AIDS PATIENT CARE and STDs Volume 28, Number 11, 2014 ª Mary Ann Liebert, Inc. DOI: 10.1089/apc.2014.0083
LETTER TO THE EDITOR
Thalidomide in the Treatment of Immune Reconstitution Inflammatory Syndrome in HIV Patients with Neurological Tuberculosis Camille Fourcade, MD,1 Jean-Marc Mauboussin, MD,1 Catherine Lechiche, MD,1 Jean-Philippe Lavigne, MD,2 and Albert Sotto, MD1
Dear Editor:
T
he case we describe here concerns paradoxical tuberculosis, which is an expansion of tuberculous lesions in patients whose clinical symptoms initially improved with tuberculosis treatment. Paradoxical tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS) occurs in patients with concomitant HIV-1 and tuberculosis infections several weeks after the introduction of combined antiretroviral therapy (ART). T-cell Type-1 lymphocyte responses are thought to be involved in the physiopathology of the disease, although the exact mechanism remains poorly understood.1 In contrast, unmasking TB-IRIS occurs after introducing ART in patients previously undiagnosed for tuberculosis. This phenomenon is due to a persistence of viable pathogens.2 About 16% of co-infected patients develop TB-IRIS2 and neurological TB-IRIS represents 12% of TB-IRIS cases, whose mortality rate is high (up to 30%).3 At present, corticosteroids comprise the only treatment with symptomatic benefit in paradoxical TB-IRIS.4 We describe here positive results using thalidomide in paradoxical neurological TB-IRIS. A 51-year-old woman without co-morbidity was admitted to the Infectious Diseases Unit in December 2012. She presented with a meningeal syndrome and fever. Physical examination showed confusion without focal neurological deficit. White blood cell (WBC) count and C-reactive protein level were normal. Cerebrospinal fluid (CSF) showed 2300 WBC/mm3 (95% of which were lymphocytes), low glucose (1.3 mmol/L), and high protein levels (1.86 g/L). Bacteriological cultures and herpes simplex virus polymerase chain reaction (PCR) in CSF were negative. HIV-1 serology was positive. The CD4 count was 74/mm3 and the HIV-1 viral load (VL) was 400 000 copies/mL. Neurological investigations were carried out: Cryptococcus neoformans antigen and cytomegalovirus PCR were negative in plasma and CSF. Epstein-Barr virus, varicellazona virus, and JC virus PCR were negative in CSF. Acidalcohol fast bacilli were not detected by smear examination of CSF. The patient was not immunized against toxoplasma. Head magnetic resonance imaging (MRI) showed three le-
1
sions (in the left temporo-orbital and frontal lobes and right orbital gyrus), suggesting tuberculoma (Fig. 1). Tuberculosis therapy was initiated several days after admission consisting of intravenous rifampicin (10 mg/kg), isoniazid (5 mg/kg), and oral pyrazinamide (15 mg/kg). A high dose of methylprednisolone was initially administered (2 mg/kg) for 3 days before being tapered off and replaced by prednisone (40 mg) in the second week. Fever, confusion, and meningeal syndrome progressively disappeared. Two weeks after initiation of tuberculosis therapy, neurological tuberculosis was confirmed by the presence of Mycobacterium tuberculosis with full drug susceptibility (rifampicin, isoniazid, streptomycin, and ethambutol) in CSF cultures. The ART regimen of tenofovir, emtricitabine, efavirenz, and raltegravir (double dose) was then initiated and rifampicin and isoniazid were orally administered. Two weeks after initiating ART, the patient manifested high fever, headache, neck stiffness, and vomiting without focal neurological deficit. A second CSF sample showed persistence of pleocytosis (650 WBC/mm3) and a high protein level (3.4 g/L). Repetition of the same CSF tests initially performed showed no other causes of meningitis. Anatomopathological analysis of CSF showed no malignant cells. A second head MRI revealed a new lesion compatible with tuberculoma. The three other lesions were unchanged (Fig. 1). Tumoral, infectious, autoimmune, and iatrogenic causes of fever were excluded. After ensuring complete compliance, tuberculosis therapy was optimized in accordance with the results of a recent randomized trial that showed safety and survival benefits with an intensified regimen,5 [i.e., moxifloxacin was added and the rifampicin dose was increased (600–900 mg/day), again administered intravenously]. Immunovirological tests showed 134 CD4/mm3 and 1000 copies/mL of VL. Efavirenz was terminated to avoid neurological symptoms. Despite these therapeutic changes, the clinical condition did not improve. This strongly suggested TB-IRIS and consequently corticosteroids were again increased with 2 mg/kg of methylprednisolone for 6 days, which was subsequently tapered off and replaced by 40 mg of prednisone one week later. The symptoms showed no improvement.
