Neuroleptic Malignant Syndrome Differential Diagnoses
- Author: Theodore I Benzer, MD, PhD; Chief Editor: Asim Tarabar, MD more...
Diagnostic ConsiderationsOther neuroleptic-induced reactionsLethal catatoniaSerotonin syndromeMalignant hyperthermiaMedical mimics
Neuroleptic malignant syndrome (NMS) is a heterogeneous condition that spans a broad severity continuum. The diagnosis is made on clinical grounds and is based on the presence of certain historical, physical, and laboratory findings. The diagnosis is confirmed by the presence of recent treatment with neuroleptics (within the past 1-4 weeks), hyperthermia (temperature above 38°C), and muscular rigidity, along with at least five of the following features:
Change in mental status
Hypertension or hypotension
Diaphoresis or sialorrhea
Increased creatine phosphokinase (CPK) or urinary myoglobin level
In addition, diagnosis of neuroleptic malignant syndrome requires exclusion of other drug-induced, systemic, or neuropsychiatric illness. The clinician must rule out another medication reaction that might be a more likely cause of the patient’s symptoms than use of a neuroleptic. Exposure to other psychotropic drugs can result in disorders very similar to neuroleptic malignant syndrome. Medical conditions must also be considered.
Diagnostic criteria created by a consensus of an international multispecialty expert panel, including psychiatrists, neurologists, anesthesiologists, and emergency physicians, were released in 2011. In addition to hyperthermia and rigidity, at least two other clinical features of neuroleptic malignant syndrome, including leukocytosis and laboratory evidence of muscle injury, should be present. Although the criteria require validation before being used in clinical settings, they can provide guidance for clinicians.
Neuroleptic syndrome also has been associated with the rapid removal of medications with dopaminergic properties. Medications in these classes often are used to treat Parkinson disease and include levodopa, bromocriptine, and amantadine. In such cases, dopaminergic drugs should be started as soon as possible to prevent rhabdomyolysis and renal failure. Evaluation and treatment is otherwise the same as in neuroleptic syndrome involving other drugs.
Antipsychotics can cause a variety of reactions that can be confused with neuroleptic malignant syndrome. These neuroleptic-induced reactions often occur with increasing medication dosages and include the following:
Acute dystonia - Abnormal contraction or spasm of a group of skeletal muscles, often involving the head or neck
Acute akathisia - Motor restlessness, particularly involving the legs
Tardive dyskinesia - Involuntary, rhythmic movements starting with mouth movements
Parkinsonism, or pseudoparkinsonism - Classically presents as the triad of tremor, muscular rigidity, and akinesia
Despite the term neuroleptic-induced, these conditions also can be caused, although less frequently, by many of the newer, nontraditional antipsychotic medications, which also have some dopamine-blocking activity. For more information, see Medication-Induced Dystonic Reactions and Neuroleptic Agent Toxicity .
Lethal catatonia (LC) is a similar condition that might be confused with neuroleptic malignant syndrome. Lethal catatonia occurs in people with schizophrenia or during manic episodes. Neuroleptics might either improve or worsen the symptoms of lethal catatonia.
Distinguishing lethal catatonia from neuroleptic malignant syndrome can be difficult, although a detailed history might reveal episodes of catatonia while a patient is not taking neuroleptics. Lethal catatonia also tends to have a prodrome of excitement and agitation prior to the onset of rigidity, while neuroleptic malignant syndrome tends to begin with rigidity.
The serotonin syndrome is similar to neuroleptic malignant syndrome. It is characterized by the triad of altered mental status, autonomic dysfunction, and movement disorder (tremor and abnormal involuntary movement) following exposure to serotonergic agents.
Diagnosis may be especially challenging in patients taking both serotonergic and neuroleptic agents, who may meet criteria for both syndromes. However, laboratory findings characteristic of neuroleptic malignant syndrome (eg, elevated creatine kinase level, liver function test results, and white blood cell count, coupled with a low serum iron level) do not occur in serotonin syndrome.
