INT J TUBERC LUNG DIS 18(4):486–491 Q 2014 The Union http://dx.doi.org/10.5588/ijtld.13.0556
Predictors of paradoxical tuberculoma in tuberculous meningitis J. Kalita, S. Prasad, U. K. Misra Department of Neurology, Sanjay Gandhi Post-Graduate Medical Sciences, Lucknow, India SUMMARY
A tertiary care teaching hospital in Lucknow,
O B J E C T I V E : To evaluate the frequency and predictors of paradoxical tuberculoma in definite tuberculous meningitis (TBM) and its influence on TBM outcome. D E S I G N : Demographic, clinical, biochemical, cerebrospinal fluid (CSF) findings, CD4 counts and magnetic resonance imaging (MRI) findings of 34 patients with definite TBM included were noted. The patients received four-drug anti-tuberculosis treatment and prednisolone. They were followed up clinically and radiologically at 3 and 6 months; serum chemistry, CD4 counts and CSF were tested at 3 months. Functional outcome was defined on the basis of the Barthel index score. Predictors of paradoxical response were evaluated using univariate and multivariate analysis. R E S U LT S : The median age of the patients was 33.5 years; 13 were females. Of the 34 study participants, 22
patients developed paradoxical tuberculoma, mostly within 3 months of initiating anti-tuberculosis treatment. Paradoxical tuberculoma was associated with clinical deterioration in 12 patients. Bacille CalmetteGu´erin vaccination, higher CSF glucose and abnormal baseline MRI were associated with paradoxical tuberculoma in univariate analysis. After adjustment of covariates, only female sex was independently associated with paradoxical tuberculoma (OR 0.06, 95%CI 0.004–0.79, P ¼ 0.03). Paradoxical response, however, did not influence 6-month outcome. C O N C L U S I O N : Paradoxical tuberculoma occurs in two thirds of patients with definite TBM, and in 50% it is asymptomatic. Females are more susceptible to paradoxical tuberculoma; however, 6-month outcome is not influenced by paradoxical tuberculoma. K E Y W O R D S : tuberculosis meningitis; paradoxical response; CD4 count; MRI; cerebrospinal fluid
TUBERCULOUS MENINGITIS (TBM) is the most common subacute/chronic form of meningitis, resulting in death in 10–30% patients; about one third of survivors have long-term sequelae.1–5 Early diagnosis and prompt treatment of TBM is associated with good outcome. Paradoxical response in tuberculosis (TB), i.e., the appearance of new lesions in TB patients on anti-tuberculosis treatment, has been reported since early times. In children, the exacerbation of fever and the appearance of new radiological lesions have frequently been reported following treatment with streptomycin (SM), and its incidence dramatically increased following the introduction of combined isoniazid (INH) and SM treatment. The mechanism of paradoxical response was attributed to marked bacteriolysis and release of tuberculin in large amounts.6 Such exacerbations have most commonly been noted in TB of the lung, pleura, lymph nodes and brain.7–11 With the availability of computed tomography
(CT) and magnetic resonance imaging (MRI), changes in the central nervous system (CNS) such as tuberculoma, exudates, infarction and hydrocephalus can be monitored after starting anti-tuberculosis treatment. There are isolated case reports and short series of paradoxical response in patients with CNS TB.7–9,11–15 The majority of these studies are based on highly probable cases of TBM. In the acquired immune-deficiency syndrome, paradoxical response is more common after highly active antiretroviral therapy and anti-tuberculosis treatment (36%) than in those on anti-tuberculosis treatment alone before the administration of antiretroviral drugs (7%).10 The incidence of paradoxical response has been reported to range between 4.5% and 28% in TBM patients.2,8,16 In a study from an Italian TB clinic, 11 of 137 (8%) human immunodeficiency virus (HIV) negative patients had a paradoxical response after a median duration of 107 days (range 31–443).
SETTING:
India.
Correspondence to: J Kalita, Department of Neurology, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Raebareily Road, Lucknow 226 014, Uttar Pradesh, India. Tel: (þ91) 522 249 4167. Fax: (þ91) 522 266 8811. e-mail: [email protected]; [email protected] Article submitted 29 July 2013. Final version accepted 22 November 2013.
Paradoxical response in TBM
Paradoxical response was related to disseminated TB (29%) and extra-pulmonary TB (11%).15 There is a paucity of prospective studies evaluating paradoxical tuberculoma in definite TBM. In the present article, we report the frequency and predictors of paradoxical tuberculoma in patients with definite TBM and its influence on TBM outcome.
METHODS The study was conducted in a tertiary care teaching hospital in India. Consecutive patients with confirmed TBM admitted to the neurology service during August 2009 to February 2012 were included prospectively. The diagnosis of TBM was based on clinical, radiological and cerebrospinal fluid (CSF) criteria and confirmed by the presence of acid-fast bacilli (AFB) in CSF smear, culture (BD BACTECe, BD, Sparks, MD, USA), positive polymerase chain reaction (PCR) or immunoglobulin M (IgM) enzymelinked immunosorbent assay (ELISA).3 Evaluation A detailed clinical history including meningitic symptoms, seizures, focal neurological deficit and alteration in sensorium was noted. Bacille CalmetteGu´erin vaccination status was evaluated by history and examining for scars. Consciousness was assessed using the Glasgow coma scale (GCS). Cranial nerve palsy, papilloedema and focal weaknesses were noted. Sensation and cerebellar signs were tested in those patients who could cooperate. Presence of extra-CNS TB, such as pulmonary, lymph node, bone and other organs, were noted. The severity of meningitis was graded as Stage I (meningitis only), Stage II (meningitis with focal neurological signs or GCS score 11–14) and Stage III (meningitis with altered sensorium, GCS score ,10).17 Investigations Blood counts, erythrocyte sedimentation rate, haemoglobin, fasting blood sugar, serum creatinine, albumin, bilirubin, transaminases, calcium and electrolytes were measured, and chest radiography, electrocardiography and HIV serology were performed. Cranial MRI was performed using a 3T MRI system (Sigma GE Medical System, Milwaukee, WI, USA). T1, T2, FLAIR, DW1 and T1 contrast images were obtained in axial, coronal and sagittal planes. Exudates, hydrocephalus, infarction and granuloma were noted. Magnetic resonance angiography and venography were performed if indicated. Lumbar CSF was analysed for cell, protein and glucose. CSF smear, BACTEC culture, polymerase chain reaction and IgM ELISA were performed for Mycobacterium tuberculosis.
487
Treatment Patients were treated with a four-drug anti-tuberculosis treatment regimen consisting of INH, pyrazinamide, ethambutol and rifampicin (RMP) for 9 months, followed by INH and RMP for another 9 months. At our centre, patients are generally administered 18 months of anti-tuberculosis treatment, as in our experience the majority of TBM patients report late with severe illness. Patients also received prednisolone 0.8 mg/kg, maximum 40 mg daily for 1 month, which was tapered over the following month. During hospitalisation, patients were given medicine by the nursing staff; after discharge, treatment was supervised by the care giver to ensure compliance. Patients with raised intracranial pressure due to hydrocephalus were treated with osmotic diuresis, repeated lumbar puncture or ventriculoperitoneal shunt. The patients were followed up clinically at 1, 3 and 6 months; MRI was repeated at 1, 3 and 6 months. Paradoxical response Paradoxical response was defined as clinical or radiological worsening in patients with previous tuberculous lesions or the development of new lesions after 1 month of stabilisation or improvement on anti-tuberculosis treatment.15 We also recorded worsening or appearance of hydrocephalus, exudates, infarction and tuberculoma on repeat MRI; however, only paradoxical tuberculoma was considered for clinical correlation and for the evaluation of predictors. At the time of paradoxical response, symptomatic patients were given corticosteroids for a period of 6–8 weeks and anti-tuberculosis treatment was continued. Functional outcome Functional outcome was defined on the basis of Barthel index (BI) score at 3 and 6 months, and was categorised as poor (BI , 12), partial or complete (BI ¼ 20) recovery.5 Deaths during the study period were recorded. Statistical analysis The relationship of dependent variable paradoxical tuberculoma (absent ¼ 1, present ¼ 2) with age, sex (male ¼ 1, female ¼ 2), duration of illness, severity of meningitis (Stage 1 ¼ 1, Stage 2 ¼ 2, and Stage 3 ¼ 3), GCS score, drug-induced hepatitis (present ¼ 1, absent ¼ 2), associated comorbidities such as diabetes and alcohol intake (absent ¼ 1, present ¼ 2), CSF cell, protein, glucose, CD4þ count, serum albumin and baseline MRI changes (present ¼ 1, absent ¼ 2) were evaluated using the v2 test for categorical and independent t-test or Mann-Whitney U-test for continuous variables. Variables with a two-tailed P value of ,0.1 on univariate analysis were included in the logistic regression analysis using Hosmer-Leme-
488
The International Journal of Tuberculosis and Lung Disease
show goodness-of-fit to derive the best set of predictors for paradoxical tuberculoma. A variable was considered significant if two-tailed P values were ,0.05. Statistical analysis was performed using SPSS version 16 software (Statistical Product and Service Solutions, Chicago, IL, USA). Ethics approval The study was approved by the Institutional Ethics Committee of the Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow.
