Central nervous system tuberculosis and paradoxical response.

Tuberculosis (TB) is the 7th leading cause of death and disability worldwide and has reached epidemic proportions in both developed and undeveloped nations. Approximately 5 to 10% of tuberculosis cases involve the brain and central nervous system. Tuberculomas account for 10 to 30% of intracranial (IC) masses in TB-endemic areas. The clinical and neuroimaging features of tuberculoma are variable and may pose a diagnostic challenge in the absence of systemic TB or tuberculous meningitis. (1)

Tuberculomas most likely represent a robust immunologic response to tuberculous infection. It is reported that HIV-infected patients have fewer tuberculomas compared with non-HIV-infected patients. IC tuberculomas are granulomatous lesions resulting from hematogenous spread from a distant focus of tuberculous infection. Small granulomatous lesions called incipient tubercles join to form tuberculomas. These tuberculomas are composed of a necrotic caseous center surrounded by a capsule containing collagenous tissue, epithelioid cells, Langhans giant cells, and lymphocytes. Acid-fast bacilli may be seen in the necrotic center and capsule. Characteristics of the central necrotic area classify it as an immature or mature tuberculoma. Occasionally, the necrotic center is transformed into pus, leading to the formation of a tuberculous abscess. Outside the capsule, the brain parenchyma shows edema and astrocytic proliferation. These pathologic differences in the maturation level of tuberculomas constitute the basis of varied signal characteristics found on MRI in IC tuberculoma.

The paradoxical response to antituberculous therapy (ATT), which usually develops after two weeks of treatment, is well known. A paradoxical response is defined as the clinical or radiological worsening of pre-existing tuberculous lesions or the development of new lesions not attributable to the normal course of disease, in a patient who initially improved with ATT. Up to 10% patients with central nervous system TB report paradoxical response, and this number may be as high as 30% in HIV-infected patients. (2,3) The paradoxical response is a component of immune reconstitution inflammatory syndrome or immune restoration syndrome, which results from an exuberant inflammatory response toward incubating opportunistic pathogens. (4) Various reports in the recent literature have documented an increased incidence and severity of the paradoxical response in HIV-infected patients on highly active antiretroviral therapy (HAART). (3) Patients demonstrating a paradoxical response are more likely to have lower baseline lymphocyte counts, followed by a surge. (5) This surge may be profound in HIV-infected patients recently started on HAART.

In this issue of the Southern Medical Journal, Kalkan et al (6) report a case of IC tuberculoma and tuberculous meningitis with a paradoxical response to ATT. The patient developed TB lymphadenitis during treatment of CNS tuberculosis. The symptoms and MRI findings resolved after 18 months of treatment. M tuberculosis, isolated in this patient, was sensitive to first line ATT. The majority of patients with a reported paradoxical response do not have multidrug resistant TB and show clinical and neuroimaging response to routine ATT.

Patients recently started on ATT should be monitored for the development of paradoxical response, but an increase in number and size of tuberculoma may not necessarily indicate treatment failure, and in fact, most authorities recommend that these patients continue treatment with routine ATT. There are many reports suggesting resolution of paradoxical response with steroids. (7) The addition or continued use of steroids may be helpful in these patients and could prevent surgical intervention. In some patients, we have used steroids for up to three months. Although there are no controlled trials, it is our observation that non-HIV infected patients initially treated with ATT and steroids develop paradoxical response less often compared with ATT alone. HIV-infected patients with paradoxical response should be continued on ATT and antiretroviral therapy. Nonsteroidal anti-inflammatory drugs may be useful in these patients, but use of steroids has not been evaluated. Patients with IC tuberculoma usually require 12 months of ATT. We use a 4-drug regimen for the first 3 months and then a 3-drug regimen for 9 months. We routinely use steroids x 4 weeks with ATT in non-HIV-infected patients with IC tuberculoma. Patients recently started on ATT should be monitored for the development of paradoxical response, but an increase in number and size of the tuberculoma may not necessarily indicate treatment failure, and in fact most authorities recommend that their patients continue treatment with routine ATT. The IC tuberculoma may persist on MRI for up to 24 months or even longer in some patients. This is not considered a treatment failure, but is most likely due to some altered immune responsiveness. We believe there is no additional benefit in continuing ATT beyond 18 months in these patients.

References

1. Wasay M, Kheleani BA, Moolani MK, et al. Brain CT and MRI findings in 100 consecutive patients with intracranial tuberculoma. J Neuroimaging 2003;13:240-247.

2. Gupta M, Bajaj BK, Khawaja G. Paradoxical response in patients with CNS tuberculosis. J Assoc Physicians India 2003;51:257-260.

3. Breen RA, Smith CJ, Bettinson H, et al. Paradoxical reactions during tuberculosis treatment in patients with and without HIV co-infection. Thorax 2004;59:704-707.

4. Shelburne SA III, Hamill RJ. The immune reconstitution inflammatory syndrome. AIDS Rev 2003;5:67-79.

5. Cheng VC, Yam WC, Woo PC, et al. Risk factors for development of paradoxical response during anti tuberculous therapy in HIV-negative patients. Eur J Clin Microbiol Infect Dis 2003;22:597-602.

6. Kalkan A, Serhatlioglu S, Ozden M, et al. Paradoxically developed optochiasmatic tuberculoma and tuberculous lymphadenitis: a case report with 18-month follow-up by MRI. South Med J 2006;99:388-392.

7. Rodriguez-Bano J, Muniain MA, Aznar J, et al. Systemic paradoxical response to anti tuberculous drugs: resolution with corticosteroid therapy. Clin Infect Dis 1997;24:517-519.

The nation ... doesn't simply need what we have. It needs what we are.
--Edith Stein

Mohammad Wasay, MD, FRCP 

From the Department of Medicine, the Aga Khan University, Karachi, Pakistan.

Reprint requests to Mohammad Wasay, MD, FRCP, Department of Medicine, the Aga Khan University, Karachi 74800, Pakistan. Email: [e-mail]

Accepted January 12, 2006.