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 tuberculous /tu·ber·cu·lous/ (too-ber´ku-lus) pertaining to or affected with tuberculosis; caused by Mycobacterium tuberculosis.
1. infection. It is reported that HIV-infected patients have fewer tuberculomas compared with non-HIV-infected patients. IC tuberculomas are granulomatous granulomatous /gran·u·lom·a·tous/ (-lom´ah-tus) containing granulomas.
Resembling a tumor made of granular material. lesions resulting from hematogenous hematogenous /he·ma·tog·e·nous/ (he?mah-toj´e-nus)
1. produced by or derived from the blood.
2. disseminated through the blood stream.
1. 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 caseous /ca·se·ous/ (ka´se-us) resembling cheese or curd; cheesy.
Of, relating to, or having the gross and microscopic features of tissue affected by caseation. 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 Parenchyma
A ground tissue of plants chiefly concerned with the manufacture and storage of food. The primary functions of plants, such as photosynthesis, assimilation, respiration, storage, secretion, and excretion—those associated with living shows edema and astrocytic as·tro·cyte
A star-shaped cell, especially a neuroglial cell of nervous tissue.
astro·cyt proliferation. These pathologic differences in the maturation level of tuberculomas constitute the basis of varied signal characteristics found on MRI 1. (application) MRI - Magnetic Resonance Imaging.
2. MRI - Measurement Requirements and Interface. in IC tuberculoma.
The paradoxical response to antituberculous therapy (ATT ATT
ammonia tolerance test. ), 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 Immune reconstitution inflammatory syndrome (IRIS) or immune reconstitution syndrome (IRS) is a condition seen in some cases of AIDS or immunosuppression, in which the immune system begins to recover, but then responds to a previously acquired opportunistic infection with an 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 Noun 1. highly active antiretroviral therapy - a combination of protease inhibitors taken with reverse transcriptase inhibitors; used in treating AIDS and HIV
drug cocktail, HAART (HAART HAART highly active antiretroviral therapy.
HAART Highly active antiretroviral therapy, triple combination therapy AIDS The concurrent administration of 2 nucleoside reverse transcriptase inhibitors–eg, AZT and 3TC, and a protease ). (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 Lymphadenitis Definition
Lymphadenitis is the inflammation of a lymph node. It is often a complication of a bacterial infection of a wound, although it can also be caused by viruses or other disease agents. during treatment of CNS See Continuous net settlement.
See continuous net settlement (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 Nonsteroidal Anti-Inflammatory Drugs Definition
Nonsteroidal anti-inflammatory drugs are medicines that relieve pain, swelling, stiffness, and inflammation. 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.
1. Wasay M, Kheleani BA, Moolani MK, et al. Brain CT and MRI CT and MRI
Two high technology methods of creating images of internal organs. Computerized axial tomography (CT or CAT) uses x rays, while magnetic resonance imaging (MRI) uses magnet fields and radio-frequency signals. Both construct images using a computer. 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 FRCP Fellow of the Royal College of Physicians.
Fellow of the Royal College of Physicians
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: firstname.lastname@example.org
Accepted January 12, 2006.