RESULTS Of 100 patients with TBM managed during the study period, 35 had definite TBM. After initiation of antituberculosis treatment, 1 patient deteriorated within 1 month and was excluded. The present study is therefore based on 34 patients with definite TBM. The median age was 33.5 years (range 16–60); 13 were females. The duration of illness ranged between 6 and 150 days (median 30). Eleven patients had extra-CNS TB (pulmonary 7, lymph node 3 and others 3). Twelve patients had seizures, 11 had cranial nerve palsy and 8 had focal weakness. Admission GCS scores ranged between 7 and 15. Nine patients had Stage I, 21 Stage II and 4 had Stage III meningitis. Eighteen patients were anaemic (haemoglobin , 12 g/dl). The mean leucocyte count was 8753 (þ standard deviation 4253/mm3) and baseline median CD4þ count was 230/mm3 (range 42 – 788). CD4þ count was .500/mm3 in 5, 300–500/mm3 in 6, 100– 300/mm3 in 12 and ,100/mm3 in 6 patients. None of the patients had HIV or had received cancer chemotherapy, radiotherapy, organ transplantation or had malignancy before manifesting TBM. Cranial MRI revealed basal exudates in 14, tuberculoma in 24, infarction in 6 and hydrocephalus in 15 patients. CSF revealed pleocytosis ranging from 10 to 1000/ mm3 (median 100), protein 71–800 mg/dl (median 199) and glucose 8–102 mg/dl (median 31). CSF smear revealed AFB in three patients; culture for AFB was positive in 13, PCR in 10 and IgM ELISA in 11 patients. Repeat CSF after 3 months of antituberculosis treatment, however, did not reveal AFB in smear and culture; drug susceptibility testing (DST) could therefore not be performed. During 6 months of anti-tuberculosis treatment, paradoxical response on repeat MRI (3 and 6 months) was noted in 27 patients, which included tuberculoma in 22, exudates in 10, hydrocephalus in 9 and infarction in 3 patients. The majority of the instances of worsening, however, were noted at 3 months. Radiological evidence of paradoxical response was associated with clinical deterioration in 11 patients; 9 deteriorated within 3 months and 2 within 3–6 months. Clinical deterioration correlated with paradoxical tuberculoma; 10/22 patients with
Table 1 Paradoxical clinical and radiological response following anti-tuberculosis treatment in patients with tuberculous meningitis Paradoxical response Clinical worsening Tuberculoma paradox Exudate paradox Hydrocephalus paradox Stroke paradox
Total
3 months
6 months
11 22 10 9 3
9 18 8 8 2
2 4 2 1 1
paradoxical tuberculoma had clinical deterioration, whereas only 1/12 patients without paradoxical tuberculoma deteriorated clinically (P ¼ 0.02). Paradoxical response in hydrocephalus, exudates and infarction, however, was not correlated with clinical deterioration. On MRI, paradoxical tuberculoma was associated with paradoxical infarction, hydrocephalus or exudates in 10 patients (Table 1). Paradoxical tuberculoma Of 22 patients with paradoxical tuberculoma, 5 did not have tuberculoma at baseline MRI; 16 patients with tuberculoma at baseline developed tuberculoma in another location, and 5 (4 of whom also had new tuberculoma) developed enlargement of existing tuberculoma (Appendix* Figures 1 and 2). Paradoxical tuberculoma was associated with paradoxical hydrocephalus in 6, exudates in 7 and infarction in 2 patients. Clinical deterioration at the time of paradoxical tuberculoma was present in 10 patients, in the form of worsening of consciousness in 5 and focal weakness in 10. These patients were given perenteral dexamethasone for a period of 1 week, followed by oral prednisolone for 6 to 8 weeks. The details of the patients with paradoxical tuberculoma are summarised in Table 2. Predictors of paradoxical tuberculoma The demographic and clinical variables were not related to occurrence of paradoxical tuberculoma. Occurrence of hepatotoxicity leading to the interruption of anti-tuberculosis treatment was also not associated with paradoxical tuberculoma (P ¼ 0.89): 10/19 (52.6%) patients with drug-induced hepatotoxicity had paradoxical tuberculoma, while 6/12 (50%) did not. Paradoxical tuberculoma was not related to baseline leukocyte count (P ¼ 0.24), haemoglobin (P ¼ 0.36), serum albumin (P ¼ 0.99), calcium (P ¼ 0.82) or alkaline phosphatase (P ¼ 0.05). Baseline mean CD4þ count in those patients with paradoxical tuberculoma was non-significantly higher than in those without (308 vs 232/mm3, P ¼ 0.34). CSF glucose was significantly higher in *The Appendix is available in the online version of this article at http://www.ingentaconnect.com/content/iuatld/ijtld/2014/ 00000018/00000004/00000020
Paradoxical response in TBM
Table 2
Clinical and radiological findings at the time of paradoxical tuberculoma and outcome at 6 months Paradoxical tuberculoma
Age Years 46 25 22 42 58 53 27 38 25 35 22 32 45 23 20 35 52 23 53 16 43 16
489
Sex
Stage
Male Female Female Male Male Male Female Female Female Male Female Female Female Male Female Male Male Female Male Male Male Female
2 1 2 2 2 2 1 1 2 1 2 3 2 2 2 2 2 1 2 3 1 2
New
Size
Other MRI findings
Both
Clinical worsening
þ
FND No FND GCS No No GCS No No No No GCS GCS FND No FND GCS No No FND No No
þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ
Exudate
Hydrocephalus
Stroke
Outcome
þ þ þ þ þ þ þ
þ þ þ þ þ þ -
þ þ -
Partial Complete Complete Expired Complete Partial Poor Complete Complete Complete Complete Poor Died Poor Complete Partial Partial Complete Partial Partial Complete Partial
and FND and FND
and FND and FND
and FND
MRI ¼ magnetic resonance imaging; ¼ increased; þ¼ positive; FND ¼ focal neurological deficit; - ¼ negative; ¼ reduced; GCS ¼ Glasgow coma scale.
patients with paradoxical tuberculoma than in those without (41.9 6 27.5 vs. 23.3613.3 mg/dl, P ¼ 0.03). CD4þ count and CSF analysis were repeated at 3 months, but did not reveal any significant difference between the patients with and those without paradoxical tuberculoma. Baseline MRI was more frequently abnormal in patients who developed paradoxical tuberculoma (P ¼ 0.01), and the frequency of exudates, infarction, hydrocephalus or tuberculoma at baseline was also higher in these than in those without tuberculoma, although this difference was not statistically significant (Table 3A and B). On logistic regression analysis, only female
sex was independently associated with paradoxical tuberculoma (OR 0.06, 95%CI 0.004–0.79, P ¼ 0.03): 11/13 (84.6%) females had paradoxical tuberculoma compared to 11/21 (52.4%) males. Outcome Among patients with paradoxical tuberculoma, 2 patients died and 3 had poor, 7 partial and 10 complete recovery, whereas in patients without paradoxical tuberculoma none died, 4 had partial and 8 had complete recovery. The outcome of the patients was not, however, related to paradoxical tuberculoma (P ¼ 0.33) (Table 3B).
