Neuroleptic Malignant Syndrome

Totally Confused
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Diagnosis and reasoning

Acute fever and confusion is not an uncommon presentation in emergency medicine; the range of etiologies is vast, encompassing infectious, vascular, metabolic, and toxic conditions. A careful history and examination is key to the timely diagnosis of these individuals; this patient is an excellent example in point. First of all, note the presence of severe hyperthermia (i.e. a temperature of over 104ºF/40ºC); relatively few conditions can give rise to this degree of fever. Key possibilities include heat stroke, central nervous system (CNS) infections, malignant catatonia, substance abuse, and drug toxidromes such as neuroleptic malignant syndrome (NMS), serotonin syndrome, and malignant hyperthermia. The generalized rigidity is another potent clue; of the above, it is mainly malignant catatonia, malignant hyperthermia, and NMS which demonstrate this finding; substance abuse also remains a possibility (particularly if multiple agents have been ingested). Conversely, patients with serotonin syndrome are typically hyperkinetic, with tremors, clonus, and prominent lower limb hyperreflexia. Furthermore, rigidity is usually not a prominent feature in heat stroke, or CNS infections. That said, malignant hyperthermia is almost exclusively a complication of anesthesia; thus, it can be safely excluded in this patient. Malignant catatonia is also less likely, as such patients typically demonstrate positive motor phenomena such as dystonic posturing, waxy flexibility and stereotyped repetitive movements. In addition, a behavioral prodrome consisting of psychosis, agitation, and catatonic excitement is often present for several weeks beforehand. NMS is a strong possibility though, given that an antipsychotic agent has been commenced within the past month; this is supported by the markedly elevated creatine phosphokinase (CPK) levels and leukocytosis. Note also that the negative toxicology screen makes substance abuse less likely, while the normal CT scan of the brain and cerebrospinal fluid (CSF) analysis provide further evidence against a CNS infection. Thus, NMS does indeed appear to be the probable diagnosis; therefore Olanzapine should be stopped immediately. Furthermore, given the high mortality of the condition, treatment in an intensive care setting is advisable. Note that the hyperthermia is secondary to excessive heat production by the rigid muscles and altered thermoregulation of the hypothalamus; this is as opposed to fever due to inflammation or endogenous pyrogens, where the hypothalamic set point is raised. Thus, antipyretic therapy is unlikely to be of benefit; cooling measures such as cooling blankets and ice packs should be employed instead. Neither is antibiotic therapy indicated.