Infectious and Tropical Diseases Unit, and 2Department of Microbiology, Nıˆmes University Hospital, Nıˆmes, France.
567
568
FOURCADE ET AL.
FIG. 1. Head magnetic resonance imaging at different time points using a T2-FLAIR sequence. (A) Shortly after hospital admission, showing lesion in the left temporo-orbital lobe compatible with tuberculoma. (B) One month after hospital admission, at the time of TB-IRIS syndrome, showing persistence of the lesion surrounding edema. (C) Six months after hospital admission, showing edema and tuberculoma disappearance. With the agreement of the patient, thalidomide was initiated 3 weeks after the appearance of neurological signs due to the efficacy of this immunosuppressive therapy in corticosteroidrefractory IRIS, as recently published.6 With an initial dose of 100 mg, the symptoms regressed within 2 weeks later and the patient could continue treatment as an outpatient. Glucocorticoids were not increased after initiating thalidomide but were gradually tapered off and stopped 3 months later (a total of 6 months).
Six weeks after initiating thalidomide therapy, the patient presented with paresthesia in the feet. The neurological examination showed no sensory or motor deficit but deep tendon reflexes were decreased. A side effect of thalidomide was first suspected. In accordance with the summary of product characteristics,7 the thalidomide dose was reduced to 50 mg. Isoniazid and HIV infection are also known to contribute to peripheral neuropathy and consequently isoniazid was terminated, B6 vitamin was added,
Table 1. Case Reports of Thalidomide Use in Neurological and Paradoxical Tuberculosis Treatment Chronological Age HIV references (years) status
Diagnosis
ART stopped
11
23
11
37
10
10
10
12
+
Intracranial tuberculoma IRIS
Yes
10
14
+
Yes
6
19
+
MDR meningitis TB-IRIS Disseminated TB-IRIS
Not Neurological done TB with paradoxical reaction Tuberculoma and acute vascular event with paradoxical reaction + Meningitis TB-IRIS
Corticosteroid dose with thalidomide
Thalidomide dose (duration)
Outcome
/
Three pulses of 100 mg/day methylprednisolone
/
80 mg of prednisolone 150 mg/day Death due to combined with vascular injury Cyclosporine A
Yes
No
High dose of 2 mg/kg/day intravenous dexamethasone Pulse of 2 mg/kg/day methylprednisolone (10 mg/kg) High dose (not specified) Reintroduced
2 mg/kg/day (6 months) 100 mg/day (14 months)
Survived
Death two weeks after initiating thalidomide Stevens Johnson reaction, thalidomide was stopped Improved Resolved
ART, combined antiretroviral treatment; IRIS, immune reconstitution inflammatory syndrome; MDR, multidrug resistant; TB, tuberculosis.