Table 3A Comparison of demographic and clinical variables of patients with tuberculous meningitis with and without paradoxical tuberculoma following anti-tuberculosis treatment Paradoxical tuberculoma (n ¼ 22 ) n
No paradoxical tuberculoma (n ¼ 12 ) n
Age, years, mean þ SD
34.1 6 13.2
34.4 6 12.8
Female
11
´ Bacille Calmette-Guerin vaccination Duration of illness, days, mean 6 SD
6 36 6 30.8
2 3 57.6 6 55.3
P value 0.95 0.06 0.02 0.15
Seizures
9
3
0.35
Focal neurological deficit
8
6
0.44
GCS score
13.5 6 2.2
Stage of meningitis I II III
6 14 2
3 7 2
0.81
6
5
0.39
11
5
0.61
Extra-CNS tuberculosis Interruption of anti-tuberculosis treatment due to hepatotoxicity
13.3 6 2.
SD ¼ standard deviation; GCS ¼ Glasgow coma scale; CNS ¼ central nervous system.
0.87
490
The International Journal of Tuberculosis and Lung Disease
Table 3B Comparison of baseline laboratory and MRI findings in patients with tuberculous meningitis with and without paradoxical tuberculoma following treatment Paradoxical tuberculoma (n ¼ 22 ) Mean 6 SD
No paradoxical tuberculoma (n ¼ 12 ) Mean 6 SD
P value
Haemoglobin, gm/dl
12.1 6 1.5
11.5 6 2.5
0.36
Serum albumin, mg/dl Serum calcium, mg/dl
3.6 6 0.46 8.7 6 0.8
3.6 6 0.56 8.8 6 0.8
0.99 0.82
Alkaline phosphatase, KA units
177.5 6 118.1
316.8 6 279
0.05
Leukocyte count, /mm3
9395 6 4019
7575 6 4592
0.24
CD4þ, /ml Baseline At Month 3
308 6 208 577 6 176
232 6 187 531 6 212
0.34 0.57
Cerebrospinal fluid Cell, /mm3 Protein, mg/dl Glucose, mg/dl
138 6 115 216.1 6 169 41.1 6 27.1
230 6 323 178.3 6 61.3 23.3 6 13.9
0.23 0.46 0.04
Baseline MRI, n Normal Exudates Hydrocephalus Infarction Tuberculoma
0 10 10 9 17
3 4 5 3 7
0.01 0.42 0.83 0.35 0.25
Outcome at month 6, n Death Poor Partial recovery Complete recovery
2 3 7 10
0 0 4 8
0.33
MRI ¼ magnetic resonance imaging; SD ¼ standard deviation.
DISCUSSION In the present study, 64.7% of patients with definite TBM had paradoxical tuberculoma, 81.8% of which developed within 3 months of initiating anti-tuberculosis treatment. More than half of the patients with paradoxical tuberculoma were clinically unchanged. The reported incidence of paradoxical tuberculoma ranged between 4% and 28%.2,8,9,16 In a study of 31 patients with definite or highly probable TBM, 10 patients deteriorated clinically within 6 weeks of starting anti-tuberculosis treatment. Repeat CT scan in these patients revealed new abnormalities, in the form of hydrocephalus in 2, infarction in 4, exudates in 4 and granuloma in 2 patients.8 In another study, 25 TBM patients were followed up: 3 developed hydrocephalus, 7 persistent exudates for 11–96 months and 3 paradoxical tuberculoma.2 Teoh et al. reported paradoxical tuberculoma in 10/121 patients with TB. The initial TB disease in these 10 patients was meningeal in 5, miliary in 3 and pulmonary in 2. All of these patients had clinical deterioration after 10 days to 5 months of anti-tuberculosis treatment, which prompted a CT scan study and led to the diagnosis of paradoxical tuberculoma. With the continuation of anti-tuberculosis treatment, 5 patients recovered and 3 had mild neurological deficit.11 The few studies on paradoxical tuberculoma are mostly based on CT scan.2,11–13,15 However, small tuberculoma may be missed on CT scan. As the present study is based on contrast MRI, small lesions are less
likely to be missed. The higher frequency of paradoxical tuberculoma in the present study may be due to the sequential MRI evaluation in all patients. Of 35 patients with definite TBM 60% had moderate, 11.4% severe and 28.6% had mild meningitis. The upregulation of immunity may be responsible for paradoxical tuberculoma. However, the baseline CD4þ count was lower in the majority of our patients, but increased substantially after 3 months of antituberculosis treatment, suggesting that primary immune deficiency was unlikely in these patients. CD4 count at 3 months of anti-tuberculosis treatment was not different between patients with and those without paradoxical tuberculoma. The higher CSF glucose and baseline CD4 count in patients with paradoxical tuberculoma may suggest better immunity. However, further studies are needed to elucidate the basis of paradoxical tuberculoma. All of the patients received prednisolone in the initial phase of treatment. Previous studies have reported a lack of benefit of corticosteroids in reducing mortality or long-term sequelae,3–5 but later studies have shown the benefit of corticosteroids in TBM.18 Drug adherence, blood-brain and blood-CSF barriers and drug resistance may also contribute to paradoxical tuberculoma. In our study, all patients were adherent to antituberculosis treatment; however, hepatotoxic antituberculosis drugs had to be withdrawn temporarily due to anti-tuberculosis treatment-induced hepatitis in 16 patients; there was no difference in the
Paradoxical response in TBM
occurrence of paradoxical tuberculoma in patients with drug-induced hepatotoxicity compared to those without hepatotoxicity. On regression analysis, female sex was independently associated with paradoxical tuberculoma. The susceptibility of females to miliary pulmonary TB and TBM has been reported; 13/20 patients with TBM and miliary TB were females, and the majority of these patients were undernourished, as evidenced by anaemia in 13 and hypocalcaemia in 18 patients.19 Female sex hormones have been shown to reduce natural killer cell and macrophage activity in an experimental study.20 These may explain the higher frequency of paradoxical tuberculoma in females in the present study. Paradoxical response in the form of tuberculoma is more common in HIV patients.21 In one report, 36.4% of patients simultaneously receiving antituberculosis and antiretroviral drugs developed paradoxical tuberculoma, whereas it occurred in 7% of patients receiving anti-tuberculosis treatment before antiretroviral treatment and in 2% of non-HIV patients.10 None of our patients had HIV co-infection. Paradoxical tuberculoma in patients suspected of having TBM should raise the possibility of an alternative diagnosis. We therefore included patients with definite TBM only based on CSF microscopy, IgM ELISA and molecular diagnosis to avoid confusion. The possibility of drug-resistant TB, however, could not be commented upon as DST was not performed. Repeat CSF at 3 months did not, however, reveal AFB in any patient. Moreover, except for two patients, the study patients had improved to a variable degree on the same anti-tuberculosis treatment regimen, which excludes the possibility of resistant TB. The high frequency of paradoxical tuberculoma in TBM raises the question as to the most effective treatment strategy and need for future research into the basis of this condition, while the susceptibility of female sex to paradoxical tuberculoma needs further study to evaluate the underlying hormonal and immunological influence of sex on tuberculous infection. Acknowledgements The authors thank R K Nigam and D K Anand for secretarial help. Conflict of interest: none declared.
References 1 Thwaites G E, Nguyen D B, Nguyen H D, et al. Dexamethasone for the treatment of tuberculosis meningitis in adolescents and adults. N Engl J Med 2004; 351: 1741–1751. 2 Kingsley D P E, Hendrickse WA, Kendall B E, Swash M, Singh V. Tuberculosis meningitis: role of CT in management and prognosis. J Neurol Neurosurg Psychiatry 1987; 50: 30–36.
