Review articleParadoxical reaction in HIV negative tuberculous meningitis
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.
Section snippets
Paradoxical manifestations
Typical clinical features of TBM include headache, vomiting, meningeal signs, focal neurological deficits, vision loss, cranial nerve palsies, and raised intracranial pressure. The presence of exudates, hydrocephalous, infarction, tuberculoma, and angiographic abnormalities are common neuroimaging abnormalities [13], [14]. During a paradoxical reaction, these clinical and neuroimaging manifestations are either aggravated or appear for the first time during illness, despite adequate
Pathogenesis
TBM is caused by MTB, an aerobic acid-fast pleomorphic bacillus. Transmission occurs primarily by inhalation of airborne droplet nuclei containing MTB into the lungs. MTB multiplies in alveolar macrophages, and soon the bacilli, by hematogenous route, disseminate to brain and other extrapulmonary sites. In the brain, MTB, typically, produces small caseating granulomas in the subpial region of the brain parenchyma. Tuberculous foci (Rich foci) may remain dormant for a long period. TBM develops
Case-1
A 24-year-old lady was admitted with fever, vomiting, and headache for 2 week duration. On examination, neck rigidity was present. CSF analysis showed an elevated protein level of 540 mg/dL, cell count of 90 cells/mm3 (all lymphocytes) and the CSF sugar level was 32 mg/dL. CT of brain was normal. CSF smear examination revealed acid-fast bacilli. She was treated with anti-tuberculous drugs and corticosteroids. There was a marked improvement in the patient with no headache at discharge. Two months
Differential diagnosis
CSF examination is required for the diagnosis of TBM. The “gold standard” for diagnosis is the demonstration of MTB in the CSF. Diagnostic confirmation is done either by Ziehl-Neelsen staining of CSF smear, CSF culture or by detection of the mycobacterial DNA by PCR. However, a majority of patients with TBM are diagnosed on clinical grounds alone without any bacteriological confirmation [13], [14].
It is crucial to recognize the phenomenon of paradoxical reaction, because it usually does not
Treatment
MTB, isolated from CSF of patients with paradoxical reaction is usually sensitive to all first-line anti-tuberculosis drugs [49]. In patients with tuberculous paradoxical reaction, World Health Organization recommended that anti-tuberculosis regimen can be administered without any alteration [61]. When paradoxical reaction, in the form of acute exacerbations, becomes a life-threatening and disabling, treatment with immuno-modulatory drugs may be required. (Table 1)
Prognosis
Reported outcomes are generally favorable in a majority of patients with paradoxical reactions during treatment for TBM. (Table 1) In a series, out of 63 TBM patients, 14 developed tuberculomas following anti-tuberculosis therapy. Eight patients had tuberculoma at inclusion and remaining 41 patients never had tuberculoma. At 12 months, the overall mortality was 14% (3/22) of whom, 2 patients had paradoxical tuberculoma. Although clinical deterioration was seen in patients with paradoxical
Conclusions
In patients with TBM, a paradoxical reaction is often associated with clinical deterioration. However, it does not necessarily represent treatment failure and anti-tuberculosis treatment need not be changed. Corticosteroids are considered to have a beneficial effect in symptomatic patients. Nonetheless, no randomized study is available to demonstrate the precise role of corticosteroids in patients with paradoxical reactions. Some forms of paradoxical reaction, like optochiasmatic and spinal
Conflict of interest
The authors declare that there are no conflicts of interest.
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