Multidrug-resistant tuberculosis of the first cervical vertebra in an immunocompetent adolescent.

Abstract

Osteomyelitis is an uncommon manifestation of Mycobacterium tuberculosis disease. Approximately 1% of tuberculosis cases result in vertebral osteomyelitis. Only 3% of these cases have a cervical location, with involvement of the first or second vertebrae a rare finding.1 A complicating factor in the management of tuberculosis is the increasing emergence of multidrug-resistant organisms, especially in high incidence areas such as Southeast Asia and the Philippines. We present the diagnostic and therapeutic challenges of a case of tuberculosis of the first cervical vertebra and skull base caused by multidrug-resistant M. tuberculosis in an immunocompetent adolescent who had lived in the Philippines. Case report. A 12-year-old male who was born in the United States had lived in the Philippines for 5 years before his return to the US in November, 1994. After returning to school in Chicago in December, 1994, he had a 15-mm reaction to a Mantoux tuberculin skin test and a normal chest radiograph. His 10-year-old sister and 6-year-old brother also had reactive tuberculin skin tests and normal chest radio-graphs. His family initially denied contact with anyone with tuberculosis. The patient and his siblings were given prescriptions for isoniazid (300 mg/day) by the health department in Chicago. He reported taking isoniazid sporadically and in February, 1995, he developed posterior neck pain and weakness which increased in severity during the ensuing 6 months. His family moved to Houston in March, 1995, and no follow-up for treatment of the tuberculosis infection was arranged. In June, 1995, he noted an anterior cervical mass that became increasingly tender during the next 2 months. He was admitted to the Texas Children's Hospital Emergency Center in August, 1995, with persistent epistaxis. He had no history of fever, chills, cough, night sweats, abdominal pain or other bone/joint pain. He had anorexia and a weight loss of ∼10 to 14 pounds during the previous 6 weeks. Examination showed a thin male adolescent with a 4- by 5-cm firm, fixed, tender, left anterior cervical mass. There was no overlying erythema. He had decreased breath sounds in the right basilar lung field. He had no palpable abdominal masses or organomegaly. He had no axillary, epitrochlear, inguinal or femoral adenopathy. He had tenderness in the upper cervical spine, with no tenderness in the thoracic, lumbar or sacral areas. He had full range of motion of all extremities but severe limitation of neck extension secondary to pain and weakness. Neurologic examination was otherwise normal. He had no paresthesia or motor or sensory deficits and his deep tendon reflexes were normal. On admission the patient had a hemoglobin of 11.8 g/dl and a white blood cell count of 12 800/mm3 (71% polymorphonuclear cells, 12% band forms, 8% lymphocytes, 9% monocytes). The platelet count was 542 000/mm3. The serum alanine and aspartate aminotransferase values were 25 IU/l and 20 IU/l, respectively. A human immunodeficiency virus enzyme-linked immunosorbent assay was negative. A chest radiograph demonstrated a right upper lobe consolidation. Computerized tomography of the head and neck demonstrated profound skull base and first cervical vertebra destruction. Numerous small abscesses were located within the prevertebral soft tissues, most markedly anterior to the second cervical vertebra. Substantial prevertebral soft tissue swelling extended from the clivus superiorly to the level of the forth and fifth cervical vertebrae inferiorly. Figure 1 demonstrates disruption of the anterior arch, with basilar invagination and compression of the medulla oblongata and upper cervical cord.Fig. 1The day after admission an incision and drainage of parapharyngeal and retropharyngeal abscesses was done with placement of halo traction. Acid-fast bacillus stains were negative. In addition to intraoperative mycobacterial cultures, three consecutive early morning gastric aspirates and urine samples were sent for mycobacterial culture. On the basis of the operative and radiographic findings and a high index of suspicion for drug-resistant tuberculosis, the patient was empirically treated with isoniazid 300 mg, rifampin 450 mg, pyrazinamide 1 g, ethambutol 300 mg and kanamycin 150 mg, each in one dose daily. The culture of the retropharyngeal pus grew M. tuberculosis after 54 days of incubation. Routine bacterial and fungal cultures were negative. The organism was sent to the National Jewish Center for Immunology and Respiratory Medicine in Denver, CO, and the organism was found to be resistant to isoniazid, rifampin, pyrazinamide, ethambutol, streptomycin, cycloserine and clarithromycin. It was moderately susceptible to ciprofloxacin and ofloxacin. The organism was susceptible to kanamycin, ethionamide, paraaminosalicylic acid and clofazimine. The susceptibility patterns were confirmed by minimum inhibitory concentration and agar plate testing, and when susceptibilities were known, isoniazid, rifampin, pyrazinamide and ethambutol were discontinued. He was then given ethionamide 500 mg daily, paraaminosalicylic acid 4 g twice a day, clofazimine 100 mg twice a day and ofloxacin 400 mg daily. Kanamycin was continued and an indwelling central venous catheter was placed for long term administration of medications. He was treated as an inpatient for 3 months while his neurologic status stabilized and the initial therapy was modified. At discharge, he was managed with outpatient directly observed therapy. He currently receives his weekly morning doses by directly observed therapy, but self-administers the evening doses of paraaminosalicylic acid and clofazamine. He has been examined monthly by one of the authors (JRS) in the county health department tuberculosis clinic to ensure medication adherence, to monitor medication side effects and to follow clinical progression. His skin has become bright orange-red from the clofazimine but he has adhered to medical therapy. His hearing, liver enzyme values and kidney function remain normal. His chest radiograph showed improvement during the initial 6 to 9 months of therapy and is now normal. He has regained his weight and is increasing in height, and his weakness, tenderness and anterior cervical mass have resolved. In September, 1996, the halo traction was removed because radiographs of his cervical spine were improved. He will continue directly observed