Neuroleptic malignant syndrome
|Neuroleptic malignant syndrome|
WikiDoc Resources for Neuroleptic malignant syndrome
Evidence Based Medicine
Guidelines / Policies / Govt
Patient Resources / Community
Healthcare Provider Resources
Continuing Medical Education (CME)
Experimental / Informatics
Keywords and synonyms: NMS
The neuroleptic malignant syndrome is an uncommon adverse reaction to medications with dopamine receptor-antagonist properties or the rapid withdrawal of dopaminergic medications. The syndrome is characterized by severe rigidity, fever, tremor, autonomic dysfunction, altered mental status, and elevated serum creatinine phosphokinase. This is a life-threatening condition, with difficulties in diagnosis and treatment. This syndrome can further complicates psychiatric treatment.
The first reported case of NMS appeared in 1956, shortly after the introduction of the antipsychotic drug chlorpromazine (Thorazine). Additional case reports quickly followed, and in a 1960 study French clinicians gave the syndrome its current name when they reported on the adverse effects of the newly introduced neuroleptic haloperidol and characterized a ‘‘syndrome malin des neuroleptiques.’’2 Pooled data from 1966 to 1997 suggested the incidence of NMS ranges from 0.2% to 3.2% of psychiatric inpatients receiving neuroleptics; however, as physicians have become increasingly aware of the syndrome and with the advent of new neuroleptic medications, the incidence has decreased to around 0.01% to 0,02%.
There is no established system for the classification of NMS.
The pathophysiologic mechanisms of NMS are complex and still under debate among physicians But the majority of physicians agree that sudden and significant reduction in central dopaminergic activity within the mesolimbic/cortical, the nigrostriatal, and hypothalamic pathways help explain the clinical features of the neuroleptic malignant syndrome. This theory is supported by the observation that the use of antipsychotic drugs that specifically block D 2 receptors primarily cause NMS and that the syndrome can also be induced by abrupt dopamine withdrawal.
Additionally, this theory is supported by the dopamine receptorimaging study of NMS patients in the acute phase which demonstrated a complete lack of D2 receptor binding. Another study demonstrated low levels of dopamine metabolite in the CSF of patients with NMS in the acute phase. However D2 receptor antagonism does not explain all the presenting signs] and symptoms of NMS, nor does it explain its occurrence with antipsychotic medications with lower D2 activity and medications without known antidopaminergic activity. Abnormalities in the sympathetic system are supported by the frequent presence of autonomic symptoms in NMS as well as demonstrated changes in the urine and plasma catecholamine levels in patients with NMS. Some have hypothesized that NMS shares pathophysiological similarities with malignant hyperthermia and that a defect in calcium regulatory proteins within sympathetic neurons may be the essential factor that brings about the onset of NMS. Another system that also appears to play a role in the signs and symptoms of NMS is the peripheral skeletal muscle system. The release of calcium is increased from the sarcoplasmic reticulum of muscle cells with antipsychotic usage, possibly leading to increased muscle contractility and rigidity, breakdown of muscle, and hyperthermia. However, these theories are unable to explain why only a small fraction of patients develop NMS after exposure to neuroleptics. Furthermore, it remains unknown why patients who develop NMS are usually able to continue being treated with similar medications and, at times, even the same offending agent.
Potent typical neuroleptics such as fluphenazine, haloperidol, trifluoperazine, chlorpromazine, and prochlorperazine have been most frequently associated with NMS and thought to confer the greatest risk. Although atypical neuroleptics appear to have reduced the risk of developing NMS compared to typical neuroleptics. But a significant number of cases have been reported with most atypical neuroleptics including clozapine, risperidone, olanzapine, quetiapine, aripiprazole, olanzapine aripiprazole, and ziprasidone. The neuroleptic malignant syndrome has also been associated with nonneuroleptic agents with antidopaminergic activity such as diatrizoate, droperidol, tetrabenazine, and metoclopramide. The rapid switching from one type of dopamine receptor agonist to another in such patients has also been associated with NMS, and there may be some risk of NMS associated with the abrupt withdrawal of Parkinson medications that are not known to have direct dopaminergic activity such as amantadine and tolcapone.
|Typical Neuroleptics||Atypical Neuroleptics||Nonneuroleptics with antidopaminergic activity||Dopaminergics (withdrawal)||Others|
2) Dopamine agonists
NMS and Serotonin Syndrome
The clinical features of NMS and serotonergic syndrome are very similar. This can make differentiating them very difficult.
