Clinical Manifestations

Ramamurthi, quoting Boyd’s textbook of pathology, wrote: “There is no organ that TB cannot affect, there is no symptom that it cannot produce, and there is no disease that it cannot simulate.”6

According to the reported literature, subaxial TB may have neurological involvement in up to 50% of patients, whereas CVJ TB may have neurological involvement in 63% to 70%.1 The most common manifestations are severe neck pain (with or without suboccipital pain), restricted neck movements, and torticollis. The severity of neck pain, feeling of instability at the upper cervical spine, and restricted neck movements often force these patients to support their chin constantly with their hands. Myelopathy, manifesting as various grades of weakness and spasticity, often associated with spinothalamic tract and posterior column dysfunction, is frequently present.2 The other important neurological manifestations are paresis of the ninth and tenth cranial nerves manifesting as dysphagia, nasal regurgitation, and hoarseness of voice; hesitancy; precipitancy of micturition; and sensation of incomplete evacuation. The respiratory status of these patients is often compromised and may be evaluated at bedside by a single breath count 10 and a breath- holding time 10 seconds.2,7,8 Often these patients have a history of systemic signs of TB in the form of weight loss, night sweats, and fever. A history of endemicity is very important, as these patients often live in an area endemic for tubercular infection. They often have a history of contact with a person with TB or may have a past history of partially or even completely treated TB. TB at other sites may also be present. Commenting on the correlation between spinal cord compression and neurological deficits, al-Mulhim et al. stated that 50% narrowing of the cervical spine produces only mild to moderate deficits, and 75% narrowing causes severe deficits.9 Because neurological deficits in CVJ TB are a result of cervicomedullary compression and instability, predicting and prognosticating the progression of neurological deficits on the basis of the extent of cervicomedullary compression may lead to a false sense of security.1,2,10 Even patients with minimal demonstrable compression may present with severe deficits. During the stages of healing, the persistence of various grades of subluxation may not correspond with either the degree of neural recovery or the quality of mechanical stabilization achieved. Fang et al. reported sudden death associated with CVJ TB probably due to unrecognized instability at the CVJ.11

Edwards et al. listed the myriad presentations of CVJ TB:12

1. 
   

   Direct compression of the neuraxis by tubercular abscess or granulation tissue: these are usually extradural; however, intradural and intramedullary lesions have been reported.

   
   
2. 
   

   Osteoligamentous destruction causing either AAD or upward translocation of dens causing secondary compression of the medulla

   
   
3. 
   

   Combination of abscess formation with AAD

   
   
4. 
   

   Abscess formation presenting with lower cranial nerve palsy or spinal nerve root compression leading to occipital pain with or without paresthesias

   
   
5. 
   

   Dysphagia or airway compromise due to mechanical obstruction from the tubercular mass, which can extend to the posterior triangle or mediastinum

   
   
6. 
   

   Neck pain, stiffness, occipital headache, torticollis, fever, night sweats, weight loss, and so on

   
   
7. 
   

   Cervical lymphadenopathy and discharging sinuses

Stages of Disease

Lifeso proposed three stages of CVJ TB:13

• 
  

  Stage 1: minimal bony or ligamentous destruction; no AAD ( Fig. 36.1 )

  
  
• 
  

  Stage 2: minimal bony or ligamentous destruction; reducible or irreducible AAD present ( Fig. 36.2 )

  
  
• 
  

  Stage 3: significant bony or ligamentous destruction evident ( Fig. 36.3 )

Bhagwati et al. use the following grading system for various stages of the disease:14

• 
  

  Grade I: merely inflammatory involvement of bony structures of the CVJ with formation of granulation tissue and destruction of bone

  
  
• 
  

  Grade II: formation of a large retropharyngeal abscess with bony changes

  
  
• 
  

  Grade III: associated subluxation of the atlantoaxial joint, by bony destruction and/or laxity of apical and transverse ligaments

  
  
• 
  

  Grade IV: formation of epidural abscess and compression of the cervicomedullary junction and the upper cervical cord, with neurological deficits that may be mild or severe