491
3 Misra U K, Kalita J, Roy A K, Mandal S K, Srivastav M. Role of clinical radiological and neurophysiological changes in predicting the outcome of tuberculous meningitis: an multivariable analysis. J Neurol Neurosurg Psychiat 2000; 68: 300–303. 4 Misra U K, Kalita J, Nair P P. Role of aspirin in tuberculous meningitis: a randomized open label placebo controlled trial. J Neurol Sci 2010; 293: 12–17. 5 Kalita J, Misra U K, Ranjan P. Predictors of long term neurological sequelae of tuberculous meningitis: a multivariate analysis. Eur J Neurol 2007; 14: 33–37. 6 Choremis C B, Padiatellis C, Zoumboulakis D, Yannakos D. Transitory exacerbation of fever and roentenographic findings during treatment of tuberculosis in children. Am Rev Tuberc 1955; 72: 527–536. 7 Smith H. Paradoxical responses during the chemotherapy of tuberculosis. J Infect 1987; 15: 1–3. 8 Ranjan P, Kalita J, Misra U K. Serial study of clinical and CT changes in tuberculous meningitis. Neuroradiology 2003; 45: 277–282. 9 Anuradha H K, Garg R K, Sinha M K, et al. Intracranial tuberculomas in patients with tuberculous meningitis: predictors and prognostic significance. Int J Tuberc Lung Dis 2011; 15: 234–239. 10 Narita M, Ashkin D, Hollender E S, Pitchenik A E. Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS. Am J Respir Crit Care Med 1998; 158: 157– 161. 11 Teoh R, Humphries M J, O’Mahony G. Symptomatic intracranial tuberculoma developing during treatment of tuberculosis: a report of 10 patients and review of the literature. Quart J Med 1987; 63: 449–460. 12 Pauranoic A, Bihjari M, Maheshwari M C. Appearance of tuberculoma during treatment of tuberculous meningitis. Jpn J Med 1987; 26: 332–334. 13 Malone J L, Paparello S, Rickman L S, Wagner K F, Monahan B, Oldfield E C. Intracranial tuberculoma developing during therapy for tuberculous meningitis. West J Med 1990; 152: 188–190. 14 Vidal C G, Fernandez S R, Lacasa J M, et al. Paradoxical response to antituberculous therapy in infliximab-treated patients with disseminated tuberculosis. Clin Infect Dis 2005; 40: 756–759. 15 Carvalho A C, De Iaco G, Saleri N, et al. Paradoxical reaction during tuberculosis treatment in HIV-seronegative patients. Clin Infect Dis 2006; 42: 893–895. 16 Ogawa S K, Smith M A, Brennessel D J, Lowy F D. Tuberculous meningitis in an urban medical center. Medicine (Baltimore) 1987; 66: 317–326. 17 British Medical Research Council. Streptomycin treatment of tuberculous meningitis. Lancet 1948; 1: 582–596. 18 Tor ¨ ok ¨ M E, Nguyen D B, Tran T H, et al. Dexamethasone and long-term outcome of tuberculous meningitis in Vietnamese adults and adolescents. PLOS ONE 2011; 6: e27821. 19 Kalita J, Misra U K, Ranjan P. Tuberculous meningitis with pulmonary miliary tuberculosis: a clinic-radiological study. Neurol India 2004; 52: 194–196. 20 Roberts C W, Walker W, Alexander J. Sex-associated hormones and immunity to protozoan parasites. Clin Microbiol Rev 2001; 14: 476–488. 21 Breen R A, Smith C J, Bettinson H, et al. Paradoxical reactions during tuberculosis treatment in patients with and without HIV coinfection. Thorax 2004; 59: 704–707.
Paradoxical response in TBM
Figure 1 Appearance of tuberculoma following anti-tuberculosis treatment in a patient with definite tuberculous meningitis. A), B) and C): baseline T1 contrast cranial MRI revealed A) acute left basal ganglia infarction. D), E) and F): imaging at 3 months revealing D) old infarction and E) appearance of tuberculoma in the left frontotemporal region and left cerebellopontine region. Radiological deterioration was associated with clinical deterioration (right hemiplegia and Glasgow coma scale score declined from 14 to 10). MRI ¼ magnetic resonance imaging.
Figure 2 Enlargement and appearance of new tuberculoma in a patient with definite tuberculous meningitis. A), B) and C): baseline T1 contrast MRI showing hydrocephalus and small ring enhancing granuloma in B) the temporal region. D), E) and F) are the corresponding MRI findings at 3 months following anti-tuberculosis treatment showing E) enlargement, as well as the appearance of new tuberculoma (D and F). MRI deterioration, however, was not associated with clinical deterioration. MRI ¼ magnetic resonance imaging.
i
ii
The International Journal of Tuberculosis and Lung Disease
RESUME
Centre hospitalier universitaire. Evaluer la fr e´ quence et les facteurs pr´edictifs de la m´eningite tuberculeuse (TBM) ainsi que leur influence sur le r´esultat. S C H E´ M A : De 34 patients pr e´ sentant une TBM confirm e´ e, on a recueilli leurs caract e´ ristiques d´emographiques, cliniques, biochimiques, l’analyse du liquide c´ephalo-rachidien (LCR), le nombre de CD4 et les r´esultats de l’imag´erie par r´esonance magn´etique (IRM). Les patients ont re¸cu quatre m´edicaments antituberculeux ainsi que de la prednisolone. Ils ont b´en´efici´e d’un suivi clinique et radiologique a` 3 et 6 mois ainsi que d’une analyse chimique du s´erum, un comptage des CD4 et une analyse du LCR a` 3 mois. Le r´esultat fonctionnel a e´ t´e d´efini sur la base de l’index de Barthel. Les facteurs pr´edictifs d’une r´eaction paradoxale ont e´ t´e e´ valu´es par analyse univari´ee puis multivari´ee. R E´ S U LT A T S : L’age ˆ m´edian des patients e´ tait de 33,5 CADRE :
OBJECTIF :
ans, 13 e´ taient des femmes ; 22 patients ont eu un tuberculome paradoxal, le plus souvent dans les 3 premiers mois du traitement anti-tuberculeux. Le tuberculome paradoxal e´ tait associ´e a` une d´et´erioration clinique chez 12 patients. La vaccination par le bacille Calmette-Gu´erin, une glycorachie plus e´ lev´ee et des anomalies initiales du IRM e´ taient associ´ees avec le tuberculome paradoxal en analyse univari´ee. Apr`es ajustement des covariates, seul le sexe f´eminin e´ tait ind´ependamment associ´e au tuberculome paradoxal (OR 0,06 ; IC95% 0,004–0,79 ; P ¼ 0,03). La r´eaction paradoxale n’avait cependant pas d’influence sur le r´esultat a` 6 mois. C O N C L U S I O N : Un tuberculome paradoxal survient chez deux tiers des patients pre´ sentant une TBM confirm´ee et il est asymptomatique chez 50% des patients. Il est plus fre´ quent chez les femmes et n’influence pas le r´esultat a` 6 mois.
RESUMEN M A R C O D E R E F E R E N C I A : Un hospital universitario de atencion ´ terciaria. O B J E T I V O : Evaluar la frecuencia y los factores pronosticos ´ de meningitis tuberculosa (TBM) y su repercusion ´ en el desenlace cl´ınico. M E´ T O D O : Participaron en el estudio 34 pacientes con TBM confirmada. Se registraron sus caracter´ısticas demogra´ficas, cl´ınicas y bioqu´ımicas, los ana´lisis del l´ıquido cefalorraqu´ıdeo (LCR), los recuentos de c´elulas CD4 y los resultados de la resonancia magn´etica (IRM). Los pacientes recibieron tratamiento con cuatro medicamentos antituberculosos y prednisolona. Se practico´ un seguimiento cl´ınico y radiogra´fico a los 3 y 6 meses y se repitieron la bioqu´ımica s´erica, el recuento de c´elulas CD4 y el ana´lisis del LCR a los 3 meses. El desenlace funcional se definio´ con base en la puntuacion ´ de la escala de Barthel. Se aplico´ un ana´lisis multifactorial a fin de examinar los factores pronosticos ´ de una respuesta paradojica. ´ R E S U LT A D O S : La mediana de la edad de los pacientes
fue 33,5 anos ´ pacientes ˜ y 13 fueron mujeres. Veintidos presentaron un tuberculoma paradojico, ´ en su mayor´ıa durante los 3 primeros meses del tratamiento antituberculoso. El tuberculoma parad ojico ´ se asocio´ con un deterioro cl´ınico en 12 pacientes. El ana´lisis monofactorial revelo´ como factores asociados con la aparici on ´ del tuberculoma la vacunaci on ´ antituberculosa, una glucorraquia ma´s alta y una IRM anormal inicial. Tras corregir las covariables, solo el sexo femenino se asocio´ de manera independiente con la aparicion ´ de tuberculoma paradojico ´ (OR 0,06; IC95% 0,004–0,79; P ¼ 0,03). La respuesta paradojica ´ no obstante, no influyo´ sobre el desenlace a los 6 meses. ´ N : El tuberculoma paradojico CONCLUSIO ´ ocurrio´ en dos tercios de los pacientes con diagnostico ´ confirmado de TBM y 50% de los casos evolucionaron de manera asintoma´tica. Las mujeres son ma´s susceptibles a la aparicion ´ del tuberculoma paradojico; ´ esta afeccion ´ no modifico´ el desenlace cl´ınico a los 6 meses.