Discussion

Neuroleptic malignant syndrome (NMS) is a rare, life threatening, idiopathic adverse reaction to certain psychotropic medications. The condition is encountered in all age groups; estimates of the incidence range from 0.01% to 3.23% of all patients treated with antipsychotics. Note that the mortality rate is as high as 10%. NMS is classically associated with the use of high-potency 'typical' antipsychotics such as Haloperidol. However, it can also occur following treatment with atypical neuroleptics, and dopamine D2-receptor antagonists (such as metoclopramide and tricyclic antidepressants). The underlying pathophysiological mechanisms are still unclear; however, a reduction in dopaminergic activity in the brain, following blockade of dopamine receptors in the hypothalamic and nigrostriatal pathways is believed to play a role. Certain factors are believed to increase the risk of NMS; these include high drug doses and high titration rates, as well as the use of depot formulations, and concomitant prescription of lithium and selective serotonin reuptake inhibitors (SSRIs). Note that the condition can occur in the absence of an underlying psychiatric or neurologic disorder; furthermore, affected patients are at risk of developing the condition again, if re-exposed to the triggering agent(s). Clinically, NMS is characterized by the tetrad of fever, altered mentation, bradykinesia/rigidity, and autonomic instability; these symptoms usually evolve over the course of a few days. The alteration in mental status is often under-appreciated due to the existing psychiatric comorbidity, the muscular rigidity is generalized, and the fever is high grade (103°F ±1.9°F). The autonomic instability may manifest as tachycardia, a labile blood pressure, and/or a wide pulse pressure. Note also that almost all cases develop within one month of initiation of antipsychotic therapy; it is unusual for NMS to occur after this time, unless dosages are increased, or an additional antipsychotic is commenced. Several laboratory abnormalities are associated with NMS, although none are specific to the condition. These include striking elevations in creatine phosphokinase (CPK) levels - typically over 1,000 IU/L, and at times, as high as 100,000 IU/L; a leukocytosis in the range of 10,000 to 40,000/mm3 is also common. Transaminases, alkaline phosphatase (ALP), and lactic acid dehydrogenase (LDH) levels may also be elevated, while electrolyte abnormalities and metabolic acidosis may be seen. Neuroimaging studies and cerebrospinal fluid (CSF) analysis are usually normal; if performed, electroencephalography (EEG) may demonstrate generalized slowing. Note also that the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) defines specific criteria for the diagnosis of NMS; these are not elaborated in this monograph, as they are readily accessible in the relevant literature. Once NMS has been diagnosed, the offending agent must be withdrawn immediately, and supportive medical therapy initiated; this includes aggressive fluid resuscitation, and serial monitoring and correction of electrolyte abnormalities. Physical cooling measures such as cooling blankets and ice packs should be employed, and deep venous thrombosis (DVT) prophylaxis commenced. Depending on unit policy, therapy with dopaminergic agonists (such as bromocriptine), the peripheral muscle relaxant dantrolene, or benzodiazepines may also be considered; these agents may help ameliorate symptoms and hasten recovery. Following discontinuation of the offending drug, most patients recover within 7 to 10 days; almost all recover within a month. That said, episodes may be prolonged where long-acting depot antipsychotics are implicated. After recovery, at least 2 weeks should be allowed to relapse before antipsychotic therapy is re-initiated; ideally, a low-potency atypical agent should be started at a low dose, and slowly titrated in a monitored setting, with careful assessment for signs of recurrent NMS.


Take home messages

  1. NMS is typically associated with antipsychotic use, but can be caused by almost any dopamine antagonist.
  2. Most cases occur within the first month of initiation of therapy, unless the dose is increased or an additional antipsychotic is administered.
  3. Immediate termination of the offending drug is the single most important aspect of the management.

