Controversies in the Pathogenesis of Neuroleptic Malignant Syndrome

  • P. J. Adnet
  • N. Bello
  • H. Reyford
  • R. M. Krivosic-Horber
Conference paper


The neuroleptic malignant syndrome (NMS) is a relatively rare, but probably underrecognized, potentially fatal complication of the use of neuroleptic drugs. This syndrome was first described in the French medical literature with the introduction of neuroleptics in 1960, where it was referred to as “akinetic hypertonic syndrome.” Over the last decade, almost a 1000 cases of NMS have been reported, but many features of this syndrome remain controversial. Indeed, a grading scale of specific signs and symptoms for the diagnosis of NMS and a spectrum of clinical severity are two issues that await resolution. Many diagnostic criteria have been proposed, but no single set of criteria has been adopted for general use. Hence, different presentations of this disorder could explain some contradictory findings associated with NMS: prospective studies have provided disparate estimates of the frequency of NMS, ranging from 0.07% to 2.20% among patients receiving neuroleptic agents; risk factors for NMS vary in different patient populations; the association between NMS and other potentially fatal syndromes such as malignant hyperthermia is unclear.


Malignant Hyperthermia Malignant Hyperthermia Neuroleptic Drug Malignant Hyperthermia Susceptibility Contracture Test 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Cox B, Kerwin R, Lee TE (1978) Dopamine receptors in the central thermoregulatory pathways of the rat. J Physiol (Lond) 282: 471–483Google Scholar
  2. 2.
    Henderson VW, Wooten GF (1981) Neuroleptic malignant syndrome: a pathogenetic role for dopamine receptor blockade? Neurology 31: 132–137PubMedGoogle Scholar
  3. 3.
    Burke RE, Fahn S, Mayeux R (1981) Neuroleptic malignant syndrome caused by dopamine depleting drugs in a patient with Huntington’s chorea. Neurology 31: 1022–1026PubMedGoogle Scholar
  4. 4.
    Toru M, Matsuda O, Makaguchi K (1981) Neuroleptic malignant syndrome-like state following a withdrawal of antiparkinsonian drug. J Nery Ment Dis 169: 324–327CrossRefGoogle Scholar
  5. 5.
    Bond WS (1984) Detection and management of the neuroleptic malignant syndrome. Clin Pharmacol 3: 302–307Google Scholar
  6. 6.
    Figa-Talamanca L, Gualandi C, Dimeo L, Dibattista G, Neri G, Lorusso F (1985) Hyperthermia after discontinuance of levodopa and bromocriptine therapy: impaired dopamine receptors a possible cause. Neurology 35: 258–261PubMedGoogle Scholar
  7. 7.
    McCarron MM, Boettger ML, Peck JI (1982) A case of neuroleptic malignant syndrome successfully treated with amantadine. J Clin Psychiatry 43: 381–382PubMedGoogle Scholar
  8. 8.
    Blingh J, Cottle WH, Maskrey M (1971) Influence of ambient temperature on the thermoregulatory responses to 5 hydroxytryptamine, noradrenalin and acetylcholine injected into the lateral cerebral ventricles of sheep, goats and rabbits. J Physiol 212: 377–392Google Scholar
  9. 9.
    Delacour JL, Daoudal P, Chapoutot JL, Rocq B (1981) Traitement du syndrome malin des neuroleptiques par le dantrolène. Nouvelle Presse Médicale, 10: 3572–3573PubMedGoogle Scholar
  10. 10.
    Tollefson G (1982) A case of neuroleptic malignant syndrome: in vitro muscle comparison with malignant hyperthermia. J Clin Psychopharmacol 2: 266–270PubMedGoogle Scholar
  11. 11.
    Denborough MA, Collins SP, Hopkinson KC (1985) Rhabdomyolysis and malignant hyperpyrexia. Br Med J 1878:iiGoogle Scholar
  12. 12.
