CNS Drugs

, Volume 24, Issue 8, pp 655–667 | Cite as

Nervous System Effects of Antituberculosis Therapy

  • Joseph S. KassEmail author
  • Wayne X. Shandera
Review Article


Nervous system toxicity with current antituberculosis pharmacotherapy is relatively uncommon, although the frequency of the usage of antituberculosis therapy requires that physicians be aware of such toxicity. Antituberculosis therapy manifests both central and peripheral nervous system effects, which may compromise patient compliance. Among the traditional forms of first-line antituberculosis therapy, isoniazid is most often associated with nervous system effects, most prominently peripheral neuropathy, psychosis and seizures. Adverse events are reported with other antituberculosis therapies, the most prominent being optic neuropathy with ethambutol and ototoxicity and neuromuscular blockade with aminoglycosides. The second-line agent with the most adverse effects is cycloserine, with psychosis and seizures, the psychosis in particular limiting its usage. Fluoroquinolones are rare causes of seizures and delirium. Newer forms of therapy are under development, but to date no significant neurotoxicity is documented with these agents.

Future needs include the development of surveillance mechanisms to increase recognition of nervous system toxicities. It is also hoped that the development of new pharmacogenomic assays will help with the identification of patients at risk for these toxicities.


Tuberculosis Peripheral Neuropathy Isoniazid Pyridoxine Linezolid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.