The proposed mechanism of serotonin syndrome is excessive 5-hydroxytryptamine (5-HT or serotonin) stimulation. Selective serotonin reuptake inhibitors (SSRIs) are the most frequently used medications in this class. Given the increasing use of SSRIs, the serotonin syndrome might become increasingly prevalent.
The serotonin syndrome can be distinguished from neuroleptic malignant syndrome in most cases by a detailed history of medication use, with particular attention to recent dosage changes and the presence of tremor and abnormal movements but the absence of severe rigidity. Treatment of this condition includes removal of the offending drug and supportive management, though 5-HT1A antagonists might have a role.[33, 36]
Malignant hyperthermia (MH) occurs after administration of halogenated inhalational anesthetics (eg, halothane) or depolarizing muscle relaxants (eg, succinylcholine) to genetically susceptible individuals. An underlying defect is an autosomal dominant mutation in the ryanodine receptor, which leads to excessive calcium release from the sarcoplasmic reticulum in skeletal muscle when one of the above agents is administered. A multifactorial pattern of inheritance also has been postulated.
Malignant hyperthermia can be distinguished readily by history. Treatment is based on supportive care, use of dantrolene to decrease calcium release, and subsequent avoidance of precipitating medications. No evidence shows that neuroleptic malignant syndrome occurs more frequently in patients susceptible to malignant hyperthermia.
General medical conditions that might mimic neuroleptic malignant syndrome include the following:
Central nervous system infections
Rhabdomyolysis in Emergency Medicine - DELETE
Selective Serotonin Reuptake Inhibitor Toxicity
Rosebush PI, Mazurek MF. Serum iron and neuroleptic malignant syndrome. Lancet. 1991 Jul 20. 338(8760):149-51. [Medline].
Tse L, Barr AM, Scarapicchia V, Vila-Rodriguez F. Neuroleptic Malignant Syndrome: A Review from a Clinically Oriented Perspective. Curr Neuropharmacol. 2015. 13 (3):395-406. [Medline].
Chiou YJ, Lee Y, Lin CC, Huang TL. A Case Report of Catatonia and Neuroleptic Malignant Syndrome With Multiple Treatment Modalities: Short Communication and Literature Review. Medicine (Baltimore). 2015 Oct. 94 (43):e1752. [Medline].
DELAY J, PICHOT P, LEMPERIERE T, ELISSALDE B, PEIGNE F. [A non-phenothiazine and non-reserpine major neuroleptic, haloperidol, in the treatment of psychoses]. Ann Med Psychol (Paris). 1960 Jan. 118(1):145-52. [Medline].
Trollor JN, Chen X, Chitty K, Sachdev PS. Comparison of neuroleptic malignant syndrome induced by first- and second-generation antipsychotics. Br J Psychiatry. 2012 Jul. 201(1):52-6. [Medline].
Trollor JN, Chen X, Sachdev PS. Neuroleptic malignant syndrome associated with atypical antipsychotic drugs. CNS Drugs. 2009. 23(6):477-92. [Medline].
Gurrera RJ, Caroff SN, Cohen A, Carroll BT, DeRoos F, Francis A, et al. An international consensus study of neuroleptic malignant syndrome diagnostic criteria using the Delphi method. J Clin Psychiatry. 2011 Sep. 72(9):1222-8. [Medline].
Jauss M, Krack P, Franz M, Klett R, Bauer R, Gallhofer B, et al. Imaging of dopamine receptors with [123I]iodobenzamide single-photon emission-computed tomography in neuroleptic malignant syndrome. Mov Disord. 1996 Nov. 11(6):726-8. [Medline].
Gurrera RJ. Sympathoadrenal hyperactivity and the etiology of neuroleptic malignant syndrome. Am J Psychiatry. 1999 Feb. 156(2):169-80. [Medline].