THALIDOMIDE FOR NEUROLOGICAL TUBERCULOSIS
and the HIV condition was tested (CD4 count: 199/mm3 and VL undetectable 6 months after initiating ART). Paresthesia no longer progressed and did not affect the patient’s quality of life, requiring no symptomatic treatment. After 5 months of thalidomide, 6 months of ART, and 7 months of tuberculosis treatment, the patient was totally asymptomatic without neurological signs of tuberculosis. Head MRI showed a regression of lesions (Fig. 1). Lumbar puncture was performed: in view of the low WBC count (8/mm3) and decreased protein level (1.99 g/L) in CSF, thalidomide was stopped and no relapses were observed after 6 months of follow-up. An acute exacerbation of tuberculin-specific immune responses to mycobacterial antigens in peripheral blood is associated with paradoxical TB-IRIS in co-infected patients.1 Some studies have demonstrated a large increase in interferon gamma (IFN-c) and tumor necrosis factor alpha (TNFa) related to these responses.8 Marais et al. showed that neurological TB-IRIS is associated with high levels of TNF-a in CSF at the onset of neurological tuberculosis.3 A compound that inhibits nonspecific pro-inflammatory cytokines could decrease inappropriate immune responses and thereby attenuate paradoxical TB-IRIS symptoms. At present, prednisone is the only evidence-based treatment,4 resulting in a decrease in TNF-a levels.8 Consequently, an alternative treatment is needed, particularly in patients with corticosteroid-refractory TB-IRIS. Thalidomide, an anti-inflammatory, immunomodulatory, anti-angiogenic agent.9 used mainly in the treatment of multiple myeloma, has been tested for various indications in HIV patients. It has already been effectively used in Kaposi sarcoma, aphthous ulcers, gastrointestinal lesions and cachexia,9 and cryptococcal meningitis or TB-IRIS.6,10 Among other effects, thalidomide inhibits TNF-a and enhances antigen-specific immunity.9 However, its effect on the paradoxical reaction in neurological tuberculosis is not yet clear. Several case reports concerning use of thalidomide for paradoxical neurological tuberculosis or TB-IRIS have been published6,10,11 (Table 1). The doses were less than 200 mg. It should be noted that all the cases were treated with a concomitant high dose of corticosteroids. National guidelines recommend adjunctive corticosteroids with tuberculosis therapy to prevent death and disability from neurological tuberculosis.12 By the time neurological TB-IRIS appears, corticosteroids have been terminated or reduced3 and the dose must be increased. In our case, when thalidomide was initiated, the corticosteroid dose was not increased. The improvement cannot be explained by the combination of thalidomide and corticosteroids. In addition to its historical teratogenicity, thalidomide side effects consist of frequent somnolence, peripheral neuropathy, and rash.9 Our patient manifested peripheral neuropathy that was not observed before treatment. This was probably due to a number of factors and cannot be attributed to thalidomide alone.
569 Author Disclosure Statement
No competing financial interests exist. References
1. Bourgarit A, Carcelain G, Martinez V, et al. Explosion of tuberculin-specific Th1-responses induces immune restoration syndrome in tuberculosis and HIV co-infected patients. AIDS 2006;20:F1–F7. 2. Mu¨ller M, Wandel S, Colebunders R, et al. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: A systematic review and meta-analysis. Lancet Infect Dis 2010;10:251–261. 3. Marais S, Meintjes G, Pepper DJ, et al. Frequency, severity, and prediction of tuberculous meningitis immune reconstitution inflammatory syndrome. Clin Infect Dis 2013;56:450–460. 4. Meintjes G, Wilkinson RJ, Morroni C, et al. Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS 2010;24:2381–2390. 5. Ruslami R, Ganiem AR, Dian S, et al. Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: An open-label, randomised controlled phase 2 trial. Lancet Infect Dis 2013;13:27–35. 6. Brunel A-S, Reynes J, Tuaillon E, et al. Thalidomide for steroid-dependent immune reconstitution inflammatory syndromes during AIDS. AIDS 2012;26:2110–2112. 7. European Medical Agency. Thalidomide Celgene(Previously Thalidomide Pharmion) -EMEA/H/C/000823 -PSU/ 0031. 25/02/2009. http://www.ema.europa.eu/docs/en_GB/ document_library/EPAR_-_Product_Information/human/ 000823/WC500037050.pdf (Last accessed August 18, 2014). 8. Tadokera R, Meintjes G, Skolimowska KH, et al. Hypercytokinaemia accompanies HIV-tuberculosis immune reconstitution inflammatory syndrome. Eur Respir J 2011;37: 1248–1259. 9. Franks ME, Macpherson GR, Figg WD. Thalidomide. Lancet 2004;363:1802–1811. 10. Van Toorn R, Rabie H, Dramowski A, Schoeman JF. Neurological manifestations of TB-IRIS: A report of 4 children. Eur J Paediatr Neurol 2012;16:676–682. 11. Roberts MTM, Mendelson M, Meyer P, Carmichael A, Lever AML. The use of thalidomide in the treatment of intracranial tuberculomas in adults: Two case reports. J Infect 2003;47:251–255. 12. WHO. Treatment of Tuberculosis Guidelines. Fourth Edition. http://whqlibdoc.who.int/publications/2010/9789241547833_ eng.pdf?ua = 1 (Last accessed August 18, 2014).