Predictors of paradoxical tuberculoma in tuberculous meningitis J. Kalita, S. Prasad, U. K. Misra Department of Neurology, Sanjay Gandhi Post-Graduate Medical Sciences, Lucknow, India SUMMARY
A tertiary care teaching hospital in Lucknow,
O B J E C T I V E : To evaluate the frequency and predictors of paradoxical tuberculoma in definite tuberculous meningitis (TBM) and its influence on TBM outcome. D E S I G N : Demographic, clinical, biochemical, cerebrospinal fluid (CSF) findings, CD4 counts and magnetic resonance imaging (MRI) findings of 34 patients with definite TBM included were noted. The patients received four-drug anti-tuberculosis treatment and prednisolone. They were followed up clinically and radiologically at 3 and 6 months; serum chemistry, CD4 counts and CSF were tested at 3 months. Functional outcome was defined on the basis of the Barthel index score. Predictors of paradoxical response were evaluated using univariate and multivariate analysis. R E S U LT S : The median age of the patients was 33.5 years; 13 were females. Of the 34 study participants, 22
patients developed paradoxical tuberculoma, mostly within 3 months of initiating anti-tuberculosis treatment. Paradoxical tuberculoma was associated with clinical deterioration in 12 patients. Bacille CalmetteGu´erin vaccination, higher CSF glucose and abnormal baseline MRI were associated with paradoxical tuberculoma in univariate analysis. After adjustment of covariates, only female sex was independently associated with paradoxical tuberculoma (OR 0.06, 95%CI 0.004–0.79, P ¼ 0.03). Paradoxical response, however, did not influence 6-month outcome. C O N C L U S I O N : Paradoxical tuberculoma occurs in two thirds of patients with definite TBM, and in 50% it is asymptomatic. Females are more susceptible to paradoxical tuberculoma; however, 6-month outcome is not influenced by paradoxical tuberculoma. K E Y W O R D S : tuberculosis meningitis; paradoxical response; CD4 count; MRI; cerebrospinal fluid
TUBERCULOUS MENINGITIS (TBM) is the most common subacute/chronic form of meningitis, resulting in death in 10–30% patients; about one third of survivors have long-term sequelae.1–5 Early diagnosis and prompt treatment of TBM is associated with good outcome. Paradoxical response in tuberculosis (TB), i.e., the appearance of new lesions in TB patients on anti-tuberculosis treatment, has been reported since early times. In children, the exacerbation of fever and the appearance of new radiological lesions have frequently been reported following treatment with streptomycin (SM), and its incidence dramatically increased following the introduction of combined isoniazid (INH) and SM treatment. The mechanism of paradoxical response was attributed to marked bacteriolysis and release of tuberculin in large amounts.6 Such exacerbations have most commonly been noted in TB of the lung, pleura, lymph nodes and brain.7–11 With the availability of computed tomography
(CT) and magnetic resonance imaging (MRI), changes in the central nervous system (CNS) such as tuberculoma, exudates, infarction and hydrocephalus can be monitored after starting anti-tuberculosis treatment. There are isolated case reports and short series of paradoxical response in patients with CNS TB.7–9,11–15 The majority of these studies are based on highly probable cases of TBM. In the acquired immune-deficiency syndrome, paradoxical response is more common after highly active antiretroviral therapy and anti-tuberculosis treatment (36%) than in those on anti-tuberculosis treatment alone before the administration of antiretroviral drugs (7%).10 The incidence of paradoxical response has been reported to range between 4.5% and 28% in TBM patients.2,8,16 In a study from an Italian TB clinic, 11 of 137 (8%) human immunodeficiency virus (HIV) negative patients had a paradoxical response after a median duration of 107 days (range 31–443).
SETTING:
India.
Correspondence to: J Kalita, Department of Neurology, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Raebareily Road, Lucknow 226 014, Uttar Pradesh, India. Tel: (þ91) 522 249 4167. Fax: (þ91) 522 266 8811. e-mail: [email protected]; [email protected] Article submitted 29 July 2013. Final version accepted 22 November 2013.
Paradoxical response in TBM
Paradoxical response was related to disseminated TB (29%) and extra-pulmonary TB (11%).15 There is a paucity of prospective studies evaluating paradoxical tuberculoma in definite TBM. In the present article, we report the frequency and predictors of paradoxical tuberculoma in patients with definite TBM and its influence on TBM outcome.
METHODS The study was conducted in a tertiary care teaching hospital in India. Consecutive patients with confirmed TBM admitted to the neurology service during August 2009 to February 2012 were included prospectively. The diagnosis of TBM was based on clinical, radiological and cerebrospinal fluid (CSF) criteria and confirmed by the presence of acid-fast bacilli (AFB) in CSF smear, culture (BD BACTECe, BD, Sparks, MD, USA), positive polymerase chain reaction (PCR) or immunoglobulin M (IgM) enzymelinked immunosorbent assay (ELISA).3 Evaluation A detailed clinical history including meningitic symptoms, seizures, focal neurological deficit and alteration in sensorium was noted. Bacille CalmetteGu´erin vaccination status was evaluated by history and examining for scars. Consciousness was assessed using the Glasgow coma scale (GCS). Cranial nerve palsy, papilloedema and focal weaknesses were noted. Sensation and cerebellar signs were tested in those patients who could cooperate. Presence of extra-CNS TB, such as pulmonary, lymph node, bone and other organs, were noted. The severity of meningitis was graded as Stage I (meningitis only), Stage II (meningitis with focal neurological signs or GCS score 11–14) and Stage III (meningitis with altered sensorium, GCS score ,10).17 Investigations Blood counts, erythrocyte sedimentation rate, haemoglobin, fasting blood sugar, serum creatinine, albumin, bilirubin, transaminases, calcium and electrolytes were measured, and chest radiography, electrocardiography and HIV serology were performed. Cranial MRI was performed using a 3T MRI system (Sigma GE Medical System, Milwaukee, WI, USA). T1, T2, FLAIR, DW1 and T1 contrast images were obtained in axial, coronal and sagittal planes. Exudates, hydrocephalus, infarction and granuloma were noted. Magnetic resonance angiography and venography were performed if indicated. Lumbar CSF was analysed for cell, protein and glucose. CSF smear, BACTEC culture, polymerase chain reaction and IgM ELISA were performed for Mycobacterium tuberculosis.
487
Treatment Patients were treated with a four-drug anti-tuberculosis treatment regimen consisting of INH, pyrazinamide, ethambutol and rifampicin (RMP) for 9 months, followed by INH and RMP for another 9 months. At our centre, patients are generally administered 18 months of anti-tuberculosis treatment, as in our experience the majority of TBM patients report late with severe illness. Patients also received prednisolone 0.8 mg/kg, maximum 40 mg daily for 1 month, which was tapered over the following month. During hospitalisation, patients were given medicine by the nursing staff; after discharge, treatment was supervised by the care giver to ensure compliance. Patients with raised intracranial pressure due to hydrocephalus were treated with osmotic diuresis, repeated lumbar puncture or ventriculoperitoneal shunt. The patients were followed up clinically at 1, 3 and 6 months; MRI was repeated at 1, 3 and 6 months. Paradoxical response Paradoxical response was defined as clinical or radiological worsening in patients with previous tuberculous lesions or the development of new lesions after 1 month of stabilisation or improvement on anti-tuberculosis treatment.15 We also recorded worsening or appearance of hydrocephalus, exudates, infarction and tuberculoma on repeat MRI; however, only paradoxical tuberculoma was considered for clinical correlation and for the evaluation of predictors. At the time of paradoxical response, symptomatic patients were given corticosteroids for a period of 6–8 weeks and anti-tuberculosis treatment was continued. Functional outcome Functional outcome was defined on the basis of Barthel index (BI) score at 3 and 6 months, and was categorised as poor (BI , 12), partial or complete (BI ¼ 20) recovery.5 Deaths during the study period were recorded. Statistical analysis The relationship of dependent variable paradoxical tuberculoma (absent ¼ 1, present ¼ 2) with age, sex (male ¼ 1, female ¼ 2), duration of illness, severity of meningitis (Stage 1 ¼ 1, Stage 2 ¼ 2, and Stage 3 ¼ 3), GCS score, drug-induced hepatitis (present ¼ 1, absent ¼ 2), associated comorbidities such as diabetes and alcohol intake (absent ¼ 1, present ¼ 2), CSF cell, protein, glucose, CD4þ count, serum albumin and baseline MRI changes (present ¼ 1, absent ¼ 2) were evaluated using the v2 test for categorical and independent t-test or Mann-Whitney U-test for continuous variables. Variables with a two-tailed P value of ,0.1 on univariate analysis were included in the logistic regression analysis using Hosmer-Leme-
488
The International Journal of Tuberculosis and Lung Disease
show goodness-of-fit to derive the best set of predictors for paradoxical tuberculoma. A variable was considered significant if two-tailed P values were ,0.05. Statistical analysis was performed using SPSS version 16 software (Statistical Product and Service Solutions, Chicago, IL, USA). Ethics approval The study was approved by the Institutional Ethics Committee of the Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow.