One the basis of stiffness and fever it can be differentiated from:
|Neuroleptic Malignant Syndrome |
|Stiff man syndrome||
|Drug induced (Tardive dyskinesia)|
Epidemiology and Demographics
The incidence of neuroleptic malignant syndrome is 0.02 % to 3% among patients taking antipsychotic medications. This wide range in the incidence probably reflects differences among population samples and differences in the surveillance methods used.
The majority of the patients is of adult populations but this rare disorder has been documented in all age groups from 0.9 to 78 years.Age is not a risk factor. In most studies, men outnumber women twofold.
- Initiation or dose escalation of neuroleptioc medication
- Use of high dose, high potency intramuscular neuroleptics
- Concurrent use of multiple neuroleptics
- physical exhaustion
- Heat stroke
- psychoactive substances
- presence of a structural or functional brain disorder such as encephalitis, tumor, delirium, or dementia
There is insufficient evidence to recommend routine screening for NMS.
Natural History, Complication and Prognosis
Most cases of neuroleptic malignant syndrome resolve within two weeks. The reported mean recovery time is 7 to 11 days. Depot antipsychotic use with concomitant structural brain disease is a risk factor for prolonged illness. Most patients recover without neurologic sequela if there is no prolonged hypoxic brain damage. The mortality rate of NMS varies from 5 to 20%. Delay in diagnosis or treatment can prolong the recovery time that may result in parkinsonism or an increase in morbidity secondary to cardiopulmonary or renal complications. When a death occurs in NMS patients that are due to DIC, arrhythmias, or cardiovascular complications.
Diagnostic Study of Choice
|Diagnostic criterion||Priority score*|
|Exposure to dopamine antagonist, or dopamine agonist withdrawal, within past 72 hours||20|
|Hyperthermia (>100.4°F or >38.0°C on at least 2 occasions, measured orally||18|
|Mental status alteration||13|
|Creatine kinase elevation||10|
|Sympathetic nervous system lability, defined as at least 2 of the following:
Blood pressure elevation (systolic or diastolic ≥25 percent above baseline) Blood pressure fluctuation (≥20 mmHg diastolic change or ≥25 mmHg systolic change within 24 hours) Diaphoresis Urinary incontinence
|Hypermetabolism, defined as heart-rate increase (≥25 percent above baseline) AND respiratory-rate increase (≥50 percent above baseline)||5|
|Negative work-up for infectious, toxic, metabolic, or neurologic causes||7|
History and Symptoms
The tetrad of neuroleptic malignant symptoms usually evolves in one to three days. About 97-100% of the patients have the following features.
- Almost 82% of the patients present with mental status change
- Generalized muscle rigidity that is often extreme
- Hyperthermia, almost 87% of patients have a temperature of more than 38°C a but even higher temperatures, greater than 40°C, is present in 40%
- Autonomic instability typically takes the form of tachycardia (88%), labile or high blood pressure (61-77 %), and tachypnea (73%). Dysrhythmias may occur. Diaphoresis is often profuse.
- Altered mental status
- Muscle rigidity
- Increased or labile blood pressure
- Resting tremor
- Elevated serum CK
- Mild elevations of LDH, ALP, and liver transaminases are common
- Electrolyte abnormalities: Hypocalcemia, metabolic acidosis, hypo or hypernatremia are common.
- Elevated creatinine may result from rhabdomyolysis
Electrolyte imbalances can cause cardiac arrhythmias that can cause cardiac arrest if not treated in a timely fashion. Both classes of antipsychotic drugs can cause serious cardiac side effects regardless of the electrolyte imbalances. One of the adverse side effects of antipsychotics is a prolongation of the QT interval that can convert into torsades de pontes causing sudden cardiac death.
There are no x-ray findings associated with NMS.
Echocardiography or Ultrasound
There are no echocardiography/ultrasound findings associated with NMS.
MRI brain does not provide any diagnostic information for NMS but can be used to rule out other conditions.
Other Imaging Findings
There are no other imaging findings associated with NMS.
Other Diagnostic Studies
There are no other diagnostic studies associated with NMS.
The management of patients with NMS should be based upon a hierarchy of clinical severity and diagnostic certainty. When manifestations are severe, intensive care unit monitoring and treatment are required.
Stop causative agent
The single most important step in the treatment of NMS is removal os causative agents. If possible, other potential contributing psychotropic agents should also be stopped. When the precipitant is the discontinuation of dopaminergic therapy, it should be reinstituted.
Complications of the NMS are often fatal and following supportive treatment is required in the intensive care unit.
- Discontinue any precipitating antipsychotic medication
- Maintain cardiorespiratory stability. Mechanical ventilation and cardio consultation may be required.