    The European Malignant Hyperpyrexia Group (1984) A protocol for the investigation of malignant hyperpyrexia susceptibility. Br J Anaesth 56: 1267–1269CrossRefGoogle Scholar
  13. 13.
    North American Malignant Hyperthermia Group (1989) Standardization of the caffeine halothane muscle contracture test. Anesth Analg 69: 511–515Google Scholar
  14. 14.
    Caroff SN, Rosenberg H, Fletcher JE, Heiman-Patterson TD, Mann SC (1987) Malignant hyperthermia susceptibility in neuroleptic malignant syndrome. Anesthesiology 67: 20–25PubMedCrossRefGoogle Scholar
  15. 15.
    Araki M, Takagi A, Higuchi I, Sugita H (1988) Neuroleptic malignant syndrome: caffeine contracture of single muscle fibers and muscle pathology. Neurology 38: 297–301PubMedGoogle Scholar
  16. 16.
    Adnet PJ, Krivosic-Horber RM, Adamantidis MM, Haudecoeur G, Adnet-Bonte CA, Saulnier F, Dupuis BA (1989) The association between the neuroleptic malignant syndrome and malignant hyperthermia. Acta Anaesthesiol Scand 33: 676–680PubMedCrossRefGoogle Scholar
  17. 17.
    Krivosic-Horber RM, Adnet P, Guevart E, Theunynck D, Lestavel P (1987) Neuroleptic malignant syndrome and malignant hyperthermia. Br J Anaesth 59: 1554–1556PubMedCrossRefGoogle Scholar
  18. 18.
    Adnet PJ, Krivosic-Horber RM, Adamantidis MM, Reyford H, Cordonnier C, Haudecoeur G (1991a) Effects of calcium-free solution, calcium antagonists, and the calcium agonist BAY K 8644 on mechanical responses of skeletal muscle from patients susceptible to malignant hyperthermia. Anesthesiology 75: 413–419PubMedCrossRefGoogle Scholar
  19. 19.
    Adnet PJ, Krivosic-Horber RM, Adamantidis MM, Haudecoeur G, Reyford HG, Dupuis BA (1991b) Is resting membrane potential a possible indicator of viability of muscle bundles used in the in vitro caffeine contracture test? Anesth Analg 74: 105–111Google Scholar
  20. 20.
    Gallant EM, Fletcher TF, Goettl VM, Rempel WE (1986) Porcine malignant hyperthermia: cell injury enhances halothane sensitivity of biopsies. Muscle Nerve 9: 174–184PubMedCrossRefGoogle Scholar
  21. 21.
    Adnet PJ, Bromberg NL, Haudecoeur G (1993) Fiber-type caffeine sensitivities in skinned muscle fibers from humans susceptible to malignant hyperthermia. Anesthesiology 78: 168–177PubMedCrossRefGoogle Scholar
  22. 22.
    Grayzel J (1989) A statistic for inferences based upon negative results. Anesthesiology 71: 320–321PubMedCrossRefGoogle Scholar
  23. 23.
    Kelkar VV, Jindal MN (1974) Chlorpromazine-induced contracture of frog rectus abdominis muscle. Pharmacology 12: 32–38PubMedCrossRefGoogle Scholar
  24. 24.
    Tagaki A (1981) Chlorpromazine and skeletal muscle: A study of skinned single fibers of the guinea pig. Exp Neurol 734: 477–486CrossRefGoogle Scholar
  25. 25.
    Reyford HG, Cordonnier C, Adnet PJ, Krivosic-Horber R, Bonte CA (1990) The in vitro exposure of muscle strips from patients with neuroleptic malignant syndrome (NMS) cannot be correlated with the clinical features. J Neurol Sci 98: (suppl 6.6): 527Google Scholar
  26. 26.
    Caroff SN (1980) The neuroleptic malignant syndrome. J Clin Psychiatry 41: 79–83PubMedGoogle Scholar
  27. 27.
    Levenson JL (1985) Neuroleptic malignant syndrome. Am J Psychiatry 142: 1137–1145PubMedGoogle Scholar

Copyright information

© Springer-Verlag Tokyo 1996

Authors and Affiliations

  • P. J. Adnet
    • 1
  • N. Bello
    • 1
  • H. Reyford
    • 1
  • R. M. Krivosic-Horber
    • 1
  1. 1.Malignant Hyperthermia Investigation UnitCentre Hospitalier UniversitaireLille CédexFrance

Personalised recommendations