,2,21,26,40e45,47,50 Some clinicians support the use of 9 months of short-term triple chemotherapy, while others advocate three or four-drug regimens for 12 months.2,6,40,47,48 In some cases, slow or doubtful responders are prescribed chemotherapy for 12e18 months.1,2,5,6 There are also no clear definitions of good (rapid), poor (slow), and non-responders to treatment. The recommended observation period for drug response is based on symptomatic improvement, normalization of inflammatory markers, arrest of the destructive process, signs of reformation on images and recovery (or not) from paralysis. This time frame has been arbitrarily assigned and not well studied. Thus, the common practice of labelling a patient a non-responder by these guidelines may not be accurate. Nevertheless, a 6- to 8-week observation period is recommended for
Figure 2 Radiographs of a 29-year-old man with tuberculous kyphosis. (a) Radiographs prior to 12 months of triple chemotherapy showing tuberculosis kyphosis at C2-4 with a substantial prevertebral abscess that displaced the trachea and oesophagus anteriorly. (b) Radiograph of the area of kyphosis after it was corrected by traction, showing that the abscess had been completely absorbed. (c) A radiograph showing the Minerva cast that was applied 2 months after traction and chemotherapy. (d) Twelve months after treatment, there was spontaneous anterior fusion without residual kyphosis.
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First-line and second-line antituberculosis drugs and recommended doses Antituberculosis agent
First line agents Isoniazid Rifampin Pyrazinamide Ethambutol Second line agents P-aminosalicylic acid Streptomycin Cycloserine Ethionamide Rifabutic Amikacin Capreomycin
Daily dosage in mg/kg (maximum total dose) Children
Adults
10e20 10e20 15e30 15e25
5 (300 mg) 19 (600 mg) 15e30 (2 g) 15e25 (1.5 g)
(300 mg) (600 mg) (2 g) (>12 years)*
200e300 mg/kg/day 20e40 (1 g)
Remarks
10e12 gm 15 (1 g) 1e2 g/day
Urinary tuberculosis
15 mg/kg/day (1.5 g) 1g/day, IM (not to exceed 20 mg/kg/day)
Used for streptomycin resistant strains
Table 2
Surgical treatment
patients without paralysis. A maximum of 3 months is suggested because accurate assessment of drug efficacy is difficult after this time. For patients with paralysis, assessment is done 3e4 weeks after the start of drug therapy.1,6 Priority has been given to the paralytic condition rather than the non-paralytic variety because studies have shown that recovery from paralysis after longer than 1 month on drug therapy is associated with a less favourable outcome.1,5,13,59,60 The failure of medical treatment is defined as lack of improvement of inflammatory markers after 6e8 weeks of adequate chemotherapy despite directly observed therapy, progression of neurological deficit, and progressive spinal deformity on radiological imaging.6 Most TB cases diagnosed after a patient has received biological therapy for rheumatoid diseases represent reactivation rather than new onset infection. To avoid such a relapse, it is critical to screen for TB prior to initiating TNF-a blocking therapy. Also, if postoperative rigor or fever develops during anti-TNF a therapy other bacterial infections must be excluded.6
Chemotherapy alone cannot solve the problems arising from bone and joint destruction. Therefore, surgical procedures still assume an important role in the management of spinal TB (Figure 3).51e57 Over the past four decades various surgical procedures have been developed to treat spinal TB and its complications and have been used with great success. The goal of surgery is to cure the disease and leave no residual deformity. Therefore, it is important to choose the appropriate surgical procedure for each patient based upon his or her overall condition, disease state, and aesthetic needs.6 Surgery is indicated only for disease-related complications such as segmental instability, deformity, and neurological deficit. The following are some of the advantages of using surgery for the management of TB: early cure of the disease by extirpation of the infected focus histological confirmation of diagnosis shortening of the duration of chemotherapy
Suggested regimens for drug-resistant tuberculosis Resistant drug regimen
Suggested regimen
Duration of therapy
Comments
HSZ
RZE, AMK
6e9 mo
HE (S)
RZ, OFL/CIP, AMK
6e9 mo
HR (S) HRE (S) HRZ (S) HRZE (S)
ZE, OFL/CIP, AMK Z, OFL/CIP, AMK, Plus 2 E, OFL/CIP, AMK, Plus 2 OFL/CIP, AMK, Plus 3
18e24 mo 24 mo after conversion 24 mo after conversion 24 mo after conversion
Estimated 100% response rate and <5% relapse rate Efficacy should be comparable to the above regimen Consider surgery Consider surgery Consider surgery Surgery, if possible
AMK, amikacin; CIP, ciprofloxacin; E, ethambutol; H, isoniazid; OFL, ofloxacin; R, rifampin; S, streptomycin; Z, pyrazinamide.