Pathophysiology

Discharged aerosolized pulmonary secretions containing tuberculous bacilli, consumption of unpasteurized milk infected with Mycobacterium bovis, and inoculation with infected material may cause transmission of TB. The ability of TB bacilli to cause infection depends on the natural immunity and the antibacterial defenses of the person being infected. In 90% of infected persons, the organism remains dormant. The remaining 10% of individuals may present with early progressive disease within 5 years of exposure (5%) or with late recrudescent disease after several years of infection (5%).15

Cell-mediated immunity and a delayed-type hyper-sensitivity immunological process develop in the host against Mycobacterium tuberculosis. In cell-mediated immunity, the lymphocytes in the presence of tuberculous mycobacterial antigens produce local cytokines that attract monocytes and macrophages from the bloodstream into the lesion and activate them. Thus, it is a beneficial host response in which the activated macrophages produce reactive oxygen and nitrogen intermediates, lysosomal enzymes, and other products that kill and digest the bacilli. The tissue-damaging delayed type of hyper-sensitivity reaction, by the same process as cell-mediated immunity, causes caseous necrosis, producing the death of local bacilli-laden nonactivated macrophages and nearby tissues.15,16

The infection is divided into five stages. In stage 1, mature activated macrophages ingest and destroy the mycobacteria. In case the bacillus is not destroyed, it grows, multiplies, and destroys the activated macrophage. In stage 2, monocytes from the bloodstream reach the site of infection, convert to nonactivated macrophages, divide, and ingest the bacilli. The bacilli in turn multiply within the nonactivated macrophages. In stage 3, caseous necrosis occurs due to apoptosis produced by cytotoxic T cells and natural killer cells; anoxia due to thrombosis initiated by clotting factors produced by the macrophages; toxic cell products, such as free radicals, cytokines, tumor necrosis factor, hydrolytic enzymes, and complement; and toxic bacillary products, such as trehalose dimycolate. A delayed-type hypersensitivity reaction kills bacilli-laden macrophages. Thus, the center of the lesion is a solid caseous area where the extracellular bacilli (released due to macrophageal death) do not multiply. The nonactivated macrophages at the periphery permit intracellular bacilli multiplication. In this region, partially activated macrophages due to cell-mediated immunity also attempt to inhibit extracellular bacilli multiplication. In stage 4, if cell-mediated immunity is deficient, the bacilli at the periphery of the caseous necrosis multiply within peripherally situated nonactivated macrophages. A delayed hyper-sensitivity reaction kills these macrophages, causing enlargement of the caseous center and producing the clinically manifest disease. In cases with a good cell-mediated immunity, the activated macrophages ingest and destroy the bacilli, often arresting the lesion before it becomes clinically manifest. In stage 5, liquefaction of the caseous center occurs, and bacilli multiply extracellularly and overcome the cell-mediated immunity (as activated macrophages are ineffective in controlling extracellular multiplication of bacilli within a cavity).15,16

Skeletal TB occurs due to the hematogenous spread of bacilli following primary infection. Lymphatic drainage from other organs in the vicinity of the spine, such as the pleura and kidneys, may spread to the periaortic lymph nodes with erosion within the spine. The lesion may be solitary or multiple. The anterior part of the vertebral body adjacent to the subchondral bony plate is most often affected. In children, the disk is vascularized; therefore, tuberculous diskitis may occur. In adults, diskitis usually follows a vertebral body infection. The narrowed disk space seen on radiology is often due to a collapsed vertebral end plate in adults. TB of the craniocervical region may cause neurological deterioration due to the formation of tuberculous abscess, granulation tissue, or vertebral body or disk sequestra that cause thecal compression; the destruction and incompetence of ligaments leading to AAD that may be irreducible (leading to a narrow spinal canal) or reducible (leading to recurrent cord injury due to repeated flexion and extension movements of the neck); or the collapse of anterior spinal elements, leading to a cervical kyphotic deformity. The angle of kyphosis depends on the loss of vertebral body volume. It progresses until the vertebral bodies meet anteriorly or until the caseation and granulation calcify or ossify. An abscess may have subligamentous spread and move into adjacent ligaments along the subaxial spine or into soft tissue, producing a paraspinal abscess; may compress the pharynx, esophagus, or trachea; or even perforate a hollow viscus or body surface.