Address correspondence to: Dr. Camille Fourcade Infectious and Tropical Diseases Unit Nıˆmes University Hospital Place du Professeur Robert Debre´ 30029, Nıˆmes cedex 9 France E-mail: [email protected]
LETTER TO THE EDITOR
Thalidomide in the Treatment of Immune Reconstitution Inflammatory Syndrome in HIV Patients with Neurological Tuberculosis Camille Fourcade, MD,1 Jean-Marc Mauboussin, MD,1 Catherine Lechiche, MD,1 Jean-Philippe Lavigne, MD,2 and Albert Sotto, MD1
Dear Editor:
T
he case we describe here concerns paradoxical tuberculosis, which is an expansion of tuberculous lesions in patients whose clinical symptoms initially improved with tuberculosis treatment. Paradoxical tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS) occurs in patients with concomitant HIV-1 and tuberculosis infections several weeks after the introduction of combined antiretroviral therapy (ART). T-cell Type-1 lymphocyte responses are thought to be involved in the physiopathology of the disease, although the exact mechanism remains poorly understood.1 In contrast, unmasking TB-IRIS occurs after introducing ART in patients previously undiagnosed for tuberculosis. This phenomenon is due to a persistence of viable pathogens.2 About 16% of co-infected patients develop TB-IRIS2 and neurological TB-IRIS represents 12% of TB-IRIS cases, whose mortality rate is high (up to 30%).3 At present, corticosteroids comprise the only treatment with symptomatic benefit in paradoxical TB-IRIS.4 We describe here positive results using thalidomide in paradoxical neurological TB-IRIS. A 51-year-old woman without co-morbidity was admitted to the Infectious Diseases Unit in December 2012. She presented with a meningeal syndrome and fever. Physical examination showed confusion without focal neurological deficit. White blood cell (WBC) count and C-reactive protein level were normal. Cerebrospinal fluid (CSF) showed 2300 WBC/mm3 (95% of which were lymphocytes), low glucose (1.3 mmol/L), and high protein levels (1.86 g/L). Bacteriological cultures and herpes simplex virus polymerase chain reaction (PCR) in CSF were negative. HIV-1 serology was positive. The CD4 count was 74/mm3 and the HIV-1 viral load (VL) was 400 000 copies/mL. Neurological investigations were carried out: Cryptococcus neoformans antigen and cytomegalovirus PCR were negative in plasma and CSF. Epstein-Barr virus, varicellazona virus, and JC virus PCR were negative in CSF. Acidalcohol fast bacilli were not detected by smear examination of CSF. The patient was not immunized against toxoplasma. Head magnetic resonance imaging (MRI) showed three le-
1
sions (in the left temporo-orbital and frontal lobes and right orbital gyrus), suggesting tuberculoma (Fig. 1). Tuberculosis therapy was initiated several days after admission consisting of intravenous rifampicin (10 mg/kg), isoniazid (5 mg/kg), and oral pyrazinamide (15 mg/kg). A high dose of methylprednisolone was initially administered (2 mg/kg) for 3 days before being tapered off and replaced by prednisone (40 mg) in the second week. Fever, confusion, and meningeal syndrome progressively disappeared. Two weeks after initiation of tuberculosis therapy, neurological tuberculosis was confirmed by the presence of Mycobacterium tuberculosis with full drug susceptibility (rifampicin, isoniazid, streptomycin, and ethambutol) in CSF cultures. The ART regimen of tenofovir, emtricitabine, efavirenz, and raltegravir (double dose) was then initiated and rifampicin and isoniazid were orally administered. Two weeks after initiating ART, the patient manifested high fever, headache, neck stiffness, and vomiting without focal neurological deficit. A second CSF sample showed persistence of pleocytosis (650 WBC/mm3) and a high protein level (3.4 g/L). Repetition of the same CSF tests initially performed showed no other causes of meningitis. Anatomopathological analysis of CSF showed no malignant cells. A second head MRI revealed a new lesion compatible with tuberculoma. The three other lesions were unchanged (Fig. 1). Tumoral, infectious, autoimmune, and iatrogenic causes of fever were excluded. After ensuring complete compliance, tuberculosis therapy was optimized in accordance with the results of a recent randomized trial that showed safety and survival benefits with an intensified regimen,5 [i.e., moxifloxacin was added and the rifampicin dose was increased (600–900 mg/day), again administered intravenously]. Immunovirological tests showed 134 CD4/mm3 and 1000 copies/mL of VL. Efavirenz was terminated to avoid neurological symptoms. Despite these therapeutic changes, the clinical condition did not improve. This strongly suggested TB-IRIS and consequently corticosteroids were again increased with 2 mg/kg of methylprednisolone for 6 days, which was subsequently tapered off and replaced by 40 mg of prednisone one week later. The symptoms showed no improvement.
