Two unusual sequelae of tuberculous meningitis despite treatment.

Abstract: We describe the case of a 22-year-old HIV-negative male who was diagnosed with tuberculous meningitis and subsequently went on to develop two highly unusual after effects of the meningitis. The first was a tuberculoma, which was discovered 28 days after the meningitis and occurred while the patient was taking a four-drug therapeutic regimen, despite adequate drug susceptibilities. The second was an even more unique sequela: tuberculous radiculomyelitis. This transpired only after the patient's glucocorticoids, which were initiated to treat the tuberculoma, were tapered off. These manifestations were successfully treated with the addition of corticosteroids to the antituberculous regimen. The typical clinical presentations of these diseases are reviewed and various means of pathogenesis proposed.

Key Words: central nervous system tuberculosis, tuberculoma, tuberculous radiculomyelitis

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The incidence of infection with Mycobacterium tuberculosis remains elevated globally. In the current decade, 300 million new infections, 90 million newly diagnosed cases, and 30 million deaths are predicted. Much of this increase can be attributed to the acquired immunodeficiency syndrome epidemic, prevailing poverty, and the lack of health care infrastructure where most needed. Although the lungs are the primary sites of the disease, other organs may also be affected. It has been estimated that as many as 10% of immunocompetent patients who have pulmonary tuberculosis (TB) will develop central nervous system disease. (1)

Tuberculous meningitis (TBM) is the most common form of central nervous system tuberculosis. It is a serious cause of morbidity and mortality in developing nations but is relatively rare in technically advanced countries. (1) We report the case of an immunocompetent patient who developed TBM and then, despite receiving optimal chemotherapy, had two atypical sequelae of TBM. The first complication was the development of an intracranial (IC) tuberculoma and the second was tuberculous radiculomyelitis, a form of neurologic tuberculosis rarely reported even in countries where tuberculosis of the central nervous system is common. (2)

Case Report

A 22-year-old Hispanic male presented to the hospital complaining of low back pain with radiculopathy and mild weakness that progressed over 2 weeks to lower extremity paralysis.

The patient was diagnosed with tuberculosis meningitis complicated by a tuberculoma in the cingulate gyrus of the frontal lobes bilaterally (Fig. 1) 4 months before this presentation. The tuberculoma developed 4 weeks after beginning therapy for TBM, despite adequate antimycobacterial therapy (based on subsequent susceptibility testing). The presenting complaints when the tuberculoma was discovered were neck stiffness, severe headache, vomiting, and confusion. The patient was also noted to have papilledema and elevated opening pressure on lumbar puncture (400 mm). At that time, the patient was started on corticosteroids in addition to his four-drug TB regimen [isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB)] and his symptoms resolved. Two months after starting therapy EMB and PZA were stopped because the drug susceptibility testing results revealed sensitivity to all first line drugs. He was placed on biweekly dosing of INH and RIF with pyridoxine 50 mg, and his steroids were tapered off. Administration of his medications was kept under direct observation; the patient was still under treatment at the time of the current presentation.

Physical examination displayed 0/5 strength in all muscle groups of both lower extremities and absent deep tendon reflexes. The patient denied urinary or fecal incontinence. Lumbar puncture was performed and cerebrospinal fluid analysis demonstrated elevated protein levels (278 mg/dL), glucose of 54 mg/dL, white blood cell count of 30 c/[micro]L (17% segmented neutrophils, 64% lymphocytes), with negative acid-fast bacillus stain and culture. MRI of the thoracolumbar spine revealed nodular enhancement of the dura covering the thoracic spinal cord and conus medullaris. There was also enhancement of the entire cauda equina (Fig. 2). The physical and radiographic findings were felt to be consistent with tuberculosis radiculomyelitis, so the patient was started on methylprednisolone 120 mg IV per day and began showing clinical improvement. By the time of discharge 10 days later, his strength had improved to 2 to 3/5 in both lower extremities. He was discharged on RIF and INH as well as prednisone 90 mg per day, with instructions to taper the dosage to 40 mg. Physical therapy was also begun. He would remain on this dosage for 6 to 12 months. After completing 12 months of treatment the patient had regained full strength and was normoreflexic in both lower extremities.

Discussion

The patient described above had two unusual and paradoxical responses to tuberculosis treatment. Initially, the patient developed an IC tuberculoma, despite being on an appropriate regimen, as evidenced by the susceptibilities. This complication typically occurs within 3 months of initial therapy and steroids improve the general outcome. (3) The common presenting signs and symptoms are headache, IC hypertension, seizures, and papilledema. (4)

Steroid use in tuberculous meningitis is controversial. There is concern regarding the bioavailability of the anti-TB drugs entering the central nervous system, upon restoration of the blood-brain barrier. This occurs due to the anti-inflammatory effects of glucocorticoids. However, there is evidence to suggest that their use is warranted and beneficial. (5) In our case, steroids were not started initially because of a delay in obtaining the positive culture results to verify tuberculous meningitis.

[FIGURE 1 OMITTED]

The above discussion is limited to steroid use in TBM. When a tuberculoma is detected, however, there is a definite indication for corticosteroids. It decreases the perilesional edema and IC pressure. In all reported cases, steroid use helped significantly. (6) Our patient had significant benefit and symptom remission upon institution of glucocorticoids.

The patient then developed TBRM, an even rarer sequela of TBM. TBRM is a generic term to include all cases of arachnoiditis, intradural spinal tuberculoma or granuloma, and spinal cord complications of TBM. (7)

The clinical picture is characterized by a variable onset of paraparesis that progresses over 1 to 2 months. Symptoms include root pain, paresthesias, bladder disturbance, and muscle atrophy. Paralysis then develops rapidly over a few days. It is not uncommon to find absent deep tendon reflexes with flaccidity in the lower limbs and the presence of an extensor plantar response. (8) Our patient had this presentation with the exception of bladder disturbance and extensor plantar response.