- Maintain euvolemic state through the administration of intravenous fluids,
- If CK is elevated then urine alkalinization with high volume fluid should be done to prevent renal failure from rhabdomyolysis
- Cooling blankets should be used to lower fever, more aggressive measures such as ice water gastric lavagemay be required.
- Lower blood pressure if markedly elevated. clonidinemay be used.
- Prescribe heparin or LMWH to prevent deep venous thrombosis
- If needed, use benzodiazepines (eg, lorazepam 0.5 to 1 mg) to control agitation
Recommendations for the treatment of NMS are based on clinical experience and case reports and randomized control trials were never done. Dantrolene, amantadine, and bromocriptine are commonly used medications. These agents are used in more severe cases and the dose is escalated if the patient gets worse. A reasonable approach is to start with benzodiazepines (lorazepam or diazepam) along with dantrolene in moderate or severe cases, followed by the addition of bromocriptine or amantadine.
Surgical intervention is not recommended for the management of NMS.
There are no established measures for the secondary prevention of NMS.
- Ayd F. Fatal hyperpyrexia during chlorpromazine therapy. J Clin Exp Psychopathol. 1956;17(2):189-192.
- Delay J, Pichot P, Lemperiere T. A non-phenothiazine and nonreserpine major neuroleptic, haloperidol, in the treatment of psychoses (in French). Ann Med Psychol (Paris). 1960;118(1): 145-152
- Pelonero AL, Levenson JL, Pandurangi AK. Neuroleptic malignant syndrome: a review. Psychiatr Serv. 1998;49(9):1163-1172
- Stubner S, Rustenbeck E, Grohmann R, et al. Severe and uncommon involuntary movement disorders due to psychotropic drugs. Pharmacopsychiatry. 2004;37(1):S54-S64.
- Adnet P, Lestavel P, Krivosic-Horber R. Neuroleptic malignant syndrome. Br J Anaesth. 2000;85(1):129-135. doi:10.1093/bja/85.1.129
- Strawn JR, Keck PE Jr, Caroff SN. Neuroleptic malignant syndrome. Am J Psychiatry. 2007;164(6):870-876. doi:10.1176/ajp.2007.164.6.870
- Jauss, M., Krack, P., Franz, M., Klett, R., Bauer, R., Gallhofer, B. and Dorndorf, W. (1996), Imaging of dopamine receptors with [123I]iodobenzamide single‐photon emission–computed tomography in neuroleptic malignant syndrome. Mov. Disord., 11: 726-728. doi:10.1002/mds.870110621
- Nisijima K, Ishiguro T. Cerebrospinal-fluid levels of monoamine metabolites and gamma-aminobutyric-acid in neuroleptic malignant syndrome. J Psychiatr Res. 1995;29(3):233-244.
- Khan FY, Qusad MJ. Neuroleptic malignant syndrome. Neurosciences. 2006;11(2):104-106
- Pasa S, Sayhan MB, Boyraz T, Urakci Z, Altintas A. A case of neuroleptic malignant syndrome accompanied to an atypical antipsychotic agent: risperidone. Neurotoxicology. 2008;29(4): 750-751.
- Pope HG, Cole JO, Choras PT, Fulwiler CE. Apparent neuroleptic malignant syndrome with clozapine and lithium. J Nervous Mental Dis. 1986;174(8):493-495.
- Diagnostic and statistical manual of mental disorders : DSM-5. Washington, D.C: American Psychiatric Association. 2013. ISBN 0890425558.
- Christensen V, Glenthøj B (2001). "[Malignant neuroleptic syndrome or serotonergic syndrome]". Ugeskr Laeger. 163 (3): 301–2. PMID 11219110.
- Birmes P, Coppin D, Schmitt L, Lauque D (2003). "Serotonin syndrome: a brief review". CMAJ. 168 (11): 1439–42. PMID 12771076.Full Free Text.
- Woldeamanuel YW, Andemeskel AT, Kyei K, Woldeamanuel MW, Woldeamanuel W (2016). "Case fatality of adult tetanus in Africa: Systematic review and meta-analysis". J Neurol Sci. 368: 292–9. doi:10.1016/j.jns.2016.07.025. PMID 27538652.
- Thwaites CL, Loan HT (2015). "Eradication of tetanus". Br Med Bull. 116: 69–77. doi:10.1093/bmb/ldv044. PMC 4674006. PMID 26598719.
- Hosseini S, Elyasi F (2017). "Olanzapine-Induced Neuroleptic Malignant Syndrome". Iran J Med Sci. 42 (3): 306–309. PMC 5429500. PMID 28533580.