RESULTS Of 100 patients with TBM managed during the study period, 35 had definite TBM. After initiation of antituberculosis treatment, 1 patient deteriorated within 1 month and was excluded. The present study is therefore based on 34 patients with definite TBM. The median age was 33.5 years (range 16–60); 13 were females. The duration of illness ranged between 6 and 150 days (median 30). Eleven patients had extra-CNS TB (pulmonary 7, lymph node 3 and others 3). Twelve patients had seizures, 11 had cranial nerve palsy and 8 had focal weakness. Admission GCS scores ranged between 7 and 15. Nine patients had Stage I, 21 Stage II and 4 had Stage III meningitis. Eighteen patients were anaemic (haemoglobin , 12 g/dl). The mean leucocyte count was 8753 (þ standard deviation 4253/mm3) and baseline median CD4þ count was 230/mm3 (range 42 – 788). CD4þ count was .500/mm3 in 5, 300–500/mm3 in 6, 100– 300/mm3 in 12 and ,100/mm3 in 6 patients. None of the patients had HIV or had received cancer chemotherapy, radiotherapy, organ transplantation or had malignancy before manifesting TBM. Cranial MRI revealed basal exudates in 14, tuberculoma in 24, infarction in 6 and hydrocephalus in 15 patients. CSF revealed pleocytosis ranging from 10 to 1000/ mm3 (median 100), protein 71–800 mg/dl (median 199) and glucose 8–102 mg/dl (median 31). CSF smear revealed AFB in three patients; culture for AFB was positive in 13, PCR in 10 and IgM ELISA in 11 patients. Repeat CSF after 3 months of antituberculosis treatment, however, did not reveal AFB in smear and culture; drug susceptibility testing (DST) could therefore not be performed. During 6 months of anti-tuberculosis treatment, paradoxical response on repeat MRI (3 and 6 months) was noted in 27 patients, which included tuberculoma in 22, exudates in 10, hydrocephalus in 9 and infarction in 3 patients. The majority of the instances of worsening, however, were noted at 3 months. Radiological evidence of paradoxical response was associated with clinical deterioration in 11 patients; 9 deteriorated within 3 months and 2 within 3–6 months. Clinical deterioration correlated with paradoxical tuberculoma; 10/22 patients with
Table 1 Paradoxical clinical and radiological response following anti-tuberculosis treatment in patients with tuberculous meningitis Paradoxical response Clinical worsening Tuberculoma paradox Exudate paradox Hydrocephalus paradox Stroke paradox
Total
3 months
6 months
11 22 10 9 3
9 18 8 8 2
2 4 2 1 1
paradoxical tuberculoma had clinical deterioration, whereas only 1/12 patients without paradoxical tuberculoma deteriorated clinically (P ¼ 0.02). Paradoxical response in hydrocephalus, exudates and infarction, however, was not correlated with clinical deterioration. On MRI, paradoxical tuberculoma was associated with paradoxical infarction, hydrocephalus or exudates in 10 patients (Table 1). Paradoxical tuberculoma Of 22 patients with paradoxical tuberculoma, 5 did not have tuberculoma at baseline MRI; 16 patients with tuberculoma at baseline developed tuberculoma in another location, and 5 (4 of whom also had new tuberculoma) developed enlargement of existing tuberculoma (Appendix* Figures 1 and 2). Paradoxical tuberculoma was associated with paradoxical hydrocephalus in 6, exudates in 7 and infarction in 2 patients. Clinical deterioration at the time of paradoxical tuberculoma was present in 10 patients, in the form of worsening of consciousness in 5 and focal weakness in 10. These patients were given perenteral dexamethasone for a period of 1 week, followed by oral prednisolone for 6 to 8 weeks. The details of the patients with paradoxical tuberculoma are summarised in Table 2. Predictors of paradoxical tuberculoma The demographic and clinical variables were not related to occurrence of paradoxical tuberculoma. Occurrence of hepatotoxicity leading to the interruption of anti-tuberculosis treatment was also not associated with paradoxical tuberculoma (P ¼ 0.89): 10/19 (52.6%) patients with drug-induced hepatotoxicity had paradoxical tuberculoma, while 6/12 (50%) did not. Paradoxical tuberculoma was not related to baseline leukocyte count (P ¼ 0.24), haemoglobin (P ¼ 0.36), serum albumin (P ¼ 0.99), calcium (P ¼ 0.82) or alkaline phosphatase (P ¼ 0.05). Baseline mean CD4þ count in those patients with paradoxical tuberculoma was non-significantly higher than in those without (308 vs 232/mm3, P ¼ 0.34). CSF glucose was significantly higher in *The Appendix is available in the online version of this article at http://www.ingentaconnect.com/content/iuatld/ijtld/2014/ 00000018/00000004/00000020
Paradoxical response in TBM
Table 2
Clinical and radiological findings at the time of paradoxical tuberculoma and outcome at 6 months Paradoxical tuberculoma
Age Years 46 25 22 42 58 53 27 38 25 35 22 32 45 23 20 35 52 23 53 16 43 16
489
Sex
Stage
Male Female Female Male Male Male Female Female Female Male Female Female Female Male Female Male Male Female Male Male Male Female
2 1 2 2 2 2 1 1 2 1 2 3 2 2 2 2 2 1 2 3 1 2
New
Size
Other MRI findings
Both
Clinical worsening
þ
FND No FND GCS No No GCS No No No No GCS GCS FND No FND GCS No No FND No No
þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ
Exudate
Hydrocephalus
Stroke
Outcome
þ þ þ þ þ þ þ
þ þ þ þ þ þ -
þ þ -
Partial Complete Complete Expired Complete Partial Poor Complete Complete Complete Complete Poor Died Poor Complete Partial Partial Complete Partial Partial Complete Partial
and FND and FND
and FND and FND
and FND
MRI ¼ magnetic resonance imaging; ¼ increased; þ¼ positive; FND ¼ focal neurological deficit; - ¼ negative; ¼ reduced; GCS ¼ Glasgow coma scale.
patients with paradoxical tuberculoma than in those without (41.9 6 27.5 vs. 23.3613.3 mg/dl, P ¼ 0.03). CD4þ count and CSF analysis were repeated at 3 months, but did not reveal any significant difference between the patients with and those without paradoxical tuberculoma. Baseline MRI was more frequently abnormal in patients who developed paradoxical tuberculoma (P ¼ 0.01), and the frequency of exudates, infarction, hydrocephalus or tuberculoma at baseline was also higher in these than in those without tuberculoma, although this difference was not statistically significant (Table 3A and B). On logistic regression analysis, only female
sex was independently associated with paradoxical tuberculoma (OR 0.06, 95%CI 0.004–0.79, P ¼ 0.03): 11/13 (84.6%) females had paradoxical tuberculoma compared to 11/21 (52.4%) males. Outcome Among patients with paradoxical tuberculoma, 2 patients died and 3 had poor, 7 partial and 10 complete recovery, whereas in patients without paradoxical tuberculoma none died, 4 had partial and 8 had complete recovery. The outcome of the patients was not, however, related to paradoxical tuberculoma (P ¼ 0.33) (Table 3B).