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  1. ANGLIN RE, ROSEBUSH PI, MAZUREK MF. Neuroleptic malignant syndrome: a neuroimmunologic hypothesis. CMAJ [online] 2010 Dec 14, 182(18):E834-8 [viewed 6 April 2015] Available from: doi:10.1503/cmaj.091442
  2. CAROFF SN, CAMPBELL EC, SULLIVAN KA. Neuroleptic malignant syndrome in elderly patients. Expert Rev Neurother [online] 2007 Apr, 7(4):423-31 [viewed 6 April 2015] Available from: doi:10.1586/14737175.7.4.423
  3. DOSI R, AMBALIYA A, JOSHI H, PATELL R. Serotonin syndrome versus neuroleptic malignant syndrome: a challenging clinical quandary. BMJ Case Rep [online] 2014 Jun 23 [viewed 10 April 2015] Available from: doi:10.1136/bcr-2014-204154
  4. FRUCHT SJ. Treatment of movement disorder emergencies. Neurotherapeutics [online] 2014 Jan, 11(1):208-12 [viewed 11 April 2015] Available from: doi:10.1007/s13311-013-0240-3
  5. GILLMAN PK. Neuroleptic malignant syndrome: mechanisms, interactions, and causality. Mov Disord [online] 2010 Sep 15, 25(12):1780-90 [viewed 5 April 2015] Available from: doi:10.1002/mds.23220
  6. GUPTA S, NIHALANI ND. Neuroleptic Malignant Syndrome: A Primary Care Perspective Prim Care Companion J Clin Psychiatry [online] 2004/01/01 00:00, 6(5):191-194 [viewed 4 April 2015] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC518983
  7. HARRISON PA, MCERLANE KS. Neuroleptic malignant syndrome. Am J Nurs [online] 2008 Jul, 108(7):35-8 [viewed 8 April 2015] Available from: doi:10.1097/01.NAJ.0000325810.75594.cb
  8. MARGETIć B, AUKST-MARGETIć B. Neuroleptic malignant syndrome and its controversies. Pharmacoepidemiol Drug Saf [online] 2010 May, 19(5):429-35 [viewed 12 April 2015] Available from: doi:10.1002/pds.1937
  9. MCALLEN KJ, SCHWARTZ DR. Adverse drug reactions resulting in hyperthermia in the intensive care unit. Crit Care Med [online] 2010 Jun, 38(6 Suppl):S244-52 [viewed 9 April 2015] Available from: doi:10.1097/CCM.0b013e3181dda0d4
  10. MOSCOVICH M, NóVAK FT, FERNANDES AF, BRUCH T, TOMELIN T, NóVAK EM, MUNHOZ RP, TEIVE HA. Neuroleptic malignant syndrome. Arq Neuropsiquiatr [online] 2011 Oct, 69(5):751-5 [viewed 8 April 2015] Available from: http://www.ncbi.nlm.nih.gov/pubmed/22042175
  11. MUNHOZ RP, MOSCOVICH M, ARAUJO PD, TEIVE HA. Movement disorders emergencies: a review. Arq Neuropsiquiatr [online] 2012 Jun, 70(6):453-61 [viewed 6 April 2015] Available from: http://www.ncbi.nlm.nih.gov/pubmed/22699544
  12. MUSSELMAN ME, SAELY S. Diagnosis and treatment of drug-induced hyperthermia. Am J Health Syst Pharm [online] 2013 Jan 1, 70(1):34-42 [viewed 10 April 2015] Available from: doi:10.2146/ajhp110543
  13. NICHOLSON D, CHIU W. Neuroleptic malignant syndrome. Geriatrics [online] 2004 Aug, 59(8):36, 38-40 [viewed 12 April 2015] Available from: http://www.ncbi.nlm.nih.gov/pubmed/15332415
  14. PERRY PJ, WILBORN CA. Serotonin syndrome vs neuroleptic malignant syndrome: a contrast of causes, diagnoses, and management. Ann Clin Psychiatry [online] 2012 May, 24(2):155-62 [viewed 11 April 2015] Available from: http://www.ncbi.nlm.nih.gov/pubmed/22563571
  15. REULBACH U, DüTSCH C, BIERMANN T, SPERLING W, THUERAUF N, KORNHUBER J, BLEICH S. Managing an effective treatment for neuroleptic malignant syndrome. Crit Care [online] 2007, 11(1):R4 [viewed 12 April 2015] Available from: doi:10.1186/cc5148
  16. RUSYNIAK DE, SPRAGUE JE. Toxin-induced hyperthermic syndromes. Med Clin North Am [online] 2005 Nov, 89(6):1277-96 [viewed 7 April 2015] Available from: doi:10.1016/j.mcna.2005.06.002
  17. SACHDEV PS. Neuroleptic-induced movement disorders: an overview. Psychiatr Clin North Am [online] 2005 Mar, 28(1):255-74, x [viewed 6 April 2015] Available from: doi:10.1016/j.psc.2004.10.004
  18. SMITH FA, WITTMANN CW, STERN TA. Medical complications of psychiatric treatment. Crit Care Clin [online] 2008 Oct, 24(4):635-56, vii [viewed 9 April 2015] Available from: doi:10.1016/j.ccc.2008.05.004
  19. STRAWN JR, KECK PE JR, CAROFF SN. Neuroleptic malignant syndrome. Am J Psychiatry [online] 2007 Jun, 164(6):870-6 [viewed 10 April 2015] Available from: doi:10.1176/ajp.2007.164.6.870
  20. STüBNER S, RUSTENBECK E, GROHMANN R, WAGNER G, ENGEL R, NEUNDöRFER G, MöLLER HJ, HIPPIUS H, RüTHER E. Severe and uncommon involuntary movement disorders due to psychotropic drugs. Pharmacopsychiatry [online] 2004 Mar:S54-64 [viewed 6 April 2015] Available from: doi:10.1055/s-2004-815511
  21. TROLLOR JN, CHEN X, SACHDEV PS. Neuroleptic malignant syndrome associated with atypical antipsychotic drugs. CNS Drugs [online] 2009, 23(6):477-92 [viewed 14 April 2015] Available from: doi:10.2165/00023210-200923060-00003