Ehara H, Maegaki Y, Takeshita K. Neuroleptic malignant syndrome and methylphenidate. Pediatr Neurol. 1998 Oct. 19(4):299-301. [Medline].
Keck PE Jr, Pope HG Jr, Cohen BM, McElroy SL, Nierenberg AA. Risk factors for neuroleptic malignant syndrome. A case-control study. Arch Gen Psychiatry. 1989 Oct. 46(10):914-8. [Medline].
Paparrigopoulos T, Tzavellas E, Ferentinos P, Mourikis I, Liappas J. Catatonia as a risk factor for the development of neuroleptic malignant syndrome: report of a case following treatment with clozapine. World J Biol Psychiatry. 2009. 10(1):70-3. [Medline].
Sachdev P, Mason C, Hadzi-Pavlovic D. Case-control study of neuroleptic malignant syndrome. Am J Psychiatry. 1997 Aug. 154(8):1156-8. [Medline].
Alexander PJ, Thomas RM, Das A. Is risk of neuroleptic malignant syndrome increased in the postpartum period?. J Clin Psychiatry. 1998 May. 59(5):254-5. [Medline].
Otani K, Horiuchi M, Kondo T, Kaneko S, Fukushima Y. Is the predisposition to neuroleptic malignant syndrome genetically transmitted?. Br J Psychiatry. 1991 Jun. 158:850-3. [Medline].
Rosebush PI, Stewart TD, Gelenberg AJ. Twenty neuroleptic rechallenges after neuroleptic malignant syndrome in 15 patients. J Clin Psychiatry. 1989 Aug. 50(8):295-8. [Medline].
Manu P, Sarpal D, Muir O, Kane JM, Correll CU. When can patients with potentially life-threatening adverse effects be rechallenged with clozapine? A systematic review of the published literature. Schizophr Res. 2012 Feb. 134(2-3):180-6. [Medline]. [Full Text].
Gelenberg AJ, Bellinghausen B, Wojcik JD, Falk WE, Sachs GS. A prospective survey of neuroleptic malignant syndrome in a short-term psychiatric hospital. Am J Psychiatry. 1988 Apr. 145(4):517-8. [Medline].
Strawn JR, Keck PE Jr, Caroff SN. Neuroleptic malignant syndrome. Am J Psychiatry. 2007 Jun. 164(6):870-6. [Medline].
Deng MZ, Chen GQ, Phillips MR. Neuroleptic malignant syndrome in 12 of 9,792 Chinese inpatients exposed to neuroleptics: a prospective study. Am J Psychiatry. 1990 Sep. 147(9):1149-55. [Medline].
Chopra MP, Prakash SS, Raguram R. The neuroleptic malignant syndrome: an Indian experience. Compr Psychiatry. 1999 Jan-Feb. 40(1):19-23. [Medline].
Lazarus A. Neuroleptic malignant syndrome. Hosp Community Psychiatry. 1989 Dec. 40(12):1229-30. [Medline].
Henderson T. Neuroleptic malignant syndrome in adolescents: four probable cases in the Western Cape. S Afr Med J. 2011 May 25. 101(6):405-7. [Medline].
Croarkin PE, Emslie GJ, Mayes TL. Neuroleptic malignant syndrome associated with atypical antipsychotics in pediatric patients: a review of published cases. J Clin Psychiatry. 2008 Jul. 69(7):1157-65. [Medline].
Modi S, Dharaiya D, Schultz L, Varelas P. Neuroleptic Malignant Syndrome: Complications, Outcomes, and Mortality. Neurocrit Care. 2016 Feb. 24 (1):97-103. [Medline].
Rani FA, Byrne P, Cranswick N, Murray ML, Wong IC. Mortality in children and adolescents prescribed antipsychotic medication: a retrospective cohort study using the UK general practice research database. Drug Saf. 2011 Sep 1. 34(9):773-81. [Medline].
