Continuing Education Activity
Neuroleptic malignant syndrome (NMS) is a life-threatening syndrome associated with the use of dopamine-receptor antagonist medications or with rapid withdrawal of dopaminergic medications. NMS has been associated with virtually every neuroleptic agent but is more commonly reported with the typical antipsychotics like haloperidol and fluphenazine. Classic clinical characteristics include mental status changes, fever, muscle rigidity, and autonomic instability. This activity describes the presentation of neuroleptic malignant syndrome and highlights the role of the interprofessional team in the management of affected patients.
Objectives:
Explain when the diagnosis of neuroleptic malignant syndrome should be considered.
Explain how to diagnose neuroleptic malignant syndrome.
Explain the management of neuroleptic malignant syndrome.
Explore strategies to optimize care coordination among interprofessional team members to improve outcomes for patients affected by neuroleptic malignant syndrome.
Introduction
Neuroleptic malignantsyndrome (NMS) is a life-threatening syndrome associated with the use of dopamine-receptor antagonist medications or with the rapid withdrawal of dopaminergic medications. NMS has been associated with virtually every neuroleptic agent but is more commonly reported with the typical antipsychotics like haloperidol and fluphenazine. Classic clinical characteristics include mental status changes, fever, muscle rigidity, and autonomic instability. While uncommon, NMS remains an important part of the differential diagnosis of fever and mental status changes because it requires early diagnosis and treatment to prevent significant mortality and death. Treatment involves immediately discontinuing the offending agent, aggressive supportive care to manage and prevent complications, and pharmacologic therapy in severe cases. Theempiric medicationsmost frequently used for refractory NMS include bromocriptine mesylate, a dopamine agonist, and dantrolene sodium, a muscle relaxant. If the syndrome is due to the rapid withdrawal of dopaminergic medication, rapid re-institution of the medication may improve symptoms.[1][2][3]
Etiology
The primary trigger for NMS is dopamine receptor blockade, most often due to an antipsychotic agent. NMS is usually associated with high-potency first-generation neuroleptic agents butalsomay be caused by low-potency and atypical antipsychotic agents, antiemetics, tricyclic antidepressants, and lithium. Rapid withdrawal of dopaminergic drugs, most often used to manage parkinsonian diseases, such as levodopa and amantadine,alsomay cause this syndrome. The rapid switching of one Parkinson medication to another alsoisassociated with the development of NMS.[4][5][6]
Medications Associated with Neuroleptic Malignant Syndrome
Typical Neuroleptics
Haloperidol
Chlorpromazine
Fluphenazine
Thioridazine
Trifluordazine
Thiothixene
Loxapine
Bromperidol
Promazine
Clopenthixol
Atypical Neuroleptics
Olanzapine
Clozapine
Risperidone
Quetiapine
Ziprasidone
Aripiprazole
Zotepine
Amisulpride
Antiemetics
Droperidol
Domperidone
Metoclopramide
Promethazine
Prochlorperazine
Others
Tetrabenazine
Reserpine
Amoxapine
Diatrizoate
Lithium
Phenelzine
Dosulepin
Trimipramine
Desipramine
Dopaminergic Agents (withdrawal)
Levodopa
Amantadine
Tolcapone
Dopamine agonists
Epidemiology
Incidence rates range from 0.01% to 3.2% of patients taking neuroleptic medications. The incidence is decreasing due to newer agents, which are less likely to cause NMS, and increased awareness of the condition. Most cases occur in young adults, but this is most likely because it is the age of first exposure to neuroleptic medications rather than an age-related risk. Men outnumber women 2:1, also related to the likelihood of exposure to the causative agent. Incidence due to the withdrawal of dopaminergic drugs is more likely in the geriatric population based on the likelihood of exposure to the inciting cause.
Pathophysiology
The pathophysiology of NMS is complex and incompletely understood. Most symptoms are attributed to thesudden reduction in central dopaminergic activity due to a D2 receptor blockade or abrupt withdrawal of D2 receptor stimulation. This accounts for the characteristic muscle rigidity, hyperthermia, and mental status changes. Other neurotransmitters are involved, and NMS has features suggestive of disruption of the sympathetic nervous system. Other theories suggest a calcium-mediated disruptionof the musculoskeletal system, pathophysiologically similar to malignant hyperthermia. Familial clusters of patients with NMS and genetic testing suggestapredisposition to the development of NMS in certain individuals.[7][8][9]
History and Physical
The main risk factor for developing NMS is the initiation or increase in the dosage of neuroleptic medication. High-potency and long-aging neuromuscular depot forms carry the greatest risk. The concurrent use of multiple neuroleptic agents or lithium also increases the risk. Abrupt withdrawal of dopaminergic agents is a less common but important cause of NMS. Symptoms of NMS develop over one to three days and include distinctive clinical features: fever, muscle rigidity, mental status changes, and autonomic rigidity.