Pathology

There are three types of tuberculous lesions:

1. 
   

   Exudative lesions: there is migration of polymorphonuclear leukocytes, monocytes, and lymphocytes with vasodilation, edema, and a fibrinous exudate in the infected region.

   
   
2. 
   

   Proliferative lesions (tubercles) ( Fig. 36.4 ): these are granulomas containing numerous macrophages, epithelioid cells, and lymphocytes. The epithelioid cells within these tubercles are the activated macrophages with a vesicular nucleus. Langhans multinucleated giant cells are formed by fusion of two or more macrophages that surround caseous tissue too large for one cell to engulf.

   
   
3. 
   

   Composite lesions with both exudative and proliferative components: within the center of the cellular reaction is a necrotic amorphous caseative necrosis. Fibrosis and calcification may surround the granuloma or occur in its center.15–17

In patients with acquired immunodeficiency syndrome (AIDS), HIV reduces both the number and the functional capacity of CD4 cells, which produce macrophage-activating factors. In patients with good CD4 count levels, the pathology is similar to that of classic TB. When CD4 counts decrease, granuloma formation decreases, and there may be a large number of bacilli and positive mycobacterial cultures. Atypical mycobacterial infection also increases.

Investigations18

1. 
   

   Complete blood picture shows a relative serum lymphocytosis and raised erythrocyte sedimentation rate (ESR).

   
   
2. 
   

   Acid fast staining: the acid fast staining may be performed using (a) carbol-fuchsin methods, including the Zeihl-Neelsen and Kinyoun staining procedures, which stain the mycobacterial walls red against a methylene blue counterstain; and (b) the fluorochrome method using auramine O or auramine-rhodamine dyes, which stain the mycobacterium wall yellow to golden against a dark background. The Zeihl-Neelsen staining method uses heated carbol-fuchsin, and Kinyoun staining uses cold phenol to increase carbol-fuchsin penetration into the cell wall. The disadvantage of acid fast staining is the indiscriminate staining of both viable and nonviable mycobacteria.

   
   
3. 
   

   Culture: mycobacteria are slow growing and have a generation time much longer than common bacterial and fungal flora. Thus, overgrowth of the latter may occur when the specimen is obtained in a nonsterile manner. The mycobacterial cell wall has high lipid content and is more resistant to strong acids and alkalis. Alkaline solutions such as benzalkonium chloride and 4% sodium hydroxide may be used to eliminate bacteria from the contaminated specimens. The culture media on which the myco-bacteria may be inoculated include (a) egg-based media: these include whole eggs, potato flour, salts, glycerol, and malachite green, as well as Lowenstein-Jensen, Petragnani, and the American Thoracic Society media; (b) agar-based media, including the Middlebrook 7H10 and 7H11 media containing agar, organic compounds, salts, glycol, and albumin (7H11 also contains casein hydrolysate, which enhances growth of mycobacteria resistant to isoniazid); (c) selective media: Lowenstein-Jensen and Middlebrook selective 7H11 media are examples. Their base media include antimicrobial agents to inhibit contaminating bacteria. All media should be incubated for 6 to 8 weeks at 35°C within the first 3 to 4 weeks in an atmosphere of 5% to 10% CO₂. The colonies (rough, cauliflower-like, and colorless) should be subjected to an acid fast smear and subculture for identification. Nucleic acid probe testing may also be performed on them.18

   
   

   For faster detection of mycobacteria (in ∼10–12 days), BACTEC 460TB (Becton, Dickinson, Franklin Lakes, New Jersey) with liquid Middlebrook 7H12 medium containing 14C-labeled palmitic acid may be used. The growth of mycobacterium releases 14C, which is detected by a sensor. Deoxyribonucleic acid (DNA) probe identification and antibiotic susceptibility may also be performed using this system.

   
   
4. 
   