  1. 1.
    World Health Organization. Global tuberculosis control: epidemiology, strategy, financing. Vol. 411. Geneva: World Health Organization Press, 2009: 9–12Google Scholar
  2. 2.
    Onyebujoh P, Zumla A, Ribeiro I, et al. Treatment of tuberculosis: present status and future prospects. Bull World Health Organ 2005; 83(11): 857–65PubMedGoogle Scholar
  3. 3.
    Bosch EP, Smith BE. Disorders of peripheral nerves. In: Bradley WF, Daroff RB, Fenichel GM, editors. Neurology in clinical practice. Boston (MA): Butterworth-Heine-mann, 2004: 2384Google Scholar
  4. 4.
    Holdiness MR. Neurological manifestations and toxicities of the antituberculosis drugs: a review. Med Toxicol 1987; 2(1): 33–51PubMedCrossRefGoogle Scholar
  5. 5.
    Ellard GA. The potential clinical significance of the isoniazid acetylator phenotype in the treatment of pulmonary tuberculosis. Tubercle 1984; 65(3): 211–27PubMedCrossRefGoogle Scholar
  6. 6.
    Thompson JE. How safe is isoniazid? Med J Aust 1978; 1(3): 165–9PubMedGoogle Scholar
  7. 7.
    Kinsella LJ. Vitamin deficiencies. In: Schapira AHV, editor. Neurology and clinical neuroscience. Philadelphia (PA): Mosby Elsevier, 2007: 1457–9Google Scholar
  8. 8.
    Pellock JM, Howell J, Kendig Jr EL, et al. Pyridoxine deficiency in children treated with isoniazid. Chest 1985; 87(5): 658–61PubMedCrossRefGoogle Scholar
  9. 9.
    Blumberg HM, Burman WJ, Chaisson RE, et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med 2003; 167(4): 603–62PubMedCrossRefGoogle Scholar
  10. 10.
    Siskind MS, Thienemann D, Kirlin L. Isoniazid-induced neurotoxicity in chronic dialysis patients: report of three cases and a review of the literature. Nephron 1993; 64(2): 303–6PubMedCrossRefGoogle Scholar
  11. 11.
    Editorial (no authors listed). Psychiatric side effects of nonpsychiatric drugs. Semin Psychiatry 1971; 3 (4): 406-20Google Scholar
  12. 12.
    Iannaccone R, Sue YJ, Avner JR. Suicidal psychosis secondary to isoniazid. Pediatr Emerg Care 2002; 18(1): 25–7PubMedCrossRefGoogle Scholar
  13. 13.
    Duncan H, Kerr D. Toxic psychosis due to isoniazid. Br J Dis Chest 1962; 56: 131–8PubMedCrossRefGoogle Scholar
  14. 14.
    Alao AO, Yolles JC. Isoniazid-induced psychosis. Ann Pharmacother 1998; 32(9): 889–91PubMedCrossRefGoogle Scholar
  15. 15.
    Wasik A. Mental disorders caused by isonicotinic acid hydrazide (INH) in the course of treatment of pulmonary tuberculosis. Pol Med J 1970; 9: 1498–503PubMedGoogle Scholar
  16. 16.
    Shah BR, Santucci K, Sinert R, et al. Acute isoniazid neurotoxicity in an urban hospital. Pediatrics 1995; 95(5): 700–4PubMedGoogle Scholar
  17. 17.
    Temmerman W, Dhondt A, Vandewoude K. Acute isoniazid intoxication: seizures, acidosis and coma. Acta Clin Belg 1999; 54(4): 211–6PubMedGoogle Scholar
  18. 18.
    Thundiyil JG, Kearney TE, Olson KR. Evolving epidemiology of drug-induced seizures reported to a Poison Control Center System. J Med Toxicol 2007; 3(1): 15–9PubMedCrossRefGoogle Scholar
  19. 19.
    Alvarez FG, Guntupalli KK. Isoniazid overdose: four case reports and review of the literature. Intensive Care Med 1995; 21(8): 641–4PubMedCrossRefGoogle Scholar
  20. 20.
    Tibussek D, Mayatepek E, Distelmaier F, et al. Status epilepticus due to attempted suicide with isoniazid. Eur J Pediatr 2006; 165(2): 136–7PubMedCrossRefGoogle Scholar
  21. 21.
    Baciewicz AM, et al. Update on rifampin and rifabutin drug interactions. Am J Med Sci 2008; 335(2): 126–36PubMedCrossRefGoogle Scholar
  22. 22.
    Kreek MJ, Garfield JW, Gutjahr CL, et al. Rifampin-induced methadone withdrawal. N Engl J Med 1976; 294(20): 1104–6PubMedCrossRefGoogle Scholar
  23. 23.
    Jenkins P, Emerson PA. Myopathy induced by rifampicin. Br Med J (Clin Res Ed) 1981; 283(6284): 105–6CrossRefGoogle Scholar
  24. 24.
    Pratt WB, Fekety R. The antimicrobial drugs. New York (NY): Oxford University Press, 1986: 293–4Google Scholar
  25. 25.