Table 3
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Antituberculous standard regimens and duration of therapy1,2,21,26,40e44,47,50 Standard TB regimens Three drug regimens HRZ, 2 moa; HR, 10 mo RHE (Z), 12 mo HPaS, 3 mo; HPa, 3 mo HPaS, 3 mo; HPa, 6 mo Four drug regimens SRHZ, 2 mo; RH, 7 mo RHEZ, 2 mo; RHE, 4 mo; RH, 6 mo RHZE, 12 mo RHE, 12 mo (at least) RHEZ, 4 mo; RHE, 14 mo
Duration of therapy (mo)
Author
12 12 6 9
Davies PC (1996) Moon et al. (1987, 1995, 1997, 2004) Upadhyay et al. (1996) Upadhyay et al. (1996)
9 12 12 12 18
Yilmaz C et al. (1999) Mehta JS et al. (2001) Govender and Kumor (2003) Hassan (2003) Sundaranaj et al. (2003)
E, Ethambutol; H, INH; Pa, P-aminosalicylic acid; R, Rifampin; S, Streptomycin; Z, Pyrazinamide. a Drug r esistant cases S(E)HRZ, 2 mo.
Table 4
reduction of late recurrence rates possible correction and/or prevention of deformity early effective neurological recovery patients’ satisfaction for aesthetically restored spinal alignment.
We would like to see the use of surgery for advanced cases and severe deformities as a thing of the past. Therefore, residual disease such as deformity, neurological deficit, and deformityrelated late adjacent joint disease must be minimized by every therapeutic effort.51e57
Figure 3 Radiographs in a 47-year-old paraparetic woman with tuberculous kyphosis of T12-L2. A preoperative radiograph (a) and preoperative myelogram (b) show 60 initial kyphosis. Myelography demonstrates the obliterated spinal canal from T10 level down. (c) Postoperative day 0 showing 30 kyphosis (c). Three months after surgery showing 42 kyphosis (d). Six months after surgery showing 43 kyphosis (e). Eighteen months after surgery showing kyphosis stable at 43 (f ). Total loss after the correction of kyphosis was 13 .
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The four conditions of spinal TB that can be managed by various surgical procedures are cold abscess, tuberculous lesions, paraplegia, and spinal deformity. In most cases, small and medium-size cold abscesses rapidly resolve spontaneously with chemotherapy alone. Surgical abscess drainage does not alter the patients’ general condition. Emergency decompression drainage should be carried out for the sudden onset of respiratory difficulty due to prevertebral abscess compressing the trachea or spinal cord compression above C4.6,32 Focal debridement of the lesion is rarely indicated because evidence suggests it does not improve healing or prevent progressive kyphosis.31 Radical debridement may also damage the uninvolved growth plates in children.1,2,6,47 Anterior radical surgery was once advocated as the treatment of choice for spinal TB; however there were problems with frequent graft failure, prevention of the progression of kyphosis and/or correcting pre-existing kyphosis.6 Posterior or anterior instrumentation surgery have since contributed greatly to the treatment of TB of spine. Early neurological recovery from paralysis can be achieved from these procedures as well as prevention and correction of deformity. Instrumentation has hastened intercoporeal fusion by maintaining stability of the graft and the diseased segment preventing graft slip out and fracture. Consequently, the patient’s quality of life has been greatly enhanced. A topic of great controversy is the degree of acceptable residual kyphosis, which is related to both aesthetic and biomechanical considerations. Deformity prevention and/or correction are currently based on the predictive value of residual kyphosis.12,39,61,62 The value can be calculated using the following formula12:
involvement, and vertebral body remnant shape. Dislocation of facets, posterior retropulsion of the diseased small remnant body fragment and toppling of the cephalad vertebra suggest a worse prognosis for kyphosis.1,5,6,12 Buckling (invaginating angulatory) collapse of the spine is unique to advanced paediatric TB at the lower dorsal and dorsolumbar spine. Fortunately, the above risk factors have not been seen in early TB. The deformity in children could correct spontaneously due to bone reformation from the growth plates.6 However, in most children with advanced disease, despite disease healing, there is a gradual increase of deformity as a consequence of growth plate destruction. When the affected unfused segment is not stabilized, the deformity progresses more rapidly than when the block vertebrae are fused.6,12,65 Therefore, prophylactic instrumentaided stabilization and/or corrective procedures should be considered to prevent further progression of kyphosis.6 There are contradicting views on the effect of a small wedged-single vertebral body remnant and the fused wedge block vertebrae on the development of kyphosis during growth. Upadhyay et al. concluded that there was no disproportionate posterior spinal growth that worsened the deformity after anterior intercorporeal fusion.46 On the contrary, Schulitz et al. observed progressive kyphosis in children with fused block vertebrae.10 Rajasekaran reported a posterior longitudinal overgrowth in cases of unfused tuberculous kyphosis after healing of TB that eventually caused facet joint subluxation with a great risk of spinal deformity, which was supported by the current authors.12,63 In children, posterior tether instrumentation is expected to be a successful procedure for growth correction of the kyphotic spine. Spontaneous intercorporeal fusion rarely occurs during chemotherapy in children.1,2,6,12,40,49,63 This phenomenon has not been satisfactorily explained. A study of bone morphogenetic protein (BMP), anti-BMP factors and other inflammatory cytokines in the tissue around the tuberculous lesion may clarify the cause.13,32