The DSM-V criteria for diagnosing NMS are as follows:
Major Criteria (all required)
Exposure to dopamine-blocking agent
Severe muscle rigidity
Fever
Other Criteria (at least two required)
Diaphoresis
Dysphagia
Tremor
Incontinence
Altered level of consciousness
Mutism
Tachycardia
Elevated or labile blood pressure
Leukocytosis
Elevated creatine phosphokinase
Evaluation
Evaluation should include a comprehensive metabolic panel including electrolytes and serum creatinine, creatine phosphokinase level, urinalysis for myoglobinuria, and arterial or venous blood gas to screen for metabolic acidosis. Diagnosis can be made clinically, but supporting lab work is usually consistent with rhabdomyolysis with an elevated CK and acutely declining renal function. The elevated CK can be profound and typically correlates with disease severity. Leukocytosis is common with white blood cell counts ranging from 10,00 to 40,000 mm3 with a left shift. Transaminases may also be mildly elevated. In patients where the diagnosis is less clear, neuroimaging and lumbar puncture may be necessary to exclude structural and infectious diagnosis from the differential.Additional laboratory testingsuch as a lithium level and screening for drugs of abuse may be helpful in selected cases.
Treatment / Management
NMS is a neurologic emergency, and delays in diagnosis and treatment can lead to significant morbidity or death. Discontinuing the offending agent is paramount, followed by supportive therapy. [10][11]This includes aggressive cooling and correction of volume deficits and any electrolyte imbalances. Patients are prone to cardiac dysrhythmias and respiratory failure due to chest wall rigidity. Treat with antiarrhythmic agents and mechanical ventilation as needed. More severe cases are managed with empiric pharmacologic therapy. Meta-analyses and case reports suggest that these may shorten the course and reduce morbidity and mortality. Bromocriptine, a dopamine agonist, given orally or via a gastric tube, is used to reverse the hypodopaminergic state.Dantrolene, a muscle relaxant may be administered intravenously or orally in less severe cases. Benzodiazepinesalsomay be useful in controlling agitation. If the syndrome is due to arapid withdrawal of dopaminergic agents, restarting the drug may reduce symptoms. Electroconvulsive therapyalsohas been reportedly effective in refractory cases. Patients should be admitted for close monitoring in an intensive care unit setting.[12]
Differential Diagnosis
NMS is one of a group of drug-related acute dysautonomias with common features of fever, rigidity, and autonomic dysfunction. Serotonin syndrome has similar features to NMS and is most easily distinguished by the causative agent, most frequently the serotonin-specific reuptake inhibitors. Hyperthermia and muscle rigidity are usually less severe with serotonin syndrome than with NMS; additionally, serotonin syndrome is more commonly associated with gastrointestinal symptoms, hyperreflexia, and myoclonus. Malignant hyperthermia is almost clinically indistinguishable from NMS, but the history of exposure to depolarizing muscle relaxants, most commonly succinylcholine, or inhaled anesthetic agents make the distinction clear in most cases. Malignant catatonia (MC) may present with fever, rigidity, akinesia, and altered mental status. It is important to distinguish from NMS becausemalignant catatoniashows robust responsiveness--reports reveal a full recovery in up to 80% of patients--with rapid initiation of benzodiazepines and electroconvulsive therapy.[13]Distinguishing features of malignant catatonic include increased positive symptoms as compared to NMS and a behavioral prodrome of automatisms, agitation, or psychosis.
Multiple other medical conditions can mimic NMS,makingit easy to misdiagnose.The most common mimics are central nervous system (CNS) infections such as meningitis or encephalitis, heatstroke, agitated delirium, toxic encephalopathies, withdrawal syndromes, metabolic emergencies, and nonconvulsive status epilepticus.
Acute encephalitis, meningitis, or brain abscess must be excluded in patients presenting with fever and mental status changes to avoid delay in treatment of CNS infection.This involves lumbar puncture for cerebrospinal fluid analysis and neuroimaging in certain cases. Patients on antipsychotic drugs are predisposed to heat-related illnesses, which mayresemble NMS. Acute intoxication with many recreational drugs such as cocaine, MDMA, amphetamines, methamphetamines, and phencyclidine may have similar features. Abuse of recreational drugs may occur in the setting of medical therapy with antipsychotics making the clinical picture ambiguous. Several withdrawal syndromes may present with features similar to NMS, especially withdrawal from muscle relaxants; the emergence of a withdrawal from an agent like baclofen is best managed by reinitiation therapy or with benzodiazepines. Alcohol and benzodiazepine withdrawalalso share features with NMS as do the withdrawal syndromes of other sedatives and hypnotics. Thyrotoxicosis and pheochromocytomaalso have overlappingmanifestations in common with NMS.