    Abramowicz M. Treatment guidelines from the Medical Letter: drugs for tuberculosis. Medical Letter 2007; 5(55): 15–21Google Scholar
  26. 26.
    Nair VS, LeBrun M, Kass I. Peripheral neuropathy associated with ethambutol. Chest 1980; 77(1): 98–100PubMedCrossRefGoogle Scholar
  27. 27.
    Tugwell P, James SL. Peripheral neuropathy with ethambutol. Postgrad Med J 1972; 48(565): 667–70PubMedCrossRefGoogle Scholar
  28. 28.
    Melamud A, Kosmorsky GS, Lee MS. Ocular ethambutol toxicity. Mayo Clin Proc 2003; 78(11): 1409–11PubMedCrossRefGoogle Scholar
  29. 29.
    Griffith DE, Brown-Elliott BA, Shepherd S, et al. Ethambutol ocular toxicity in treatment regimens for Mycobacterium avium complex lung disease. Am J Respir Crit Care Med 2005; 172(2): 250–3PubMedCrossRefGoogle Scholar
  30. 30.
    Seth V, Khosla PK, Semwal OP, et al. Visual evoked responses in tuberculous children on ethambutol therapy. Indian Pediatr 1991; 28(7): 713–7PubMedGoogle Scholar
  31. 31.
    Yiannikas C, Walsh JC, McLeod JG. Visual evoked potentials in the detection of subclinical optic toxic effects secondary to ethambutol. Arch Neurol 1983; 40(10): 645–8PubMedCrossRefGoogle Scholar
  32. 32.
    Kumar A, Sandramouli S, Verma L, et al. Ocular ethambutol toxicity: is it reversible? J Clin Neuroophthalmol 1993; 13(1): 15–7PubMedGoogle Scholar
  33. 33.
    Menon V, Jain D, Saxena R, et al. Prospective evaluation of visual function for early detection of ethambutol toxicity. Br J Ophthalmol 2009; 93(9): 1251–4PubMedCrossRefGoogle Scholar
  34. 34.
    Bhansali SA. Medication side effects. In: Goebel JA, editor. Practical management of the dizzy patient. Philadelphia (PA): Lippincott, Williams, and Wilkins, 2008: 46–8Google Scholar
  35. 35.
    Guthrie OW. Aminoglycoside induced ototoxicity. Toxicology 2008; 249(2-3): 91–6PubMedCrossRefGoogle Scholar
  36. 36.
    Peloquin CA, Berning SE, Nitta AT, et al. Aminoglycoside toxicity: daily versus thrice-weekly dosing for treatment of mycobacterial diseases. Clin Infect Dis 2004; 38(11): 1538–44PubMedCrossRefGoogle Scholar
  37. 37.
    Fischel-Ghodsian N. Genetic factors in aminoglycoside toxicity. Pharmacogenomics 2005; 6(1): 27–36PubMedCrossRefGoogle Scholar
  38. 38.
    Bitner-Glindzicz M, Rahman S. Ototoxicity caused by aminoglycosides. BMJ 2007; 335(7624): 784–5PubMedCrossRefGoogle Scholar
  39. 39.
    Pratt WB, Fekety R. The antimicrobial drugs. New York (NY): Oxford University Press, 1986: 172–5Google Scholar
  40. 40.
    Brazil OV, Corrado AP. The curariform action of streptomycin. J Pharmacol Exp Ther 1957; 120(4): 452–9PubMedGoogle Scholar
  41. 41.
    Fiekers JF. Effects of the aminoglycoside antibiotics, streptomycin and neomycin, on neuromuscular transmission: II. Postsynaptic considerations. J Pharmacol Exp Ther 1983; 225(3): 496–502Google Scholar
  42. 42.
    Sokoll MD, Gergis SD. Antibiotics and neuromuscular function. Anesthesiology 1981; 55(2): 148–59PubMedCrossRefGoogle Scholar
  43. 43.
    Pasquale TR, Tan JS. Nonantimicrobial effects of antibacterial agents. Clin Infect Dis 2005; 40(1): 127–35PubMedCrossRefGoogle Scholar
  44. 44.
    Yamada S, Kuno Y, Iwanaga H. Effects of aminoglycoside antibiotics on the neuromuscular junction: part I. Int J Clin Pharmacol Ther Toxicol 1986; 24(3): 130–8PubMedGoogle Scholar
  45. 45.
    Barrons RW. Drug-induced neuromuscular blockade and myasthenia gravis. Pharmacotherapy 1997; 17(6): 1220–32PubMedGoogle Scholar
  46. 46.
    Storey PB, McLean RL. Some considerations of cycloserine toxicity. Am Rev Tuberc 1957; 75(3): 514–6PubMedGoogle Scholar
  47. 47.
    Daddi G. Proceedings of the International Symposium on Cycloserine/organized with the cooperation of AB KABI, Stockholm, Sweden; FARMITALIA, Soc. Farmaceutici Italia An. p. Az. Milan, Italy; 1968 May 11–12; Milan. Scand J Respir Dis 1970; 71. Copenhagen: Munksgaard, 1970Google Scholar
  48. 48.
    Helmy B. Side effects of cycloserine. Scand J Respir Dis Suppl 1970; 71: 220–5PubMedGoogle Scholar
  49. 49.