Table 3A Comparison of demographic and clinical variables of patients with tuberculous meningitis with and without paradoxical tuberculoma following anti-tuberculosis treatment Paradoxical tuberculoma (n ¼ 22 ) n
No paradoxical tuberculoma (n ¼ 12 ) n
Age, years, mean þ SD
34.1 6 13.2
34.4 6 12.8
Female
11
´ Bacille Calmette-Guerin vaccination Duration of illness, days, mean 6 SD
6 36 6 30.8
2 3 57.6 6 55.3
P value 0.95 0.06 0.02 0.15
Seizures
9
3
0.35
Focal neurological deficit
8
6
0.44
GCS score
13.5 6 2.2
Stage of meningitis I II III
6 14 2
3 7 2
0.81
6
5
0.39
11
5
0.61
Extra-CNS tuberculosis Interruption of anti-tuberculosis treatment due to hepatotoxicity
13.3 6 2.
SD ¼ standard deviation; GCS ¼ Glasgow coma scale; CNS ¼ central nervous system.
0.87
490
The International Journal of Tuberculosis and Lung Disease
Table 3B Comparison of baseline laboratory and MRI findings in patients with tuberculous meningitis with and without paradoxical tuberculoma following treatment Paradoxical tuberculoma (n ¼ 22 ) Mean 6 SD
No paradoxical tuberculoma (n ¼ 12 ) Mean 6 SD
P value
Haemoglobin, gm/dl
12.1 6 1.5
11.5 6 2.5
0.36
Serum albumin, mg/dl Serum calcium, mg/dl
3.6 6 0.46 8.7 6 0.8
3.6 6 0.56 8.8 6 0.8
0.99 0.82
Alkaline phosphatase, KA units
177.5 6 118.1
316.8 6 279
0.05
Leukocyte count, /mm3
9395 6 4019
7575 6 4592
0.24
CD4þ, /ml Baseline At Month 3
308 6 208 577 6 176
232 6 187 531 6 212
0.34 0.57
Cerebrospinal fluid Cell, /mm3 Protein, mg/dl Glucose, mg/dl
138 6 115 216.1 6 169 41.1 6 27.1
230 6 323 178.3 6 61.3 23.3 6 13.9
0.23 0.46 0.04
Baseline MRI, n Normal Exudates Hydrocephalus Infarction Tuberculoma
0 10 10 9 17
3 4 5 3 7
0.01 0.42 0.83 0.35 0.25
Outcome at month 6, n Death Poor Partial recovery Complete recovery
2 3 7 10
0 0 4 8
0.33
MRI ¼ magnetic resonance imaging; SD ¼ standard deviation.
DISCUSSION In the present study, 64.7% of patients with definite TBM had paradoxical tuberculoma, 81.8% of which developed within 3 months of initiating anti-tuberculosis treatment. More than half of the patients with paradoxical tuberculoma were clinically unchanged. The reported incidence of paradoxical tuberculoma ranged between 4% and 28%.2,8,9,16 In a study of 31 patients with definite or highly probable TBM, 10 patients deteriorated clinically within 6 weeks of starting anti-tuberculosis treatment. Repeat CT scan in these patients revealed new abnormalities, in the form of hydrocephalus in 2, infarction in 4, exudates in 4 and granuloma in 2 patients.8 In another study, 25 TBM patients were followed up: 3 developed hydrocephalus, 7 persistent exudates for 11–96 months and 3 paradoxical tuberculoma.2 Teoh et al. reported paradoxical tuberculoma in 10/121 patients with TB. The initial TB disease in these 10 patients was meningeal in 5, miliary in 3 and pulmonary in 2. All of these patients had clinical deterioration after 10 days to 5 months of anti-tuberculosis treatment, which prompted a CT scan study and led to the diagnosis of paradoxical tuberculoma. With the continuation of anti-tuberculosis treatment, 5 patients recovered and 3 had mild neurological deficit.11 The few studies on paradoxical tuberculoma are mostly based on CT scan.2,11–13,15 However, small tuberculoma may be missed on CT scan. As the present study is based on contrast MRI, small lesions are less
likely to be missed. The higher frequency of paradoxical tuberculoma in the present study may be due to the sequential MRI evaluation in all patients. Of 35 patients with definite TBM 60% had moderate, 11.4% severe and 28.6% had mild meningitis. The upregulation of immunity may be responsible for paradoxical tuberculoma. However, the baseline CD4þ count was lower in the majority of our patients, but increased substantially after 3 months of antituberculosis treatment, suggesting that primary immune deficiency was unlikely in these patients. CD4 count at 3 months of anti-tuberculosis treatment was not different between patients with and those without paradoxical tuberculoma. The higher CSF glucose and baseline CD4 count in patients with paradoxical tuberculoma may suggest better immunity. However, further studies are needed to elucidate the basis of paradoxical tuberculoma. All of the patients received prednisolone in the initial phase of treatment. Previous studies have reported a lack of benefit of corticosteroids in reducing mortality or long-term sequelae,3–5 but later studies have shown the benefit of corticosteroids in TBM.18 Drug adherence, blood-brain and blood-CSF barriers and drug resistance may also contribute to paradoxical tuberculoma. In our study, all patients were adherent to antituberculosis treatment; however, hepatotoxic antituberculosis drugs had to be withdrawn temporarily due to anti-tuberculosis treatment-induced hepatitis in 16 patients; there was no difference in the
Paradoxical response in TBM
occurrence of paradoxical tuberculoma in patients with drug-induced hepatotoxicity compared to those without hepatotoxicity. On regression analysis, female sex was independently associated with paradoxical tuberculoma. The susceptibility of females to miliary pulmonary TB and TBM has been reported; 13/20 patients with TBM and miliary TB were females, and the majority of these patients were undernourished, as evidenced by anaemia in 13 and hypocalcaemia in 18 patients.19 Female sex hormones have been shown to reduce natural killer cell and macrophage activity in an experimental study.20 These may explain the higher frequency of paradoxical tuberculoma in females in the present study. Paradoxical response in the form of tuberculoma is more common in HIV patients.21 In one report, 36.4% of patients simultaneously receiving antituberculosis and antiretroviral drugs developed paradoxical tuberculoma, whereas it occurred in 7% of patients receiving anti-tuberculosis treatment before antiretroviral treatment and in 2% of non-HIV patients.10 None of our patients had HIV co-infection. Paradoxical tuberculoma in patients suspected of having TBM should raise the possibility of an alternative diagnosis. We therefore included patients with definite TBM only based on CSF microscopy, IgM ELISA and molecular diagnosis to avoid confusion. The possibility of drug-resistant TB, however, could not be commented upon as DST was not performed. Repeat CSF at 3 months did not, however, reveal AFB in any patient. Moreover, except for two patients, the study patients had improved to a variable degree on the same anti-tuberculosis treatment regimen, which excludes the possibility of resistant TB. The high frequency of paradoxical tuberculoma in TBM raises the question as to the most effective treatment strategy and need for future research into the basis of this condition, while the susceptibility of female sex to paradoxical tuberculoma needs further study to evaluate the underlying hormonal and immunological influence of sex on tuberculous infection. Acknowledgements The authors thank R K Nigam and D K Anand for secretarial help. Conflict of interest: none declared.
References 1 Thwaites G E, Nguyen D B, Nguyen H D, et al. Dexamethasone for the treatment of tuberculosis meningitis in adolescents and adults. N Engl J Med 2004; 351: 1741–1751. 2 Kingsley D P E, Hendrickse WA, Kendall B E, Swash M, Singh V. Tuberculosis meningitis: role of CT in management and prognosis. J Neurol Neurosurg Psychiatry 1987; 50: 30–36.