Infectious and Tropical Diseases Unit, and 2Department of Microbiology, Nıˆmes University Hospital, Nıˆmes, France.
567
568
FOURCADE ET AL.
FIG. 1. Head magnetic resonance imaging at different time points using a T2-FLAIR sequence. (A) Shortly after hospital admission, showing lesion in the left temporo-orbital lobe compatible with tuberculoma. (B) One month after hospital admission, at the time of TB-IRIS syndrome, showing persistence of the lesion surrounding edema. (C) Six months after hospital admission, showing edema and tuberculoma disappearance. With the agreement of the patient, thalidomide was initiated 3 weeks after the appearance of neurological signs due to the efficacy of this immunosuppressive therapy in corticosteroidrefractory IRIS, as recently published.6 With an initial dose of 100 mg, the symptoms regressed within 2 weeks later and the patient could continue treatment as an outpatient. Glucocorticoids were not increased after initiating thalidomide but were gradually tapered off and stopped 3 months later (a total of 6 months).
Six weeks after initiating thalidomide therapy, the patient presented with paresthesia in the feet. The neurological examination showed no sensory or motor deficit but deep tendon reflexes were decreased. A side effect of thalidomide was first suspected. In accordance with the summary of product characteristics,7 the thalidomide dose was reduced to 50 mg. Isoniazid and HIV infection are also known to contribute to peripheral neuropathy and consequently isoniazid was terminated, B6 vitamin was added,
Table 1. Case Reports of Thalidomide Use in Neurological and Paradoxical Tuberculosis Treatment Chronological Age HIV references (years) status
Diagnosis
ART stopped
11
23
11
37
10
10
10
12
+
Intracranial tuberculoma IRIS
Yes
10
14
+
Yes
6
19
+
MDR meningitis TB-IRIS Disseminated TB-IRIS
Not Neurological done TB with paradoxical reaction Tuberculoma and acute vascular event with paradoxical reaction + Meningitis TB-IRIS
Corticosteroid dose with thalidomide
Thalidomide dose (duration)
Outcome
/
Three pulses of 100 mg/day methylprednisolone
/
80 mg of prednisolone 150 mg/day Death due to combined with vascular injury Cyclosporine A
Yes
No
High dose of 2 mg/kg/day intravenous dexamethasone Pulse of 2 mg/kg/day methylprednisolone (10 mg/kg) High dose (not specified) Reintroduced
2 mg/kg/day (6 months) 100 mg/day (14 months)
Survived
Death two weeks after initiating thalidomide Stevens Johnson reaction, thalidomide was stopped Improved Resolved
ART, combined antiretroviral treatment; IRIS, immune reconstitution inflammatory syndrome; MDR, multidrug resistant; TB, tuberculosis.