Final kyphosis ¼ 5:5 þ 30:5 degree of vertebral body destruction in 10 gradesð0:1 1:0Þ The predictive value of this formula was initially reported by Rajasekaran et al. to be around 90%, though when reassessed by Jain et al. this value was reported to be around 78%.12,39 The current authors’ view is that the discrepancy arose because of the inaccurate estimation of initial vertebral body loss, since perfect estimation of vertebral body loss at pre-chemotherapy is impossible. The numerical discrepancy of final kyphosis can reach 6.1 (30.5 0.2) because of 10% over- or underestimation of vertebral body destruction. In 2008, Oguz et al. presented a new classification and guideline for surgical treatment; however it did not address several important issues such as consideration of the patients’ aesthetic demands associated with long-term outcome, posterior element TB, adjacent segment disease and compensatory hyperlordosis above and below the residual kyphotic segment. It also did not include information in children and subsequently has not been widely advocated.27,64
Tuberculosis in the elderly The ageing body’s weakened immune system may contribute to the re-emergence of TB in previously infected individuals as they grow older. Indeed, the increased rates of TB, both endogenous reactivation and exogenous infection, may be associated with recently observed increases in life expectancy.20,24 Three and four drug regimens are well tolerated and effective. However, elderly patients frequently have co-morbidities, and the presence of concomitant diseases such as liver or renal failure may necessitate dosage adjustment of some of the treatment regimens.6,20,25 For example, streptomycin is excreted exclusively, and ethambutol predominantly, by the kidney. The dose of these drugs should be adjusted accordingly if prescribed for patients with renal insufficiency. The serum concentration of streptomycin should not exceed 5 mg/ml. If the patient is on dialysis, the dose should be given 5 h beforehand. Ethambutol should be given in a dose of 25 mg/kg three times weekly if the creatinine clearance is between 30 and 50 ml/min. Most of the other antituberculous medicines can be hepatotoxic. In patients with alcoholism or those who are hepatitis B antigen carriers, isoniazid, rifampicin, and one non-hepatotoxic drug should be given
Tuberculous kyphosis in children The risk of late kyphosis in children with Pott’s disease depends on age (greatest <5 years), level of involvement (thoracic most likely to occur), extent of the disease (>2 vertebrae make kyphosis most likely), growth plate damage, the patterns of
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to ensure that the duration of treatment does not need to be prolonged. 5
Pott’s paraplegia 6
Many factors affect recovery from Pott’s paraplegia.6,65,69,70 There are two treatment approaches: conservative (medical) and surgical decompression.6,64e68 The time-frame for surgery clearly depends on the intensity of the neurological deficit; dense and progressive deficits need much earlier surgical management because paraplegia usually resolves rapidly after adequate decompression6,65e67 The more severe the kyphosis, the worse the prognosis. In 1995, Tuli stated that a 60 kyphosis seems to be the watershed for possible neurological recovery after decompression surgery.16,39 He found that better neurological recovery was achieved in the early paralysis of the conservatively treated group, and in children.58,66 If neurological function in an adult with severe kyphosis worsens during chemotherapy, decompressive surgery alone is recommended in an attempt to restore normal neurology, though some surgeons have recommended combined decompression and corrective surgery.6 Our experience has been that posterior instrument-aided stabilization alone under the cover of antitubercular chemotherapy, regardless of the disease stage and/or severity of deformity, can hasten neurological recovery without direct decompression surgery.6,65,66,71 Historically, spinal cord tuberculoma has been excised surgically because there was no other therapeutic choice. However, we recommend combined antitubercular and degranulating agent therapy (anti-TNFa blocker treatment; subcutaneous injection of etanercept, 25 mg twice weekly up to 6e8 weeks) or steroids after the diagnostic biopsy.6 This therapy can obviate the need for total excisional surgery for tuberculoma.
7 8
9
10
11
12
13
14 15
16
Conclusions
17
Spinal TB is a curable disease with currently available chemotherapeutic agents. Due to the early detection and initiation of chemotherapy, and to improved surgical techniques, patients with kyphosis are nowadays rare. Selection of the correct therapeutic measures to minimize residual kyphosis in the highly mobile spinal segments after disease healing is important for the restoration of sagittal alignment. Even paraplegic patients can be well managed, with minimal residual effects, if early diagnosis and effective treatment are achieved. The development of posterior instrumentation has hastened neural recovery without the need for direct decompression. Spinal cord tuberculoma can be effectively treated without radical excision by combining the antituberculous medication and anti-TNFa blocker therapy with minimal residual disease. A
18 19
20
21 22
23
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Acknowledgements The authors thank Mr. Seog In Moon for his secretariat work.
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