491
3 Misra U K, Kalita J, Roy A K, Mandal S K, Srivastav M. Role of clinical radiological and neurophysiological changes in predicting the outcome of tuberculous meningitis: an multivariable analysis. J Neurol Neurosurg Psychiat 2000; 68: 300–303. 4 Misra U K, Kalita J, Nair P P. Role of aspirin in tuberculous meningitis: a randomized open label placebo controlled trial. J Neurol Sci 2010; 293: 12–17. 5 Kalita J, Misra U K, Ranjan P. Predictors of long term neurological sequelae of tuberculous meningitis: a multivariate analysis. Eur J Neurol 2007; 14: 33–37. 6 Choremis C B, Padiatellis C, Zoumboulakis D, Yannakos D. Transitory exacerbation of fever and roentenographic findings during treatment of tuberculosis in children. Am Rev Tuberc 1955; 72: 527–536. 7 Smith H. Paradoxical responses during the chemotherapy of tuberculosis. J Infect 1987; 15: 1–3. 8 Ranjan P, Kalita J, Misra U K. Serial study of clinical and CT changes in tuberculous meningitis. Neuroradiology 2003; 45: 277–282. 9 Anuradha H K, Garg R K, Sinha M K, et al. Intracranial tuberculomas in patients with tuberculous meningitis: predictors and prognostic significance. Int J Tuberc Lung Dis 2011; 15: 234–239. 10 Narita M, Ashkin D, Hollender E S, Pitchenik A E. Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS. Am J Respir Crit Care Med 1998; 158: 157– 161. 11 Teoh R, Humphries M J, O’Mahony G. Symptomatic intracranial tuberculoma developing during treatment of tuberculosis: a report of 10 patients and review of the literature. Quart J Med 1987; 63: 449–460. 12 Pauranoic A, Bihjari M, Maheshwari M C. Appearance of tuberculoma during treatment of tuberculous meningitis. Jpn J Med 1987; 26: 332–334. 13 Malone J L, Paparello S, Rickman L S, Wagner K F, Monahan B, Oldfield E C. Intracranial tuberculoma developing during therapy for tuberculous meningitis. West J Med 1990; 152: 188–190. 14 Vidal C G, Fernandez S R, Lacasa J M, et al. Paradoxical response to antituberculous therapy in infliximab-treated patients with disseminated tuberculosis. Clin Infect Dis 2005; 40: 756–759. 15 Carvalho A C, De Iaco G, Saleri N, et al. Paradoxical reaction during tuberculosis treatment in HIV-seronegative patients. Clin Infect Dis 2006; 42: 893–895. 16 Ogawa S K, Smith M A, Brennessel D J, Lowy F D. Tuberculous meningitis in an urban medical center. Medicine (Baltimore) 1987; 66: 317–326. 17 British Medical Research Council. Streptomycin treatment of tuberculous meningitis. Lancet 1948; 1: 582–596. 18 Tor ¨ ok ¨ M E, Nguyen D B, Tran T H, et al. Dexamethasone and long-term outcome of tuberculous meningitis in Vietnamese adults and adolescents. PLOS ONE 2011; 6: e27821. 19 Kalita J, Misra U K, Ranjan P. Tuberculous meningitis with pulmonary miliary tuberculosis: a clinic-radiological study. Neurol India 2004; 52: 194–196. 20 Roberts C W, Walker W, Alexander J. Sex-associated hormones and immunity to protozoan parasites. Clin Microbiol Rev 2001; 14: 476–488. 21 Breen R A, Smith C J, Bettinson H, et al. Paradoxical reactions during tuberculosis treatment in patients with and without HIV coinfection. Thorax 2004; 59: 704–707.
Paradoxical response in TBM
Figure 1 Appearance of tuberculoma following anti-tuberculosis treatment in a patient with definite tuberculous meningitis. A), B) and C): baseline T1 contrast cranial MRI revealed A) acute left basal ganglia infarction. D), E) and F): imaging at 3 months revealing D) old infarction and E) appearance of tuberculoma in the left frontotemporal region and left cerebellopontine region. Radiological deterioration was associated with clinical deterioration (right hemiplegia and Glasgow coma scale score declined from 14 to 10). MRI ¼ magnetic resonance imaging.
Figure 2 Enlargement and appearance of new tuberculoma in a patient with definite tuberculous meningitis. A), B) and C): baseline T1 contrast MRI showing hydrocephalus and small ring enhancing granuloma in B) the temporal region. D), E) and F) are the corresponding MRI findings at 3 months following anti-tuberculosis treatment showing E) enlargement, as well as the appearance of new tuberculoma (D and F). MRI deterioration, however, was not associated with clinical deterioration. MRI ¼ magnetic resonance imaging.
i
ii
The International Journal of Tuberculosis and Lung Disease
RESUME
Centre hospitalier universitaire. Evaluer la fr e´ quence et les facteurs pr´edictifs de la m´eningite tuberculeuse (TBM) ainsi que leur influence sur le r´esultat. S C H E´ M A : De 34 patients pr e´ sentant une TBM confirm e´ e, on a recueilli leurs caract e´ ristiques d´emographiques, cliniques, biochimiques, l’analyse du liquide c´ephalo-rachidien (LCR), le nombre de CD4 et les r´esultats de l’imag´erie par r´esonance magn´etique (IRM). Les patients ont re¸cu quatre m´edicaments antituberculeux ainsi que de la prednisolone. Ils ont b´en´efici´e d’un suivi clinique et radiologique a` 3 et 6 mois ainsi que d’une analyse chimique du s´erum, un comptage des CD4 et une analyse du LCR a` 3 mois. Le r´esultat fonctionnel a e´ t´e d´efini sur la base de l’index de Barthel. Les facteurs pr´edictifs d’une r´eaction paradoxale ont e´ t´e e´ valu´es par analyse univari´ee puis multivari´ee. R E´ S U LT A T S : L’age ˆ m´edian des patients e´ tait de 33,5 CADRE :
OBJECTIF :
ans, 13 e´ taient des femmes ; 22 patients ont eu un tuberculome paradoxal, le plus souvent dans les 3 premiers mois du traitement anti-tuberculeux. Le tuberculome paradoxal e´ tait associ´e a` une d´et´erioration clinique chez 12 patients. La vaccination par le bacille Calmette-Gu´erin, une glycorachie plus e´ lev´ee et des anomalies initiales du IRM e´ taient associ´ees avec le tuberculome paradoxal en analyse univari´ee. Apr`es ajustement des covariates, seul le sexe f´eminin e´ tait ind´ependamment associ´e au tuberculome paradoxal (OR 0,06 ; IC95% 0,004–0,79 ; P ¼ 0,03). La r´eaction paradoxale n’avait cependant pas d’influence sur le r´esultat a` 6 mois. C O N C L U S I O N : Un tuberculome paradoxal survient chez deux tiers des patients pre´ sentant une TBM confirm´ee et il est asymptomatique chez 50% des patients. Il est plus fre´ quent chez les femmes et n’influence pas le r´esultat a` 6 mois.
RESUMEN M A R C O D E R E F E R E N C I A : Un hospital universitario de atencion ´ terciaria. O B J E T I V O : Evaluar la frecuencia y los factores pronosticos ´ de meningitis tuberculosa (TBM) y su repercusion ´ en el desenlace cl´ınico. M E´ T O D O : Participaron en el estudio 34 pacientes con TBM confirmada. Se registraron sus caracter´ısticas demogra´ficas, cl´ınicas y bioqu´ımicas, los ana´lisis del l´ıquido cefalorraqu´ıdeo (LCR), los recuentos de c´elulas CD4 y los resultados de la resonancia magn´etica (IRM). Los pacientes recibieron tratamiento con cuatro medicamentos antituberculosos y prednisolona. Se practico´ un seguimiento cl´ınico y radiogra´fico a los 3 y 6 meses y se repitieron la bioqu´ımica s´erica, el recuento de c´elulas CD4 y el ana´lisis del LCR a los 3 meses. El desenlace funcional se definio´ con base en la puntuacion ´ de la escala de Barthel. Se aplico´ un ana´lisis multifactorial a fin de examinar los factores pronosticos ´ de una respuesta paradojica. ´ R E S U LT A D O S : La mediana de la edad de los pacientes
fue 33,5 anos ´ pacientes ˜ y 13 fueron mujeres. Veintidos presentaron un tuberculoma paradojico, ´ en su mayor´ıa durante los 3 primeros meses del tratamiento antituberculoso. El tuberculoma parad ojico ´ se asocio´ con un deterioro cl´ınico en 12 pacientes. El ana´lisis monofactorial revelo´ como factores asociados con la aparici on ´ del tuberculoma la vacunaci on ´ antituberculosa, una glucorraquia ma´s alta y una IRM anormal inicial. Tras corregir las covariables, solo el sexo femenino se asocio´ de manera independiente con la aparicion ´ de tuberculoma paradojico ´ (OR 0,06; IC95% 0,004–0,79; P ¼ 0,03). La respuesta paradojica ´ no obstante, no influyo´ sobre el desenlace a los 6 meses. ´ N : El tuberculoma paradojico CONCLUSIO ´ ocurrio´ en dos tercios de los pacientes con diagnostico ´ confirmado de TBM y 50% de los casos evolucionaron de manera asintoma´tica. Las mujeres son ma´s susceptibles a la aparicion ´ del tuberculoma paradojico; ´ esta afeccion ´ no modifico´ el desenlace cl´ınico a los 6 meses.