The typical cerebrospinal fluid (CSF) findings in patients with TBRM reveal an active inflammatory response with lymphocytosis, hypoglycorrhachia, and elevated protein level, probably as a result of CSF flow blocks. These alterations may persist despite sterilization of the CSF by treatment. (9)

[FIGURE 2 OMITTED]

As in the treatment of tuberculous meningitis, the use of glucocorticoids in TBRM is disputed. As a delay in treatment can lead to irreversible weakness, however, the use of steroids is justifiable. (2,8) A randomized trial is needed to help provide clarification on this matter.

The pathogenesis of progression of tuberculoma or TBRM while on adequate therapy is poorly understood. One theory suggests that chemotherapy against tuberculosis lesions causes destruction of bacilli and release of the tuberculous proteins, which mediate an immune reaction, resulting in expansion of the lesions. This is similar to lymph node enlargement in adequately treated glandular TB. Another possibility is that the agents have poor penetration into the CSF after the initial inflammation subsides. A third theory is that the mycobacteria are resistant to these agents and continue to grow. These explanations are not entirely plausible. If inflammation was the cause, reactions would be expected to occur more commonly and at relatively fixed intervals, rather than being a rare and random event. The issue of CSF penetration is also unlikely because the penetration of INH and PZA have been shown to be adequate even with a normal blood-brain barrier. (1) Neither can drug resistance explain the progression, as these patients later responded to the original drug regimen. (6)

The course of the above complications in our patient is noteworthy. As is typically the case, the patient developed the tuberculoma within 4 weeks of beginning therapy. The patient was started on glucocorticoid therapy for treatment of the tuberculoma and only started developing the symptoms of TBRM 2 weeks after the steroids were tapered off. Bouchez et al reported a case where the tuberculoma increased in size while corticosteroids were being reduced. (10) It can be conjectured that the steroids suppressed the inflammatory response that, upon discontinuation, ultimately resulted in the TBRM. We did not find any other reported cases of a patient developing both a tuberculoma and TBRM while on the appropriate treatment regimen.

One issue that needs further clarification is the efficacy of intermittent dosing of antituberculous agents following TBM. In our case the patient developed the TBRM after being switched to intermittent dosing.

Conclusion

The case presented displays two unusual complications of TBM. Both of the problems responded well to corticosteroids and continued tuberculous chemotherapy. The clinician needs to be aware of the potential for these sequelae in any patient with a history of TBM who develops worsening despite sufficient therapy. The pathoetiology of these processes is still not clear, but prompt recognition and treatment are necessary to prevent irreversible weakness and paralysis.

References

1. Garcia-Monco JC. Centralnervous system tuberculosis. NeurolClin 1999;17:737-759.

2. Prasad K, Volmink J, Menon GR. Steroids for treating tuberculous meningitis. Cochrane Infectious Disease Group, Cochrane Database of Systematic Reviews. 1, 2003.

3. Rao GP, Nadh BR, Hemaratnan A, et al. Paradoxical progression of tuberculous lesions during chemotherapy of central nervous system tuberculosis. J Neurosurg 1995;83:359-362.

4. Afghani B, Lieberman JM. Paradoxical enlargement or development of intracranial tuberculomas during therapy: Case report and review. Clin Infect Dis 1994;19:1092-1099.

5. Prasad K, Volmink J, Menon GR. Steroids for treating tuberculous meningitis. Cochrane Infectious Disease Group, Cochrane Database of Systematic Reviews. 1, 2003.

6. Naidoo, DP, Desai D, Kranidiotis L. Tuberculous meningomyeloradiculitis- a report of two cases. Tubercle 1991;72:65-69.

7. Wadia NH. Radiculomyelopathy associated with spinal meningitis (arachnoiditis) with special reference to the spinal tuberculosis variety. In: Spillane JD, ed. Tropical Neurology. Oxford: Oxford University Press, 1973, pp 63-69.

8. Wadia, NH, Dastur DK. Spinal meningitides with radiculomyelopathy. I. Clinical and radiological features. J Neurol Sci 1969;8:239-260.

9. Humphries M. The management of tuberculous meningitis. Thorax 1992;47:577-581.

10. Bouchez B, Arnott G. Paradoxical expansion of intracranial tuberculomas during chemotherapy. Lancet 1984;ii: 470-471.

Allen J. Blaivas, DO, Alfred Lardizabal, MD, and Reynard Macdonald, MD

From the Division of Pulmonary and Critical Care Medicine and the National Tuberculosis Center, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ.

Reprint requests to Allen J. Blaivas, DO, Division of Pulmonary and Critical Care Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, University Hospital I-354, Newark, NJ 07103. Email: [e-mail] (preferred for correspondence)

Accepted April 19, 2005.

The authors assert that they have not received any financial support during the writing of this paper, nor do have any proprietary interest in any product named in this paper.

RELATED ARTICLE: Key Points

* Tuberculoma and tuberculous radiculomyelitis are possible sequelae of even appropriately treated tuberculous meningitis.

* Corticosteroids are useful to treat both of these manifestations of central nervous system tuberculosis in conjunction with continued use of antituberculous treatment.

* The exact etiologies of these diseases are poorly understood, though several theories have been advanced.

* Unrecognized tuberculoma or tuberculous radiculomyelitis can lead to severe dysfunction and require prompt recognition and treatment.