Tuberculous bacilli have lived in symbiosis with mankind since time immemorial. 6 Tuberculosis will effect mankind as long as there is malnutrition, poor sanitation, and overcrowding. Exanthematous fevers, diabetes, aging, repeated pregnancies, and immunodeficiency also predispose to the disease. Development of clinical tuberculosis of the skeletal system is a reflection of a weakened immune status of the patient.
Currently, there are approximately 30 million people with tuberculosis worldwide, and of these 1% to 3% have involvement of the skeletal system. 24 Vertebral tuberculosis is the most common form of skeletal tuberculosis, accounting for 50% of all cases in some series. 15,24 The major areas of predilection are, in order of frequency, the spine, hip, knee, foot, elbow, hand, shoulder, bursal sheaths, and other sites. 3,15,24 In general, tuberculosis is monoarticular or in a localized segment of the vertebral column; however, in approximately 10% of patients, multiple lesions can be detected clinically and radiologically. 24,27
Pathology and Pathogenesis
An osteoarticular tubercular lesion results from hematogenous dissemination from a primarily infected focus, which may be active or quiescent, apparent or latent, in the lungs, lymph glands, or other viscera. The infection reaches the skeletal system through vascular channels, generally the arteries, as a result of bacteremia, or in the axial skeleton through Batson’s plexus of veins. Simultaneous involvement of the paradiscal parts of contiguous vertebrae in a typical spinal tuberculous lesion lends support to the concept that the bacilli are blood-borne. On routine investigation 20% of patients, and on isotope bone scans of the entire body and magnetic resonance imaging (MRI), 40% of patients have tuberculous involvement of viscera, lymph nodes, or other parts of the skeletal system which suggests spread of infection through the arterial blood supply.
Tuberculosis of Joints and Bones
Tubercular bacilli reach the joint space via the blood stream through subsynovial vessels, or indirectly from epiphyseal (more common in adults) or metaphyseal (more common in children) lesions, which erode into the joint space. Articular cartilage destruction begins peripherally and the weightbearing surfaces are preserved for a few months, providing the potential for good functional recovery with effective treatment in patients with early disease.
The disease may start in bone or in the synovial membrane, but one rapidly infects the other. The initial focus starts in the metaphysis in childhood or at the end of the bone in adults. An example of articular tuberculosis of the typical osseous areas of predilection for hip disease is shown in Figure 1.
Radiologically, there is local destruction and marked demineralization. In bones with superficial cortical surfaces (such as the metacarpals, metatarsals, phalanges, tibia, and ulna) the lesions may produce reactive subperiosteal new bone formation surrounding lytic areas. Metaphyseal tuberculous lesions may infect the neighboring joint through the capsule, or through destruction of the epiphyseal plate. Once the tubercular process has reached the subchondral region, the articular cartilage loses its nutrition and attachment to the bone, and may lie free in the joint cavity. Damage to the physis in childhood may result in shortening or angulation of the limb.
When infection starts as tuberculous synovitis, the course usually is slow. The synovial membrane becomes swollen and congested and an effusion develops. The granulation tissue from the synovium extends over the bone at the synovial reflections, producing erosions. At the periphery of the articular cartilage, granulation tissue forms a pannus, which erodes the margins and surface of the joint. In long-standing disease, flakes or loose sheets of necrotic articular cartilage and accumulations of fibrinous material in the synovial fluid may produce the rice bodies found in synovial joints, tendon sheaths, and bursae. Where articular surfaces are in contact, the cartilage is preserved for a long time because of the prevention of spread of the pannus. Necrosis of subchondral bone by the in-growth of tuberculous granulation tissue produces kissing lesions or sequestra on either side of the joint.