- Leenhardt F, Perier D, Pinzani V, Giraud I, Villiet M, Castet-Nicolas A; et al. (2017). "Pharmacist intervention to detect drug adverse events on admission to the emergency department: Two case reports of neuroleptic malignant syndrome". J Clin Pharm Ther. doi:10.1111/jcpt.12531. PMID 28488314.
- Chow E, Troy SB (2014). "The differential diagnosis of hypoglycorrhachia in adult patients". Am J Med Sci. 348 (3): 186–90. doi:10.1097/MAJ.0000000000000217. PMC 4065645. PMID 24326618.
- Leen WG, Willemsen MA, Wevers RA, Verbeek MM (2012). "Cerebrospinal fluid glucose and lactate: age-specific reference values and implications for clinical practice". PLoS One. 7 (8): e42745. doi:10.1371/journal.pone.0042745. PMC 3412827. PMID 22880096.
- Tyler KL (2004). "Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret's". Herpes. 11 Suppl 2: 57A–64A. PMID 15319091.
- Deng ZD, Li DY, Zhang CC, Pan YX, Zhang J, Jin H; et al. (2017). "Long-term follow-up of bilateral subthalamic deep brain stimulation for refractory tardive dystonia". Parkinsonism Relat Disord. doi:10.1016/j.parkreldis.2017.05.010. PMID 28552340.
- "Valbenazine (Ingrezza) for tardive dyskinesia". Med Lett Drugs Ther. 59 (1521): 83–84. 2017. PMID 28520698.
- Voelker R (2017). "Tardive Dyskinesia Drug Approved". JAMA. 317 (19): 1942. doi:10.1001/jama.2017.5537. PMID 28510661.
- Charlotte Duverneuil, Geoffroy Lorin de la Grandmaison, Philippe de Mazancourt & Jean-Claude Alvarez (2004). "Liquid chromatography/photodiode array detection for determination of strychnine in blood: a fatal case report". Forensic science international. 141 (1): 17–21. doi:10.1016/j.forsciint.2003.12.010. PMID 15066709. Unknown parameter
- B. A. Smith (1990). "Strychnine poisoning". The Journal of emergency medicine. 8 (3): 321–325. PMID 2197324. Unknown parameter
- B. J. Maron, J. R. Krupp & B. Tune (1971). "Strychnine poisoning successfully treated with diazepam". The Journal of pediatrics. 78 (4): 697–699. PMID 5547830. Unknown parameter
- B. Oberpaur, A. Donoso, C. Claveria, C. Valverde & M. Azocar (1999). "Strychnine poisoning: an uncommon intoxication in children". Pediatric emergency care. 15 (4): 264–265. PMID 10460082. Unknown parameter
- Chhabra P, Rana SS, Sharma V, Sharma R, Bhasin DK (2016). "Hypocalcemic tetany: a simple bedside marker of poor outcome in acute pancreatitis". Ann Gastroenterol. 29 (2): 214–20. doi:10.20524/aog.2016.0015. PMC 4805743. PMID 27065735.
- Desai M, Kolla PK, Reddy PL (2013). "Calcium unresponsive hypocalcemic tetany: gitelman syndrome with hypocalcemia". Case Rep Med. 2013: 197374. doi:10.1155/2013/197374. PMC 3792521. PMID 24171002.
- Olanow CW, Watts RL, Koller WC (2001). "An algorithm (decision tree) for the management of Parkinson's disease (2001): treatment guidelines". Neurology. 56 (11 Suppl 5): S1–S88. PMID 11402154.
- Connolly BS, Lang AE (2014). "Pharmacological treatment of Parkinson disease: a review". JAMA. 311 (16): 1670–83. doi:10.1001/jama.2014.3654. PMID 24756517.
- Levenson JL. Neuroleptic malignant syndrome. Am J Psychiatry. 1985;142(10):1137-1145. doi:10.1176/ajp.142.10.1137
- Berardi D, Amore M, Keck PE, Troia M, Dell’Atti M. Clinical and pharmacologic risk factors for neuroleptic malignant syndrome: a case-control study. Biol Psychiatry. 1998;44(8): 748-754.
- Keck PE, Pope HG, Cohen BM, McElroy SL, Nierenberg AA. Risk-factors for neuroleptic malignant syndrome—a casecontrol study. Arch Gen Psychiatry. 1989;46(6):914-918.
- Kuno S, Mizuta E, Yamasaki S. Neuroleptic malignant syndrome in parkinsonian patients: Risk factors. Eur Neurol. 1997; 38(2):56-59.