THALIDOMIDE FOR NEUROLOGICAL TUBERCULOSIS
and the HIV condition was tested (CD4 count: 199/mm3 and VL undetectable 6 months after initiating ART). Paresthesia no longer progressed and did not affect the patient’s quality of life, requiring no symptomatic treatment. After 5 months of thalidomide, 6 months of ART, and 7 months of tuberculosis treatment, the patient was totally asymptomatic without neurological signs of tuberculosis. Head MRI showed a regression of lesions (Fig. 1). Lumbar puncture was performed: in view of the low WBC count (8/mm3) and decreased protein level (1.99 g/L) in CSF, thalidomide was stopped and no relapses were observed after 6 months of follow-up. An acute exacerbation of tuberculin-specific immune responses to mycobacterial antigens in peripheral blood is associated with paradoxical TB-IRIS in co-infected patients.1 Some studies have demonstrated a large increase in interferon gamma (IFN-c) and tumor necrosis factor alpha (TNFa) related to these responses.8 Marais et al. showed that neurological TB-IRIS is associated with high levels of TNF-a in CSF at the onset of neurological tuberculosis.3 A compound that inhibits nonspecific pro-inflammatory cytokines could decrease inappropriate immune responses and thereby attenuate paradoxical TB-IRIS symptoms. At present, prednisone is the only evidence-based treatment,4 resulting in a decrease in TNF-a levels.8 Consequently, an alternative treatment is needed, particularly in patients with corticosteroid-refractory TB-IRIS. Thalidomide, an anti-inflammatory, immunomodulatory, anti-angiogenic agent.9 used mainly in the treatment of multiple myeloma, has been tested for various indications in HIV patients. It has already been effectively used in Kaposi sarcoma, aphthous ulcers, gastrointestinal lesions and cachexia,9 and cryptococcal meningitis or TB-IRIS.6,10 Among other effects, thalidomide inhibits TNF-a and enhances antigen-specific immunity.9 However, its effect on the paradoxical reaction in neurological tuberculosis is not yet clear. Several case reports concerning use of thalidomide for paradoxical neurological tuberculosis or TB-IRIS have been published6,10,11 (Table 1). The doses were less than 200 mg. It should be noted that all the cases were treated with a concomitant high dose of corticosteroids. National guidelines recommend adjunctive corticosteroids with tuberculosis therapy to prevent death and disability from neurological tuberculosis.12 By the time neurological TB-IRIS appears, corticosteroids have been terminated or reduced3 and the dose must be increased. In our case, when thalidomide was initiated, the corticosteroid dose was not increased. The improvement cannot be explained by the combination of thalidomide and corticosteroids. In addition to its historical teratogenicity, thalidomide side effects consist of frequent somnolence, peripheral neuropathy, and rash.9 Our patient manifested peripheral neuropathy that was not observed before treatment. This was probably due to a number of factors and cannot be attributed to thalidomide alone.
569 Author Disclosure Statement
No competing financial interests exist. References
1. Bourgarit A, Carcelain G, Martinez V, et al. Explosion of tuberculin-specific Th1-responses induces immune restoration syndrome in tuberculosis and HIV co-infected patients. AIDS 2006;20:F1–F7. 2. Mu¨ller M, Wandel S, Colebunders R, et al. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: A systematic review and meta-analysis. Lancet Infect Dis 2010;10:251–261. 3. Marais S, Meintjes G, Pepper DJ, et al. Frequency, severity, and prediction of tuberculous meningitis immune reconstitution inflammatory syndrome. Clin Infect Dis 2013;56:450–460. 4. Meintjes G, Wilkinson RJ, Morroni C, et al. Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS 2010;24:2381–2390. 5. Ruslami R, Ganiem AR, Dian S, et al. Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: An open-label, randomised controlled phase 2 trial. Lancet Infect Dis 2013;13:27–35. 6. Brunel A-S, Reynes J, Tuaillon E, et al. Thalidomide for steroid-dependent immune reconstitution inflammatory syndromes during AIDS. AIDS 2012;26:2110–2112. 7. European Medical Agency. Thalidomide Celgene(Previously Thalidomide Pharmion) -EMEA/H/C/000823 -PSU/ 0031. 25/02/2009. http://www.ema.europa.eu/docs/en_GB/ document_library/EPAR_-_Product_Information/human/ 000823/WC500037050.pdf (Last accessed August 18, 2014). 8. Tadokera R, Meintjes G, Skolimowska KH, et al. Hypercytokinaemia accompanies HIV-tuberculosis immune reconstitution inflammatory syndrome. Eur Respir J 2011;37: 1248–1259. 9. Franks ME, Macpherson GR, Figg WD. Thalidomide. Lancet 2004;363:1802–1811. 10. Van Toorn R, Rabie H, Dramowski A, Schoeman JF. Neurological manifestations of TB-IRIS: A report of 4 children. Eur J Paediatr Neurol 2012;16:676–682. 11. Roberts MTM, Mendelson M, Meyer P, Carmichael A, Lever AML. The use of thalidomide in the treatment of intracranial tuberculomas in adults: Two case reports. J Infect 2003;47:251–255. 12. WHO. Treatment of Tuberculosis Guidelines. Fourth Edition. http://whqlibdoc.who.int/publications/2010/9789241547833_ eng.pdf?ua = 1 (Last accessed August 18, 2014).
Address correspondence to: Dr. Camille Fourcade Infectious and Tropical Diseases Unit Nıˆmes University Hospital Place du Professeur Robert Debre´ 30029, Nıˆmes cedex 9 France E-mail: [email protected]