The initial response to infection is in the reticuloendothelial system. Polymorphonuclear cells accumulate and are placed rapidly by macrophages and mononuclear cells, which are highly phagocytic. The tubercle bacilli are phagocytosed and broken down. Their lipid is dispersed throughout the cytoplasm of the mononuclear cells, transforming them into epithelioid cells, characteristic of the tuberculous reaction. These are large, pale cells with a vesicular nucleus, abundant cytoplasm, indistinct margins and processes, which form an epithelioid reticulum. Langhans’ giant cells probably are formed by fusion of numerous epithelioid cells. Langhans’ cells are produced only if caseation necrosis has occurred in the lesion, and they often contain tubercle bacilli. Their main function is to digest and remove necrosed tissue. After approximately 1 week, lymphocytes form a ring around the peripheral part of the lesion. This mass, formed by the reactive cells of the reticuloendothelial tissues, constitutes a 1- to 2-mm nodule popularly known as the tubercle. Tubercles grow by expansion and coalescence. During the second week, caseation occurs in the center of the tubercle in patients who are not treated. This coagulation necrosis is caused by the protein fraction of tubercle bacilli. The caseous material may soften and liquefy, and this caseation necrosis (soft tubercle) is most diagnostic of tuberculosis or tuberculoid leprosy. In countries where tuberculosis is common and the physician has made the diagnosis based on clinical assessment and imaging modalities, histologic findings of chronic granulomas even without caseation necrosis establishes the diagnosis of tuberculous infection. 10
A marked exudative reaction is common in tuberculous infection of the skeletal system. This, and the products of liquefaction, form the cold abscess. It is composed of serum, leukocytes, caseous material, bone debris, and tubercle bacilli. The abscess penetrates the periosteum and the ligaments, and migrates or gravitates in various directions, following fascial planes and the sheaths of vessels and nerves. The cold abscess feels warm although the temperature is not elevated as high as in acute pyogenic infections. A superficial abscess may burst to form a sinus or an ulcer, lined with tuberculous granulation tissue. The size of a cold abscess is not proportionate to the degree of destruction caused by infection. The sinuses and superficial abscesses permit secondary bacterial infection that modifies the clinical, radiologic, and pathologic picture.
Osseous Changes and Tubercular Sequestra
After the infection, marked hyperemia and severe osteoporosis occur. The softened bone easily yields under the effect of gravity and muscle action, leading to compression, collapse, or deformation. Necrosis also may be caused by ischemic infarction of segments of bone.
Sequestration gives the appearance of coarse sand and rarely produces a radiologically visible sequestrum. Because of loss of nutrition, the adjacent articular cartilage or the intervening disc degenerate and also may become separated as sequestra. Some of the radiologically visible smaller sequestra in tuberculous cavities may result from calcification of caseous matter.
The Future Course of Tubercle
Before the availability of antitubercular drugs, the 5–year followup mortality of patients with osteoarticular tuberculosis was approximately 30%. 5,11 Modern antitubercular agents have changed the outlook considerably. Depending on the sensitivity pattern, host resistance, and the stage of the lesion at the inception of treatment, the tuberculous lesion may behave as follows. It may resolve completely; the disease may heal with residual deformity and loss of function; the lesion may be walled off completely and the caseous tissue may calcify; low-grade chronic fibromatous granulating and caseating lesion may persist (grumbling disease); and the infection may spread locally by contiguity and systematically by the blood stream.
Before pasteurization, the bovine type of bacillus was responsible for a great deal of osteoarticular tuberculosis. Most skeletal tuberculosis is a paucibacillary disease and is caused by typical mycobacteria. Positive cultures for acid-fast bacilli in osteoarticular tuberculous lesions are obtained in less than ½ of the patients. The best material for microbiologic assessment seems to be centrifuged material from an abscess, curettings from the walls of a cold abscess, or from the lining of sinus tract as close to the base (source) as possible in untreated patients.
Sensitivity of the Organism
There are several reports regarding the culture and sensitivity of tubercle bacilli isolated from osteoarticular lesions. 2,7,8,13,17,24 Resistance to various drugs is as follows: 7% to 10% for streptomycin; 4% to 10% for paraaminosalicylic acid; 8% to 20% for isoniazid; 5% to 15% for thiacetazone; 2% to 9% for ethambutol; and approximately 2% for rifampicin. The development of resistant strains is minimized by multidrug therapy. Microbiologically, if the organism is resistant to isoniazid and rifampicin, it is called multidrug-resistant mycobacterium.
