Paradoxical reaction in HIV negative tuberculous meningitis

Highlights

• A paradoxical reaction is a worsening of tuberculosis lesions or the appearance of a new lesion in patients who improved with treatment.

• In TBM, a paradoxical reaction does not represent treatment failure.

• Paradoxical reaction occurs as the result of an exaggerated immune response to mycobacterial antigens.

• Expansion of existing cerebral tuberculomas or appearance of a new tuberculoma is a frequent manifestation.

• Paradoxical reaction, like optochiasmatic and spinal arachnoiditis, is devastating.

• Corticosteroids have a beneficial effect. Mortality is rare.

Abstract

This review focusses on paradoxical reactions occurring during the treatment of tuberculous meningitis (TBM) in human immunodeficiency virus-negative cases. A paradoxical reaction is defined as the worsening of a pre-existing lesion or the appearance of new lesion in a patient whose clinical symptoms initially improved with anti-tuberculosis treatment. A number of different paradoxical reactions have been reported in patients with TBM including expansion of existing cerebral tuberculomas, and appearance of new tuberculomas, hydrocephalus, and optochiasmatic and spinal arachnoiditis. While the exact mechanism of paradoxical reactions is uncertain, an exaggerated immune reaction against Mycobacterium tuberculosis-associated antigens is currently the most accepted theory for tuberculous paradoxical reaction. Corticosteroids are considered to have a beneficial effect in the management of paradoxical reactions. Immuno-modulatory drugs, including tumor necrosis factor-α antagonists, thalidomide and interferon-γ have been used in isolated cases with more severe forms of paradoxical reactions.

Introduction

A paradoxical reaction is defined as the worsening of pre-existing tuberculous lesions or the appearance of new tuberculous lesions in patients whose clinical symptoms initially improved with anti-tuberculosis treatment [1], [2]. Paradoxical reactions must be distinguished from treatment failure, multidrug-resistance, drug toxicity, or clinical deterioration due to another infection or condition. Tuberculous meningitis (TBM) may be a manifestation of tuberculosis (TB)-associated immune reconstitution inflammatory syndrome (IRIS) [3]. IRIS refers to a paradoxical clinical deterioration following the initiation of antiretroviral therapy in patients co-infected with human immunodeficiency virus (HIV) and receiving anti-tuberculosis treatment [4]. High pathogen load and very low CD4⁺ T cell count are major risk factors of IRIS [4].

In 1974, Thrush and Barwick, for the first time, documented paradoxical reaction in a patient with central nervous system TB, who had multiple tuberculomas and developed a new tuberculoma during treatment with anti-tuberculosis drugs [5]. In 1980, Lees and co-workers described the first report of paradoxical reaction of TBM in 2 female patients, who paradoxically developed multiple cerebral tuberculoma and basal arachnoiditis [6].

Paradoxical reactions in HIV-negative patients have been reported with varying frequencies in literature. In 253 patients with pulmonary and/or extra-pulmonary TB, paradoxical reactions occurred in 1 out of 86 HIV-uninfected patients (< 1%) and IRIS in 21 of 167 HIV-infected patients (13%) [7]. In a cohort of 104 HIV-negative patients with culture-proven TB, paradoxical reactions were observed in 16 patients (15.4%) with a median time to onset of 56 days (range, 20–109 days) [8]. A study of 76 HIV-negative patients with extra-pulmonary TB showed a relatively high incidence of paradoxical reactions, occurring in 19 patients (25%) with median time to onset of 86 days [9]. Carvalho et al. reported paradoxical reactions in 11 of 137 HIV-negative patients having TB (8%) with a median time to onset of 107 days (range, 31–443 days) [10]. In 115 HIV-negative children with pulmonary and extra-pulmonary TB, 12 patients (10%) developed a paradoxical reaction [11]. None of the children in the paradoxical reaction group had received Bacillus Calmette–Guérin (BCG) vaccination, compared to 34 children (33%) in the other group who received BCG vaccination [11]. In a retrospective analysis of 61 HIV-negative patients with TBM, paradoxical changes in cerebrospinal fluid (CSF) were seen in 20 patients (32.8%) [12]. A CSF paradoxical reaction is defined as a progressive increase of lymphocytes or an increase in polymorphonuclear cells instead of lymphocytes.

For this review, we conducted an extensive literature search for case reports of paradoxical reactions occurring in HIV-uninfected patients receiving anti-tuberculosis treatment for TBM. Three cases treated by the authors are also presented.