Prognosis
Early mortality reports weregreater than 30% for NMS; however, increased awareness, earlier detection,and better supportive care have reduced mortality to less than 10%. With early recognition and aggressive treatment, most patients will fully recover in 2to 14 days. Delayed treatment may result in significant morbidity such as residual catatonia, parkinsonism, renal, or cardiopulmonary complications. When fatal, deaths are usually due to cardiac arrhythmias, disseminated intravascular coagulation, respiratory failure, or renal failure. Many patients may be successfully restarted on neuroleptic medications, but some will develop recurrent symptoms. Guidelines for re-initiation of neuroleptic therapy recommend waiting at least two weeks after resolution of symptoms, using lower-potency agents, starting with low doses and slowly titrating to effect, and avoiding lithium in conjunction with neuroleptics. Patients should be instructed to avoid dehydration and should be carefully monitored for any symptoms of recurrent NMS.
Enhancing Healthcare Team Outcomes
NMS is a medical emergency that is best managed by an interprofessional team. These patients are ideally managed in the ICU with very close nursing monitoring and reporting to the team. A pharmacist trained in toxicology and a toxicologist should be involved in assisting with treatment and management decisions. The key is hydration and supportive therapy. There is no specific drug to reverse this disorder. Anecdotal reports on dantrolene continue to appear but a few case studies indicate that the drug may neither be effective or safe.[14]
For most patients in whom the offending drug is discontinued, the prognosis is good. An interprofessional approach to the education of the family, monitoring, and treatment by clinicians, nurses, and pharmacists will provide the best outcomes. [Levell 5]
References
- 1.
Duma SR, Fung VS. Drug-induced movement disorders. Aust Prescr. 2019 Apr;42(2):56-61. [PMC free article: PMC6478951] [PubMed: 31048939]
- 2.
Ott M, Werneke U. A Mixed Presentation of Serotonin Syndrome Versus Neuroleptic Malignant Syndrome in a 12-Year-Old Boy. Pediatr Emerg Care. 2019 May;35(5):e98. [PubMed: 30964850]
- 3.
van Rensburg R, Decloedt EH. An Approach to the Pharmacotherapy of Neuroleptic Malignant Syndrome. Psychopharmacol Bull. 2019 Feb 15;49(1):84-91. [PMC free article: PMC6386430] [PubMed: 30858642]
- 4.
Salik I, Marwaha R. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Sep 19, 2022. Electroconvulsive Therapy. [PubMed: 30855854]
- 5.
Manabe S, Yanagi H, Ozawa H, Takagi A. Neuroleptic malignant syndrome as part of an akinetic crisis associated with sepsis in a patient with Lewy body disease. BMJ Case Rep. 2019 Feb 28;12(2) [PMC free article: PMC6398821] [PubMed: 30824461]
- 6.
Jamshidi N, Dawson A. The hot patient: acute drug-induced hyperthermia. Aust Prescr. 2019 Feb;42(1):24-28. [PMC free article: PMC6370613] [PubMed: 30765906]
- 7.
Kane JM, Correll CU, Delva N, Gopal S, Savitz A, Mathews M. Low Incidence of Neuroleptic Malignant Syndrome Associated With Paliperidone Palmitate Long-Acting Injectable: A Database Report and Case Study. J Clin Psychopharmacol. 2019 Mar/Apr;39(2):180-182. [PMC free article: PMC6392211] [PubMed: 30811377]
- 8.
Grover S, Sathpathy A, Reddy SC, Mehta S, Sharma N. Parkinsonism-hyperpyrexia syndrome: A case report and review of literature. Indian J Psychiatry. 2018 Oct-Dec;60(4):499-503. [PMC free article: PMC6278220] [PubMed: 30581218]
- 9.
Ratto D, Joyner RW. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Apr 3, 2023. Dantrolene. [PubMed: 30571019]
- 10.
Kaliora SC, Zervas IM, Papadimitriou GN. [Electroconvulsive therapy: 80 years of use in psychiatry]. Psychiatriki. 2018 Oct-Dec;29(4):291-302. [PubMed: 30814039]
- 11.
Park J, Tan J, Krzeminski S, Hazeghazam M, Bandlamuri M, Carlson RW. Malignant Catatonia Warrants Early Psychiatric-Critical Care Collaborative Management: Two Cases and Literature Review. Case Rep Crit Care. 2017;2017:1951965. [PMC free article: PMC5303832] [PubMed: 28250995]
- 12.
Litman RS, Smith VI, Larach MG, Mayes L, Shukry M, Theroux MC, Watt S, Wong CA. Consensus Statement of the Malignant Hyperthermia Association of the United States on Unresolved Clinical Questions Concerning the Management of Patients With Malignant Hyperthermia. Anesth Analg. 2019 Apr;128(4):652-659. [PubMed: 30768455]
Disclosure: Leslie Simon declares no relevant financial relationships with ineligible companies.
Disclosure: Muhammad Hashmi declares no relevant financial relationships with ineligible companies.
Disclosure: Avery Callahan declares no relevant financial relationships with ineligible companies.