antituberculosis therapy for a total of 2 years. Discussion. Tuberculosis can affect all levels of the spine, most commonly the thoracic vertebrae. The cervical spine is involved in only 2 to 3.5% of cases of spinal tuberculosis.1-3 Our patient had involvement of the first cervical vertebra as well as the base of the skull, which is even more rare, occurring in only 0.3% of reported cases of tuberculosis of the spine.1 The symptoms of tuberculosis of the cervical spine can persist for an extended period before an accurate diagnosis is made. Symptoms are usually present from 3 to 30 months, with an average of 16 months before diagnosis.1, 3 Tuberculosis of the cervical spine most frequently manifests itself initially by stiff neck, pain, dysphagia, torticollis, hoarseness and the constitutional symptoms of fever, anorexia and weight loss.4, 5 The role of our patient's epistaxis is unclear. Cervical lymphadenopathy is usually noted; it was present in all patients in one study of tuberculosis of the cervical spine.6 This is usually an unrecognized clinical finding that can be a clue to underlying spinal involvement. If significant neck pain or stiffness is present and cervical adenitis is encountered, the cervical vertebrae should be evaluated radiographically. Paraplegia or other abnormal findings on the neurologic examination are less common but can also be important clues to the presence of tuberculosis of the spine. The overall incidence of cord compression in cases of tuberculosis of the cervical spine is 42%, and 80% of affected patients are older than 10 years of age. Neurologic involvement tends to be gradual and symmetric in contrast to the usually acute and asymmetric involvement seen in metastatic disease.7 Our patient was fortunate to have no paraplegia or abnormal neurologic signs except for the marked neck extension pain and weakness. Neurologically normal patients with tuberculosis of the cervical spine have been described previously.6 The radiographic evidence of vertebral destruction, with anterior arch destruction of the first cervical vertebra, was typical of involvement by M. tuberculosis(Fig. 1). Osteolysis of the posterior portion of the vertebrae is more characteristic of pyogenic and metastatic diseases and is rarely seen with tuberculosis. Paravertebral abscess formation is common for tuberculosis of the spine, with an incidence of 57 to 62%.3, 8 Our patient's initial chest radiograph did not show the area of spinal involvement. Radiographic confirmation of tuberculosis of the cervical spine often requires computed tomography or magnetic resonance imaging which will also detect the presence of paravertebral abscesses. One complicating factor in our patient was the presence of multidrug-resistant tuberculosis. Both primary and acquired drug-resistant tuberculosis have become increasingly important in the global community.9 The rate of tuberculosis cases in the Philippines in 1993 was 274.4 cases per 100 000 population which was the second highest rate in the world.10 In a study of community-based treatment for tuberculosis in Manila, almost 80% of adult patients had tuberculosis with organisms that were resistant to one or more drugs at the start of therapy.11 This may represent a biased selection because of the availability of free medications in the study; overall the prevalence is probably closer to 40 to 65% (Resistance patterns of tuberculosis in metro Manila. Coalition against tuberculosis, Philippines, unpublished data). Our patient was an adolescent who was born in the United States but lived in the Philippines for several years and likely became infected in the Philippines. An uncle who died of "incurable" tuberculosis in the Philippines lived in his house and was the presumed source case. Because our patient was a US citizen he did not have an evaluation for tuberculosis as a requirement for reentry to the United States.12 His school screening elicited a reactive tuberculin skin test. A local health department was notified and follow-up was arranged. Isoniazid therapy was started; however, he had poor compliance and poor clinical follow-up was demonstrated. While receiving isoniazid he developed signs and symptoms compatible with tuberculosis. This emphasizes the importance of regularly scheduled follow-up appointments and physical examinations for all children being treated for tuberculosis infection. The treatment of tuberculosis of the cervical spine is a multidisciplinary approach consisting of abscess drainage, spinal stabilization, antituberculosis therapy and rehabilitation. The indications for operative management include neurologic deficits, spinal instability and unresponsiveness to medical therapy.5 Our patient's treatment was further complicated by the presence of drug-resistant organisms. Patients from communities in which there is a risk of single drug resistance (>4%) should be treated with isoniazid, rifampin, pyrazinamide and ethambutol until the drug susceptibilities are known.13 The ultimate regimen of antimicrobial therapy in patients with proved multidrug-resistant tuberculosis is determined by the susceptibility of the specific strain. Duration of therapy is determined by the location and extent of involvement. We chose 24 months of therapy because of severe bone and soft tissue involvement in an area that provides critical stability to the head and neck. The treatment of our patient's siblings is complicated. Neither of his two siblings has evidence of disease; however it is likely they are infected with the same strain of M. tuberculosis as our patient. Because we know the susceptibilities of our patient's strain, we chose ethionamide and paraaminosalicylic acid to treat his siblings, although there are limited data supporting clinical efficacy in this circumstance. Therefore close clinical follow-up will be the single most important aspect of their treatment. Both siblings have completed 10 months of this regimen and are doing well. Tuberculosis of the cervical spine should be considered in any patient who presents with neck pain, cervical adenopathy, neurologic abnormalities and a history of tuberculosis exposure or a reactive tuberculin skin test. The clinician must be aware of the possibility of drug-resistant tuberculosis in all patients who were born or lived in areas with a high prevalence of drug-resistant M. tuberculosis. Scott W. Lindquist, M.D. Barry A. Steinmetz, M.D. Jeffrey R. Starke, M.D. Department of Pediatrics; Baylor College of Medicine; Houston, TX