Disease Caused by Atypical Mycobacteria
The term atypical mycobacteria refers to mycobacteria other than mycobacterium tuberculosis and mycobacterium bovis. These organisms rarely may be responsible for infective lesions in the skeletal system. Synovial sheath infections are more common with atypical mycobacteria than infection of osseous tissue. With atypical mycobacterial infection, human-to-human transmission is uncommon. A history of trauma such as a puncture wound, open fracture, steroid injections, surgery, or exposure to contaminated marine life often is found. Many patients may have concomitant diabetes or immunodeficiency. A few reports of skeletal infection caused by mycobacterium kansasii, mycobacterium avium complex, mycobacterium fortuitum, and mycobacterium marinum are available in the literature. 12,19,21,22
Diagnosis and Investigation
Skeletal tuberculosis occurs mostly during the first 3 decades of life. In affluent societies, the disease is reported in the elderly. 1,16 The characteristics are insidious onset, monoarticular or single-bone involvement, and the constitutional symptoms of low-grade fever, lassitude (especially in the afternoon), anorexia, loss of weight, night sweats, tachycardia, and anemia. Local symptoms and signs are pain and night cries, painful limitation of movement of the afflicted joint, muscle wasting, and regional lymph node enlargement. During the acute stage, protective muscle spasm is severe. During sleep, the spasm relaxes and permits movement between the inflamed surfaces, resulting in pain and night cries.
In developing countries in general, the diagnosis of tuberculosis of bones and joints can be made reliably on clinical and radiologic examinations. However, in affluent countries tuberculosis has been reduced to the status of a rare disease, and the current generation of doctors is unfamiliar with the skeletal manifestations of the disease. In such situations and whenever there is doubt, positive proof of the disease must be obtained by semiinvasive investigations. Skeletal tuberculosis must be included in the differential diagnosis of chronic or subacute monoarticular arthritis, chronic abscess, a draining sinus, or chronic osteomyelitis. Local pain, swelling, and limitation of joint movement may precede discernible radiologic changes by 4 to 8 weeks. Pain usually is localized to the joint but can be referred to other areas. The imaging characteristics of osteoarticular tuberculosis were described by Griffith et al. 7
A relative lymphocytosis, low hemoglobin, and increased erythrocyte sedimentation rate often are found in patients with the active stage of disease. An increased erythrocyte sedimentation rate, however, is not necessarily proof of activity of the infection. Its repeated estimation at 3- to 6-month intervals gives an index of the activity of the disease.
As a rule, a positive reaction is present in a patient infected with tuberculosis for more than 1 month. A negative test, in general, rules out the disease. The tuberculin test rarely may be negative although active tuberculosis is present, such as in immune deficiency states.
Whenever there is doubt (particularly in the early stages) it is mandatory to prove the diagnosis by obtaining a biopsy specimen of the diseased tissue (granulations, synovium, bone, lymph nodes, or margins of tuberculous ulcers). Microscopic examination of an aspiration, core biopsy, needle biopsy, or open biopsy will reveal typical tubercles in patients who are not treated. Epithelioid cells surrounded by lymphocytes, even without central necrosis or peripheral foreign-body giant cells, are adequate histologic evidence of tuberculosis in a patient who is suspected to have the disease. At the time of open biopsy of a joint or bone, the orthopaedic surgeon should do therapeutic synovectomy or curettage. The infections of bone and joint that present as granulomatous lesions in order of frequency are tuberculosis, mycotic infection, brucellosis, sarcoidosis, and tuberculoid leprosy.
Guinea Pig Inoculation
The tuberculous pus, joint aspirate, or diseased material may be injected intraperitoneally into a guinea pig. Examination in positive cases shows tubercles on the peritoneum 5 to 8 weeks later. Although it currently is not considered a cost-effective test, it perhaps is the most reliable proof of tuberculosis.
Smear, Culture, and Serology
The material prepared for guinea pig inoculation also may be submitted for smear and culture examination for acid-fast bacilli. In superficial joints, one may be able to aspirate synovial fluid. Analysis of synovial fluid does not provide pathognomonic information; however, in general the leukocyte count is elevated to approximately 20,000 mm3, there is a lowered glucose level, and poor mucin. Clear synovial aspirate is not an appropriate material for microbiologic investigation; however, it is an excellent material for polymerase chain reaction and nucleic acid probes.
