Neuroleptic Malignant Syndrome
Introduction
Neuroleptic Malignant Syndrome (NMS) is a rare but potentially fatal syndrome most commonly associated with the use of dopamine-antagonising neuroleptic medications.
NMS is manifested by the gradual onset of;
Altered mental status
Muscular rigidity
Autonomic dysfunction including hyperthermia
These lead to potentially fatal complications such as rhabdomyolysis, renal failure, cardiac arrhythmias and disseminated intravascular coagulation (DIC).
Treatment is largely supportive, aimed at minimising hyperthermia and preventing complications. Similar to its onset, the resolution of symptoms can be slow, potentially taking days to weeks. Even with early detection and institution of excellent supportive care, mortality rates for NMS are approximately 5-10%.
Risk Factors
Whilst the exact pathophysiology of NMS is not entirely understood, it is believed that a sudden decrease in dopamine within the CNS plays a large role. This results in muscular contraction, temperature dysregulation and an altered mental status. It develops in up to 2.5% of patients taking neuroleptic medications.
Antipsychotic medications are dopamine antagonists and all agents have the potential to cause NMS. The highly potent first-generation antipsychotics (eg. haloperidol) and depot preparations pose a particularly high risk. NMS is usually associated with therapeutic dose adjustments or medication additions, and is not commonly seen after acute overdoses. Higher doses of neuroleptics increase the risk of NMS, as do large magnitude dose increases or the simultaneous use of other antipsychotics or lithium. The highest rates of NMS are seen in young males, though this may simply reflect the epidemiology of psychotic disorders and the age of first exposure to neuroleptic medication.
Less frequently, patients who depend on pro-dopaminergic drugs (as seen with Parkinson’s Disease) can develop NMS from rapid withdrawal of their dopaminergic agents.
Clinical Features
NMS is a syndrome of gradual symptom onset, usually over days following medication alterations. According to the DSM-5, the presence of the following cardinal features suggests a diagnosis of NMS:
Exposure to a dopamine-blocking agent (or dopamine-agonist withdrawal) within the previous 72 hours
Generalised muscle rigidity
Hyperthermia (>38.0 degrees celsius on two occasions)
Elevated creatine kinase (CK) at least 4 times the upper limit
Altered mental status
Autonomic instability (labile/raised blood pressure, tachycardia, diaphoresis, pallor, urinary incontinence)
Altered Mental Status
Confusion
Delirium
Stupor
Coma
Neuromuscular Rigidity
“Lead-pipe” rigidity
Generalised bradykinesia or akinesia
Mutism, Staring
Dysarthria
Dystonia and abnormal postures
Abnormal involuntary movements
Autonomic Instability
Hyperthermia
Tachycardia
Hypertension
Cardiac arrhythmias
Urinary incontinence
Diaphoresis
Differential Diagnosis
Toxicology
Seretonin Syndrome
Malignant Hyperthermia
Sympathomimetic Toxicity e.g. cocaine, MDMA, amphetamines
Withdrawal syndromes
CNS
CNS Infections e.g. meningitis, encephalitis, abscess
Metabolic encephalopathies e.g. hepatic or thyrotoxicosis
Non convulsive status epilpeticus
Psychiatry
Psychiatric causes of catatonia
Clinical Investigations
Neuroleptic Malignant Syndrome is a clinical diagnosis based on a history of neuroleptic use, presence of characteristic signs and exclusion of important alternative diagnoses.
Bedside
ECG
cardiac arrythmias are an important complication.
Glucose
VBG
Metabolic/mixed acidosis is common.
Urine hCG in all females of child-bearing age.
Laboratory
Creatine Kinase (CK)
levels are typically at least 4 times higher than the upper limit of normal.
FBC
A significant leucocytosis is common
U&E
? AKI secondary to rhabdomyolisis
LFTs
mild transaminitis is common.
Lumbar puncture
To outrule CNS infection. NMS may show an increase in CSF protein.
Radiology/Other
CT/MRI Brain
normal NMS, though may be performed to rule out alternative structural/infective diagnoses.
EEG
NMS may show generalised slow wave activity.
Management & Disposition
Discontinuing the offending agent is the most important measure. In cases where the syndrome is due to withdrawal of dopaminergic agents, reinstitution of the drug may reduce symptoms.
Supportive Care
Good supportive care is paramount
Chest wall rigidity may cause impaired respiration and mechanical ventilation may be required
Replace fluids losses. Correct electrolytes
Benzodiazepines if agitated
Manage hyperthermia proactively with active cooling i.e. fanning, cold fluids
No role for anti-pyretics
If severe and refractory may need RSI, paralysis and invasive cooling
Specific Treatment
Most cases do not require antidotal therapy and should improve with cessation of the offending agent and good supportive care. In severe cases, pharmacological management can be considered:
Bromocriptine is a dopamine agonist that may help symptoms in severe NMS.
Dantrolene may have a role in severe muscle rigidity and fever
Electroconvulsive Therapy (ECT) may have a role in severe refractory cases.
Seek and treat complications e.g. rhabdomyolysis, coagulopathy, arrhythmias, AKI.
Disposition
Patients will typically require admission for close monitoring and supportive care. Severe cases should be discussed with the intensive-care unit.
Patients who have experienced NMS have a significant risk of further episodes on repeat exposure to neuroleptics. Once medically stabilised, the treating physician should liaise closely with the Psychiatry team for careful psychopharmacotherapy review.
References
American Psychiatric Association (2013) ‘Diagnostic and Statistical Manual of Mental Disorders.’ 5th ed. Arlington, VA: American Psychiatric Association Publishing
Bateman, N., Jefferson, R., Thomas, S., Thompson, J., Vale, A. (2014) Toxicology (Oxford Desk Reference): Oxford University Press.
Dear, J., Bateman, N. (2015) 'Antipsychotic Drugs', Medicine, 44(3), pp. 143-4 [Online]. Available at: https://doi.org/10.1016/j.mpmed.2015.12.026 (Accessed: 22nd March 2021).
Frucht, S.J. (2014) 'Treatment of Movement Disorder Emergencies', Neurotherapeutics, 11(1), pp. 208-12.
Murray, L., Daly, F., Little, M., Cadogan, M. (2007) Toxicology Handbook, Australia: Elsevier Australia.
Ngo, V. et al (2019) 'Emergent Treatment of Neuroleptic Malignant Syndrome Induced by Antipsychotic Monotherapy Using Dantrolene', Clin Pract Cases Emerg Med., 3(1), pp. 16-23.
Rasmussen, S.A., Mazurek, M.F., Rosebush, P.I. (2016) 'Catatonia: Our current understanding of its diagnosis, treatment and pathophysiology', World J Psychiatry. , 6(4), pp. 391-8
Simon L.V., Hashmi M.F., Callahan A.L. (2021) ‘Neuroleptic Malignant Syndrome’. [Updated 2021 Feb 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; Available from: https://www.ncbi.nlm.nih.gov/books/NBK482282/
This blog was written by Dr Ruadhán O’Laoi and was last updated in May 2021