Editorial

Central Nervous System

Tuberculosis and Paradoxical
Response
Mohammad Wasay, MD, FRCP
T
uberculosis (TB) is the 7th leading cause of death and
disability worldwide and has reached epidemic propor-
tions in both developed and undeveloped nations. Approxi-
mately 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 immuno-
logic response to tuberculous infection. It is reported that
HIV-infected patients have fewer tuberculomas compared
with non-HIV-infected patients. IC tuberculomas are granu-
lomatous 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 cen-
ter surrounded by a capsule containing collagenous tissue,
epithelioid cells, Langhans giant cells, and lymphocytes. Ac-
id-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 paren-
chyma shows edema and astrocytic proliferation. These patho-
logic differences in the maturation level of tuberculomas con-
stitute 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 clin-
ical or radiological worsening of pre-existing tuberculous le-
sions 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 re-
sponse is a component of immune reconstitution inflamma-
tory syndrome or immune restoration syndrome, which re-
sults 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 menin-
gitis with a paradoxical response to ATT. The patient devel-
oped TB lymphadenitis during treatment of CNS tuberculo-
sis. 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 in-
crease in number and size of tuberculoma may not neces-
sarily indicate treatment failure, and in fact, most author-
ities 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 use-
ful in these patients, but use of steroids has not been eval-
uated. 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 rou-
tinely use steroids x 4 weeks with ATT in non-HIV-in-
fected 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 treat-
ment 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.
From the Department of Medicine, the Aga Khan University, Karachi, Pa-
kistan.
Reprint requests to Mohammad Wasay, MD, FRCP, Department of Medi-
cine, the Aga Khan University, Karachi 74800, Pakistan. Email:
mohammad.wasay@aku.edu
Accepted January 12, 2006.
Copyright 2006 by The Southern Medical Association
0038-4348/02000/9900-0331
Southern Medical Journal Volume 99, Number 4, April 2006
331
References
1. Wasay M, Kheleani BA, Moolani MK, et al. Brain CT and MRI findings
in 100 consecutive patients with intracranial tuberculoma. J Neuroimag-
ing 2003;13:240247.
2. Gupta M, Bajaj BK, Khawaja G. Paradoxical response in patients with
CNS tuberculosis. J Assoc Physicians India 2003;51:257260.
3. Breen RA, Smith CJ, Bettinson H, et al. Paradoxical reactions during
tuberculosis treatment in patients with and without HIV co-infection.
Thorax 2004;59:704707.
4. Shelburne SA III, Hamill RJ. The immune reconstitution inflammatory
syndrome. AIDS Rev 2003;5:6779.
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;22:597602.
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;24:517519.
Please see Paradoxically Developed
Optochiasmatic Tuberculoma and Tuberculous
Lymphadenitis: A Case Report with 18 Month
Followup by MRI on page 388 of this issue.
The nation . . . doesnt simply need what we have. It
needs what we are.
Edith Stein
Editorial
332
2006 Southern Medical Association