Principles of Treatment of Osteoarticular Tuberculosis
Modern drugs promote the healing of sinuses, ulcers, and abscesses in patients previously unresponsive to extensive surgery. They also eliminate the danger of postoperative miliary and meningeal disease caused by dissemination of the tuberculous infection.
Death caused by uncontrolled disease, meningitis, miliary tuberculosis, amyloidosis, paralysis, and crippling now is rare. If a patient is diagnosed early and treated vigorously, healing can be accomplished without residual joint ankylosis or deformity.
With the use of modern drugs, the indications for surgery have become universally more selective and directed toward the prevention and correction of deformities, and the improvement in function of the diseased joints. 15,23,24,28 At the stage of tuberculous arthritis, if abscess formation has not occurred, the natural outcome generally is a fibrous ankylosis. If an abscess discharges and sinuses develop, the outcome may be a bony ankylosis. The prognosis in articular tuberculosis depends on the stage of the disease 24 when the specific treatment is started (Table 1). Concomitant disease must be treated and hospitalization is necessary only for patients with complications, or for patients requiring traction under supervision to correct deformities.
Rest, Immobilization, and Braces
In the active stage of disease, the joints are rested in the position of function using removable splints. Prolonged immobilization can lead to spontaneous ankylosis when joints are grossly destroyed. Patients with early disease are allowed 1 to 2 hours of intermittent, guarded active and assisted exercises while taking antitubercular drugs, with the aim of retaining a useful range of movement in the functional arc of the involved joint. Traction helps to correct deformity and to rest the diseased part. Gradual ambulation is encouraged with the help of suitable braces approximately 3 months after the start of treatment while healing is progressing. As the disease heals and pain subsides, weightbearing and activity are permitted. If there is steady progress, activity is increased within the limits of discomfort. The use of a brace is discontinued gradually after approximately 2 years.
Treatment of Abscess, Effusion, and Sinus
Palpable and large joint effusions are aspirated and 1000 mg of streptomycin alone or combined with injectable isoniazid (300 mg) is instilled at each aspiration. Local concentrations of antibiotics after parenteral administration may make this local instillation unnecessary. 26 Open drainage of an abscess is indicated if aspiration fails. Radiologically visible paravertebral abscess shadows do not need to be drained, unless decompression is done in patients with paraplegia or when diseased vertebrae are debrided. A prevertebral abscess in the cervical region is drained if it causes difficulty in swallowing or breathing. Drainage of a large paravertebral abscess also may be considered when its radiologic size increases markedly despite treatment.
A majority of ulcers and sinuses heal within 6 to 12 weeks under the influence of systemic antitubercular drugs. Less than 1% of patients with sinuses require longer treatment and excision of the tract, with or without debridement. Sinus ramification always is greater than can be appreciated and complete surgical excision therefore is impractical.
Combination chemotherapy should be used for an adequate length of time. Most of the antitubercular drugs potentially are toxic and resistance or intolerance to the drugs should be suspected when a patient fails to respond.
Multidrug Resistant Tuberculosis and Patients Who do not Respond
If the disease is caused by organisms resistant to isoniazid and rifampicin (multidrug resistant tuberculosis), if the disease is not controlled within 4 to 5 months, or if despite multidrug therapy, more active tuberculous lesions appear, one has to resort to second line drugs or potential antituberculous drugs. The situation is desperate in patients who do not respond. Immunomodulation in conjunction with drugs may be used in such patients. 20 A favorable response was reported in approximately 85% of patients. 25
Pending the availability of better immunomodulation techniques 20 the current author has evolved the following outline during the past 12 years to upgrade cell-mediated immunity. In brief, 150 mg of levamisol is given at night for 3 days at weekly intervals for a total of 45 tablets. 25 Four injections are administered once a month. The first and second infections are 0.1 mL intradermal (Bacillus Calmett-Guérin) injections and the third and fourth are intramuscular DPT injections (diphtheria vaccine + tetanus vaccine + Bordetella pertussis 20,000 million per 0.5 mL).
