title: Adjunctive thalidomide therapy for childhood tuberculous meningitis: results of a randomized study.
abstract: Childhood tuberculous meningitis is associated with serious long-term sequelae, including mental retardation, behavior disturbances, and motor handicap. Brain damage in tuberculous meningitis results from a cytokine-mediated inflammatory response, which causes vasculitis and obstructive hydrocephalus. Thalidomide, a potent tumor necrosis factor alpha inhibitor, was well tolerated and possibly showed some clinical benefit in children with tuberculous meningitis during a pilot study. The purpose of the present study was to assess the effect of adjunctive thalidomide in addition to standard antituberculosis and corticosteroid therapy on the outcome of tuberculous meningitis. Thalidomide (24 mg/kg/day orally) or placebo was administered in a double-blind randomized fashion for 1 month to patients with stage 2 or 3 tuberculous meningitis. The study was terminated early because all adverse events and deaths occurred in one arm of the study (thalidomide group). Thirty of the 47 children enrolled received adjunctive thalidomide, of whom 6 (20%) developed a skin rash, 8 (26%) hepatitis, and 2 (6%) neutropenia or thrombocytopenia. Four deaths (13%) occurred in patients with very severe neurologic compromise at baseline; two deaths were associated with a rash. Motor outcome after 6 months of antituberculosis therapy was similar in the two groups, even though the thalidomide group showed greater neurologic compromise on admission. In addition, the mean IQ of the two treatment groups did not differ significantly (mean IQ thalidomide group 57.8 versus mean IQ control group 67.5; P = .16). These results do not support the use of adjunctive high-dose thalidomide therapy in the treatment of tuberculous meningitis.
authors.affiliation: Department of Pediatrics and Child Health, Tygerberg Children's Hospital, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, South Africa. jfs@sun.ac.za
authors.forename: Johan F
authors.initials: JF
authors.lastname: Schoeman
authors.forename: Priscilla
authors.initials: P
authors.lastname: Springer
authors.forename: Anita Janse
authors.initials: AJ
authors.lastname: van Rensburg
authors.forename: Sonja
authors.initials: S
authors.lastname: Swanevelder
authors.forename: Willem A
authors.initials: WA
authors.lastname: Hanekom
authors.forename: Patrick A J
authors.initials: PA
authors.lastname: Haslett
authors.forename: Gilla
authors.initials: G
authors.lastname: Kaplan
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000627:therapeutic use; D017024:Chemotherapy, Adjuvant; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003128:Coma / Q000209:etiology; D016207:Cytokines / Q000097:blood / Q000134:cerebrospinal fluid; D004311:Double-Blind Method; D005076:Exanthema / Q000139:chemically induced; D006505:Hepatitis / Q000209:etiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007223:Infant; D007360:Intelligence / Q000187:drug effects; D010291:Paresis / Q000209:etiology; D013019:South Africa; D018709:Statistics, Nonparametric; D013792:Thalidomide / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D014390:Tuberculosis, Meningeal / Q000188:drug therapy* / Q000401:mortality
chemical_list: D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D000995:Antitubercular Agents; D016207:Cytokines; D007166:Immunosuppressive Agents; D013792:Thalidomide