Picard LS, Lindsay S, Strawn JR, Kaneria RM, Patel NC, Keck PE Jr. Atypical neuroleptic malignant syndrome: diagnostic controversies and considerations. Pharmacotherapy. 2008 Apr. 28(4):530-5. [Medline].
Oomura M, Terai T, Sueyoshi K, Shigeno K. Reversible cardiomyopathy as the autonomic involvement of neuroleptic malignant syndrome. Intern Med. 2004 Dec. 43(12):1162-5. [Medline].
Newman EJ, Grosset DG, Kennedy PG. The parkinsonism-hyperpyrexia syndrome. Neurocrit Care. 2009. 10(1):136-40. [Medline].
Ward C. Neuroleptic malignant syndrome in a patient with Parkinson's disease: a case study. J Neurosci Nurs. 2005 Jun. 37(3):160-2. [Medline].
Osman AA, Khurasani MH. Lethal catatonia and neuroleptic malignant syndrome. A dopamine receptor shut-down hypothesis. Br J Psychiatry. 1994 Oct. 165(4):548-50. [Medline].
Martin TG. Serotonin syndrome. Ann Emerg Med. 1996 Nov. 28(5):520-6. [Medline].
Dosi R, Ambaliya A, Joshi H, Patell R. Serotonin syndrome versus neuroleptic malignant syndrome: a challenging clinical quandary. BMJ Case Rep. 2014 Jun 23. 2014:[Medline].
Perry PJ, Wilborn CA. Serotonin syndrome vs neuroleptic malignant syndrome: a contrast of causes, diagnoses, and management. Ann Clin Psychiatry. 2012 May. 24(2):155-62. [Medline].
Odagaki Y. Atypical neuroleptic malignant syndrome or serotonin toxicity associated with atypical antipsychotics?. Curr Drug Saf. 2009 Jan. 4(1):84-93. [Medline].
Heiman-Patterson TD. Neuroleptic malignant syndrome and malignant hyperthermia. Important issues for the medical consultant. Med Clin North Am. 1993 Mar. 77(2):477-92. [Medline].
Vörös V, Osváth P, Fekete S, Tényi T. [Antipsychotics and rhabdomyolysis. Differential diagnosis and clinical significance of elevated serum creatine kinase levels in psychiatric practice]. Psychiatr Hung. 2009. 24(3):175-84. [Medline].
Schneider SM. Neuroleptic malignant syndrome: controversies in treatment. Am J Emerg Med. 1991 Jul. 9(4):360-2. [Medline].
Addonizio G, Susman VL. ECT as a treatment alternative for patients with symptoms of neuroleptic malignant syndrome. J Clin Psychiatry. 1987 Mar. 48(3):102-5. [Medline].
Shoirah H, Hamoda HM. Electroconvulsive therapy in children and adolescents. Expert Rev Neurother. 2011 Jan. 11(1):127-37. [Medline].
Ozer F, Meral H, Aydin B, Hanoglu L, Aydemir T, Oral T. Electroconvulsive therapy in drug-induced psychiatric states and neuroleptic malignant syndrome. J ECT. 2005 Jun. 21(2):125-7. [Medline].
Hermesh H, Aizenberg D, Weizman A. A successful electroconvulsive treatment of neuroleptic malignant syndrome. Acta Psychiatr Scand. 1987 Mar. 75(3):237-9. [Medline].
Rosebush PI, Stewart T, Mazurek MF. The treatment of neuroleptic malignant syndrome. Are dantrolene and bromocriptine useful adjuncts to supportive care?. Br J Psychiatry. 1991 Nov. 159:709-12. [Medline].
Sakkas P, Davis JM, Janicak PG, Wang ZY. Drug treatment of the neuroleptic malignant syndrome. Psychopharmacol Bull. 1991. 27(3):381-4. [Medline].
Ghaziuddin N, Dhossche D, Marcotte K. Retrospective chart review of catatonia in child and adolescent psychiatric patients. Acta Psychiatr Scand. 2012 Jan. 125(1):33-8. [Medline].