Surgery in Patients with Tuberculosis of Bones and Joints
No surgery is a substitute for a prolonged course of antitubercular drugs. A trial of conservative treatment is justified in most patients before surgery is contemplated. Nonoperative treatment usually is adequate in patients with pure synovial tuberculosis, low-grade or early arthritis of any joint, and even advanced (Stage III or IV) arthritis, especially in the upper extremity.
Surgery only should be considered once the general condition of the patient is stabilized by drug therapy, before the development of drug resistance. In general, a minimum of 1 to 4 weeks of therapy is advisable before any major surgical intervention.
Extent and Type of Surgery
Juxtaarticular osteotomy (to correct a fixed deformity), soft tissue release, synovectomy, and debridement should produce mobile, stable joints. If juxtaarticular osseous focus is threatening the joint, despite adequate antitubercular drugs, excisional surgery of the focus should be done. If activity of the disease does not resolve by drugs alone patients with tubercular synovitis and early arthritis respond to subtotal synovectomy combined with joint debridement, respectively. At any stage of the disease, if a lesion is resistant or the diagnosis is doubtful, surgery should be done. Debridement should be limited to infected synovium, sequestra, and cavities of pus and sinuses. Repetitive active and assisted movements of the joint preserve a functional arc of movement postoperatively.
In advanced arthritis of the knee, ankle, wrist, hip, and elbow, the position of function, if required, is achieved by operative debridement followed by the use of a splint for 3 to 6 months. If the disease has healed leaving a painless range of movement (20° or more) in an unacceptable position, a juxtaarticular osteotomy may be done to yield the best functional arc. Osteotomy also may be indicated to correct varus or valgus deformity. If the growth plates of the involved joint are open, surgical arthrodesis should be deferred until the child is older than 12 years.
Arthrodesis for the ankle and the wrist is acceptable to many patients because it causes the least disability. Arthrodesis of the knee may cause significant disability. There is, however, no better alternative to obtain a stable painless healed status in a patient with painful tuberculous arthritis of the knee. Arthrodesis for advanced disease of the hip is an accepted procedure; however, the satisfaction of the patient depends on his or her occupation and sociocultural environment. In the eastern hemisphere, patients would accept excisional arthroplasty to obtain a mobile painless hip despite the handicap of some degree of shortening and instability. The elbow is another joint where excision arthroplasty provides a satisfactory functional range of the joint with a varying degree of instability.
Total hip and total knee arthroplasty has been reported for healed or quiescent tuberculous disease. 4,10 Currently, the consensus is to consider the option of joint replacement in patients whose disease has remained inactive for approximately 10 years. Such operations must be followed with multidrug antitubercular therapy for 3 to 5 months after the procedure.
Relapse of Osteoarticular Tuberculosis or Recurrence of Complications
The incidence of relapse or recurrence is unknown because these complications may occur at any period during the lifetime of a patient, whether the initial treatment included excisional surgery. Reactivation may occur in 2% to 5% of patients as late as 20 years or more after apparent healing. 9,14,18,24
The causes of reactivation include prolonged use of systemic cortisone therapy, malnutrition, the development of diabetes or an immune deficiency state, or a surgical procedure or injury to the previously infected area. Dormant bacilli persisting in tissue for years may start multiplying under such circumstances.
Tuberculosis of the Spine
Vertebral tuberculosis accounts for 50% of all cases of skeletal tuberculosis. 1,3,6,15,24 In the majority of patients, the disease typically started in the paradiscal region. Narrowing of the disc often is the earliest radiologic finding. Any reduction in disc space, if it is associated with a loss of definition of the paradiscal margins of the vertebrae, suggests tuberculosis and occurs before the appearance of frank osseous destruction. These changes usually are evident only after infection has been present for 3 to 6 months, although advanced imaging may detect changes at approximately 6 weeks.
Most cases of tuberculosis of the spine heal without surgical intervention. However, uncertainty about the diagnosis, progressive bone destruction, and neurologic symptoms despite chemotherapy are definite indications for surgery in the active stage of disease (Fig 2).
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