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;

  1. Altered mental status

  2. Muscular rigidity

  3. 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:  

  1. Exposure to a dopamine-blocking agent (or dopamine-agonist withdrawal) within the previous 72 hours

  2. Generalised muscle rigidity

  3. Hyperthermia (>38.0 degrees celsius on two occasions)

  4. Elevated creatine kinase (CK) at least 4 times the upper limit

  5. Altered mental status

  6. 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.jpg

Bedside

  • ECG

    • cardiac arrythmias are an important complication.

  • Glucose

  • VBG

    • Metabolic/mixed acidosis is common.

  • Urine hCG in all females of child-bearing age.

LP+procedure.jpg

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.

CTB%25252525252Bwork%25252525252Bstation.jpg

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

  1. American Psychiatric Association (2013) ‘Diagnostic and Statistical Manual of Mental Disorders.’ 5th ed. Arlington, VA: American Psychiatric Association Publishing

  2. Bateman, N., Jefferson, R., Thomas, S., Thompson, J., Vale, A. (2014) Toxicology (Oxford Desk Reference): Oxford University Press.

  3. 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).

  4. Frucht, S.J. (2014) 'Treatment of Movement Disorder Emergencies', Neurotherapeutics, 11(1), pp. 208-12.

  5. Murray, L., Daly, F., Little, M., Cadogan, M. (2007) Toxicology Handbook, Australia: Elsevier Australia.

  6. 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.

  7. 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

  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

 Before you go have another look at the case and see if any of your answers have changed?