    Pasargiklian M, Biondi L. Neurologic and behavioural reactions of tuberculous patients treated with cycloserine. Scand J Respir Dis Suppl 1970; 71: 201–8PubMedGoogle Scholar
  50. 50.
    Jancik E, Bouckova I, Jancikova M, et al. Clinical and laboratory experiences with cycloserine. Scand J Respir Dis Suppl 1970; 71: 306–13PubMedGoogle Scholar
  51. 51.
    Esteves Pinto E. Suicide of two patients during the postoperative course after pulmonary resection: possible effect of cycloserine. Scand J Respir Dis Suppl 1970; 71: 256–8PubMedGoogle Scholar
  52. 52.
    Miyakawa T, Suzuki T, Nakamura K, et al. An autopsy case of cycloserine poisoning. Folia Psychiatr Neurol Jpn 1977; 31(2): 235–41PubMedGoogle Scholar
  53. 53.
    Villar TG. Personal experience with cycloserine in 206 patients with pulmonary tuberculosis. Scand J Respir Dis Suppl 1970; 71: 196–200PubMedGoogle Scholar
  54. 54.
    Evins AE, Amico E, Posever TA, et al. D-Cycloserine added to risperidone in patients with primary negative symptoms of schizophrenia. Schizophr Res 2002; 56(1–2): 19–23PubMedCrossRefGoogle Scholar
  55. 55.
    Lane HY, Huang CL, Wu PL, et al. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to clozapine for the treatment of schizophrenia. Biol Psychiatry 2006; 60(6): 645–9PubMedCrossRefGoogle Scholar
  56. 56.
    Kontaxakis VP, Ferentinos PP, Havaki-Kontaxaki BJ, et al. Randomized controlled augmentation trials in clozapine-resistant schizophrenic patients: a critical review. Eur Psychiatry 2005; 20(5–6): 409–15PubMedCrossRefGoogle Scholar
  57. 57.
    van Berckel BN, Lipsch C, Timp S, et al. Behavioral and neuroendocrine effects of the partial NMDA agonist D-cycloserine in healthy subjects. Neuropsychopharmacology 1997; 16(5): 317–24PubMedCrossRefGoogle Scholar
  58. 58.
    Reznik SE, Vilderman AM. Use of pyridoxine in the treatment of side effects of antitubercular agents. Probl Tuberk 1963; 41: 76–7PubMedGoogle Scholar
  59. 59.
    Nair S, Maguire W, Baron H, et al. The effect of cycloserine on pyridoxine-dependent metabolism in tuberculosis. J Clin Pharmacol 1976; 16(8–9): 439–43PubMedGoogle Scholar
  60. 60.
    Pratt WB, Fekety R. The antimicrobial drugs. New York (NY): Oxford University Press, 1986: 299Google Scholar
  61. 61.
    Girling DJ. Adverse effects of antituberculosis drugs. Drugs 1982; 23(1–2): 56–74PubMedCrossRefGoogle Scholar
  62. 62.
    Fox W, Robinson DK, Tall R, et al. A study of acute intolerance to ethionamide, including a comparison with prothionamide, and of the influence of a vitamin B-complex additive in prophylaxis. Tubercle 1969; 50(2): 125–43PubMedCrossRefGoogle Scholar
  63. 63.
    Miller AB. Thiacetazone toxicity: a general review. Tubercle 1968; 49 Suppl. : 54–6PubMedCrossRefGoogle Scholar
  64. 64.
    Poole GW, Schneeweiss J. Peripheral neuropathy due to ethioniamide. Am Rev Respir Dis 1961; 84: 890–2PubMedGoogle Scholar
  65. 65.
    Pamra SP. A co-operative trial on the toxicity and efficacy of thiacetazone. Indian J Med Res 1971; 59(5): 683–98PubMedGoogle Scholar
  66. 66.
    Webb AH. A thiacetazone toxicity trial in Sarawak. N Z Med J 1973; 78(502): 490–2PubMedGoogle Scholar
  67. 67.
    Ziganshina LE, Squire SB. Fluoroquinolones for treating tuberculosis. Cochrane Database Syst Rev 2008; (1): CD004795Google Scholar
  68. 68.
    Owens RC Jr, Ambrose PG. Antimicrobial safety: focus on fluoroquinolones. Clin Infect Dis 2005; 41 Suppl. 2: S144–57PubMedCrossRefGoogle Scholar
  69. 69.
    Thomas RJ, Reagan DR. Association of a Tourette-like syndrome with ofloxacin. Ann Pharmacother 1996; 30(2): 138–41PubMedGoogle Scholar
  70. 70.
    Schwartz MT, Calvert JF. Potential neurologic toxicity related to ciprofloxacin. DICP 1990; 24(2): 138–40PubMedGoogle Scholar
  71. 71.
    Kushner JM, Peckman HJ, Snyder CR. Seizures associated with fluoroquinolones. Ann Pharmacother 2001; 35(10): 1194–8PubMedCrossRefGoogle Scholar
  72. 72.