   Chromatography: with gas liquid chromatography and high-performance liquid chromatography, the long-chain fatty acids extracted from M. tuberculosis yield species-specific chromatographic peaks that may be used for the identification of mycobacteria. The results may be available within a few hours.

   
   
5. 
   

   Nucleic acid probes: mycobacterial cells are lysed. An acridinium-labeled DNA binds with the ribosomal ribonucleic acid (RNA) of the mycobacterium. The resultant DNA-RNA complex exhibits a chemiluminescence that may be measured in a luminometer.

   
   
6. 
   

   Detection of drug-resistant M. tuberculosis: drug resistance may be seen in patients who have already been treated for TB, patients living in endemic areas, and contacts of patients with resistant TB. When the M. tuberculosis is inoculated in the agar medium or in the BACTEC medium, the failure of the organism to multiply or to produce14 CO₂, respectively, in the presence of antibiotic is indicative of antibiotic susceptibility. Detection of molecular mutations associated with specific drug resistance may also be studied.

   
   
7. 
   

   Nucleic acid amplification methods: these facilitate early detection of M. tuberculosis by target, probe, or signal amplification systems. A transcription-based amplification system generates multiple copies of mycobacterial ribosomal RNA after the nucleic acids are released from the mycobacterial cells by sonication and their secondary structure has been disrupted by heat. Chemiluminescent-labeled DNA probes then detect these amplified ribosomal RNA. Another method uses a polymerase chain reaction–based assay that detects the ribosomal gene in the genome (DNA). The amplification is facilitated by oligonucleotide polymers, and the color developed by the horseradish peroxidase system detects the mycobacterium. The total time required with these methods is 5 to 7 hours. These tests, however, must be used in conjunction with conventional cultures and staining techniques or the diagnosis of TB.

   
   
8. 
   

   Tuberculin skin testing: this is used to diagnose tuberculous infection and not tuberculous disease. Subcutaneous infection with M. tuberculosis with tuberculin, composed primarily of tuberculoprotein obtained from heat-sterilized filtered and concentrated cultures of tubercle bacilli, induces a delayed type of hypersensitivity reaction in the infected patient. The initial tuberculous infection brings about a period of 6 to 8 weeks of sensitization when the sensitized T lymphocytes developing in the regional lymph nodes enter circulation. Restimulation of these lymphocytes by tuberculin subcutaneous injection in the form of purified protein derivative (0.1 mL of 5 tuberculin units; the Mantoux test) causes an indurated skin reaction in infected patients that is maximal at 48 to 72 hours and lasts for more than 96 hours. A r eaction size 5 mm after 48 to 72 hours clearly separates the reactors and nonreactors. In the presence of HIV virus infection, a reaction 5 mm to 5 tuberculin units of protein purified derivative is considered positive for tuberculous infection; a reaction size 10 mm is considered positive in the high-risk population, such as those belonging to countries with a high tuberculosis prevalence, intravenous drug users, residents of long-term facilities, such as prisons and mental institutions, those having conditions where the risk of tuberculosis is increased, such as diabetes mellitus, those on immunosuppressive treatment, and those with hematological and other malignancies. A reaction 15 mm is considered positive in other persons. A negative reaction to tuberculin testing does not rule out tuberculosis infection, as this may occur in renal failure, immunosuppression, AIDS, malignancies, fulminant bacterial and tuberculosis infection, and malnutrition. Positive reactions are obtained when patients have been infected with M. tuberculosis but do not have active disease, and when persons have been sensitized by nontuberculous mycobacteria or bacille Calmette-Guérin (BCG) vaccination (derived from M. bovis).

   
   
9. 
   

   Cytokine release assays: QuantiFERON-TB (Cellestis, Carnegie, Victoria, Australia) is used for the diagnosis of latent tubercular infection in a population with low to moderate risk. The test’s performance will probably be enhanced by the use of antigens such as ESAT-6 and CPF-10 that are present in M. tuberculosis but absent from BCG strains and most nontuberculous mycobacteria.19

   
   
10. 
    

    Serological evaluation for HIV 1 and 2 in immuno-compromised patients