    Christie MJ, Wong K, Ting RH, et al. Generalized seizure and toxic epidermal necrolysis following levofloxacin exposure. Ann Pharmacother 2005; 39(5): 953–5PubMedCrossRefGoogle Scholar
  73. 73.
    Walton GD, Hon JK, Mulpur TG. Ofloxacin-induced seizure. Ann Pharmacother 1997; 31(12): 1475–7PubMedGoogle Scholar
  74. 74.
    Halliwell RF, Davey PG, Lambert JJ. Antagonism of GA-BAA receptors by 4-quinolones. J Antimicrob Chemother 1993; 31(4): 457–62PubMedCrossRefGoogle Scholar
  75. 75.
    Karki SD, Bentley DW, Raghavan M. Seizure with ciprofloxacin and theophylline combined therapy. DICP 1990; 24(6): 595–6PubMedGoogle Scholar
  76. 76.
    Pashko S, Simons WR, Sena MM, et al. Rate of exposure to theophylline-drug interactions. Clin Ther 1994; 16(6): 1068–77PubMedGoogle Scholar
  77. 77.
    Stahlmann R, Lode H. Fluoroquinolones in the elderly: safety considerations. Drugs Aging 2003; 20(4): 289–302PubMedCrossRefGoogle Scholar
  78. 78.
    Olsen PZ, Torning K. Psychological side-effects during long-term ambulatory chemotherapy with isoniazid and PAS. Acta Tuberc Scand 1959; 37: 89–103PubMedGoogle Scholar
  79. 79.
    Brennan P, Young D, editors. Capreomycin, in tuberculosis. Edinburgh: Churchill Livingstone, 2008: 89–91Google Scholar
  80. 80.
    Liu XM, Xie JP. Action and resistance mechanisms of capreomycin: a functional genomic perspective. Yao Xue Xue Bao 2008; 43(8): 788–92PubMedGoogle Scholar
  81. 81.
    Hoff DR, Caraway ML, Brooks EJ, et al. Metronidazole lacks antibacterial activity in guinea pigs infected with Mycobacterium tuberculosis. Antimicrob Agents Chemother 2008; 52(11): 4137–40PubMedCrossRefGoogle Scholar
  82. 82.
    Klinkenberg LG, Sutherland LA, Bishai WR, et al. Metronidazole lacks activity against Mycobacterium tuberculosis in an in vivo hypoxic granuloma model of latency. J Infect Dis 2008; 198(2): 275–83PubMedCrossRefGoogle Scholar
  83. 83.
    Freeman CD, Klutman NE, Lamp KC. Metronidazole: a therapeutic review and update. Drugs 1997; 54(5): 679–708PubMedCrossRefGoogle Scholar
  84. 84.
    Riccardi G, Pasca MR, Buroni S. Mycobacterium tuberculosis: drug resistance and future perspectives. Future Microbiol 2009; 4: 597–614PubMedCrossRefGoogle Scholar
  85. 85.
    Schaaf HS, Willemse M, Donald PR. Long-term linezolid treatment in a young child with extensively drug-resistant tuberculosis. Pediatr Infect Dis J 2009; 28(8): 748–50PubMedCrossRefGoogle Scholar
  86. 86.
    Narita M, Tsuji BT, Yu VL. Linezolid-associated peripheral and optic neuropathy, lactic acidosis, and serotonin syndrome. Pharmacotherapy 2007; 27(8): 1189–97PubMedCrossRefGoogle Scholar
  87. 87.
    Taylor JJ, Wilson JW, Estes LL. Linezolid and serotonergic drug interactions: a retrospective survey. Clin Infect Dis 2006; 43(2): 180–7PubMedCrossRefGoogle Scholar
  88. 88.
    Deresinski S. Beta-lactam therapy of tuberculosis? Clin Infect Dis 2009; 49(10): iiiCrossRefGoogle Scholar
  89. 89.
    Hugonnet JE, Tremblay LW, Boshoff HI, et al. Mero-penem-clavulanate is effective against extensively drug-resistant Mycobacterium tuberculosis. Science 2009; 323(5918): 1215–8PubMedCrossRefGoogle Scholar
  90. 90.
    Check E. After decades of drought, new drug possibilities flood TB pipeline. Nat Med 2007; 13(3): 266PubMedCrossRefGoogle Scholar
  91. 91.
    Jia L, Tomaszewski JE, Hanrahan C, et al. Pharmacodynamics and pharmacokinetics of SQ109, a new diamine-based antitubercular drug. Br J Pharmacol 2005; 144(1): 80–7PubMedCrossRefGoogle Scholar
  92. 92.
    Manjunatha UH, Boshoff H, Dowd CS, et al. Identification of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 2006; 103(2): 431–6PubMedCrossRefGoogle Scholar
  93. 93.
    Andries K, Verhasselt P, Guillemont J, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 2005; 307(5707): 223–7PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2010

Authors and Affiliations

  1. 1.Department of Neurology, Ben Taub General HospitalBaylor College of MedicineHoustonUSA

Personalised recommendations