Neuroleptic malignant syndrome: a neuro-psychiatric emergency

Neuroleptic malignant syndrome—or antidopaminergic syndrome, as Dietrichs and Dietrichs (2022) suggested it should be called, given the move away from the use of the term ‘neuroleptic’ when referring to antipsychotic medication—is a potentially fatal neuropsychiatric medical emergency characterised by mental status change, parkinsonism, hyperthermia and dysautonomia. First reported in 1956, shortly after the introduction of the antipsychotic medication chlorpromazine (Ayd, 1956), neuroleptic malignant syndrome is caused by a severe adverse reaction to medications with dopamine receptor-agonist properties or the rapid withdrawal of dopaminergic medications.

Despite ambulance services increasingly including clinical practice guidelines for serotonin syndrome, an important differential diagnosis for neuroleptic malignant syndrome (Ott and Werneke, 2019; Viveiros, 2021), there is limited guidance on the recognition and management of neuroleptic malignant syndrome in the prehospital setting.

In cases where there is a history of schizophrenia, acute agitation, bipolar disorder, personality disorder, obsessive compulsive disorder, acute delirium, generalised anxiety disorder or treatment-resistant depression (Stroup and Gray, 2018), paramedics should have a high index of suspicion for neuroleptic malignant syndrome.

Antipsychotics are commonly prescribed for the management of symptoms including hallucinations, delusions and disordered thinking and behaviour associated with mental health conditions (Stroup and Gray, 2018). The side effects of antipsychotics range from orthostatic hypotension to involuntary muscle contractions causing repetitive movement or abnormal postures (dystonia) to more serious neurological side effects including changes in consciousness ranging from confusion to coma (Berman, 2011). Neuroleptic malignant syndrome is the most serious side effect associated with antipsychotic use, with approximately 10 per cent of cases ending in cardiac arrest (Dolp et al, 2020; Sharman, 2020).

While the standard causative agent for neuroleptic malignant syndrome is a neuroleptic antipsychotic (Berman, 2011), atypical neuroleptics including risperidone (Pasa et al, 2008), clozapine (Pope et al, 1986), quetiapine (El-Gaaly et al, 2009), olanzapine (Kantrowitz and Citrome, 2008) and ziprasidone (Ozen et al, 2007) are also known to cause this presentation. Pharmacological agents such as metoclopramide (Nonino, 1999), promethazine (Khan and Qusad, 2006), droperidol (Edgar, 1999) and amoxapine (Washington et al, 1989) have also been associated with neuroleptic malignant syndrome resulting from antidopaminergic activity.

The objectives of this article are to provide an understanding of neuroleptic malignant syndrome along with information on a safe and comprehensive approach to management of this presentation in the paramedic setting.

Pathophysiology

While the pathophysiology of neuroleptic malignant syndrome is complex and not fully understood (Berman, 2011), experts agree it involves a marked, sudden reduction in central dopaminergic activity resulting from D2 dopamine receptor blockade within the nigrostriatal, hypothalamic and mesolimbic/cortical pathways. The blocking of dopamine transmission in the nigrostriatum causes muscle rigidity, tremor and rhabdomyolysis, while the blocking of dopamine in the hypothalamus causes hyperthermia (Stojanović and Spirić, 2014; Gall-Ojurongbe and Williams, 2015; Wadoo et al, 2021).

A decrease in central dopamine levels resulting from D2 receptor antagonism is a common side effect of first-generation (or typical) antipsychotics such as haloperidol and chlorpromazine (Grant et al, 2021; Guinart et al, 2021a because of their affinity to D2 receptors (Gall-Ojurongbe and Williams, 2015). D2 receptor antagonism results in a steep decline in dopamine activity as the medication blocks the receptors within the dopamine systems of the brain. This in turn leads to the removal of tonic inhibition from the sympathetic nervous system pathway (Sharman, 2020), leading to sympathoadrenal hyperactivity and dysregulation causing autonomic dysfunction (Sharman, 2020). Second-generation (atypical) antipsychotic medications such as risperidone and olanzapine are less often associated with neuroleptic malignant syndrome, because of their antagonism to 5HT2 receptors rather than D2 receptors (Gall-Ojurongbe and Williams, 2015).

The reduction in dopamine levels resulting from the sudden withdrawal or a reduction in the dose of dopaminergic medication leads to a reduction in dopamine signalling (Grant et al, 2021). At the peripheral level, the medication can lead to an increase in calcium release from the sarcoplasmic reticulum, resulting in increased contractility, which can exacerbate rigidity and hyperthermia and increase the chance of rhabdomyolysis (Sharman, 2020).

Risk factors

There are several risk factors that should lead to paramedics having a high degree of suspicion that a patient is presenting with neuroleptic malignant syndrome.

Stroup and Gray (2018) suggested that the most important risk factor for neuroleptic malignant syndrome is a previous history of the condition; it has a recurrence rate of 10%–40%. Men are at a higher risk of presenting with it than women as they are more likely to be prescribed antipsychotic medications (Sharman, 2020).

Patients who have had a recent change of antipsychotic medication or are on multiple antipsychotic drugs, particularly first-generation antipsychotics, are at an increased risk of developing neuroleptic malignant syndrome (Stroup and Gray, 2018). First-generation neuroleptics pose the greatest risk, but neuroleptic malignant syndrome has been reported with second-generation neuroleptics, with clozapine presenting the highest risk. Table 1 provides an overview of first- and second-generation antipsychotics, along with antiemetic medications that are known to trigger neuroleptic malignant syndrome.

Patients with a recent history of an onset of psychosis or starting antipsychotic medication, having a change in their antipsychotic medications such as using a new antipsychotic, withdrawal of an antipsychotic or an alteration in dose are also at increased risk of developing neuroleptic malignant syndrome (Stroup and Gray, 2018; Dolp et al, 2020; Grant et al, 2021; Guinart et al, 2021b; Wadoo et al, 2021). Guinart et al (2021a; 2021b) and Grant et al (2021) suggest that the cessation of dopaminergic medication such as L-dopa and a history of Parkinson's disease with a recent change in medication are potential presentations that may be seen by paramedics.

Discontinuation of anticholinergic medications (Grover et al, 2022) or the use of an antiemetic such as metoclopramide or promethazine also increases the risk of developing neuroleptic malignant syndrome (Sharman, 2020). Kawanishi (2003) suggested there may be genetic susceptibility to neuroleptic malignant syndrome, with individuals with genetic factors linked to the dopamine D2 receptor gene being overrepresented in neuroleptic malignant syndrome presentations. This was also confirmed more recently by Sharman (2020). Stojanović and Spirić (2014) suggested that infection, particularly of the central nervous system, may be risk factor, with a more rapid onset of neuroleptic malignant syndrome when antipsychotic medication is started when infection is present.

Higher mortality rates from neuroleptic malignant syndrome are most commonly associated with older age, potentially because of a deterioration in health owing to normal ageing processes, and a greater likelihood that the individual will have comorbidities (Guinart, et al, 2021a; 2021b; Wadoo, 2021). Hypertension, diabetes, chronic kidney disease and congestive heart failure are associated with an increase in mortality (Wadoo, 2021). Hyperthermia above 39°C, tachypnoea and a severe alteration in conscious state also increases the risk of mortality (Wadoo et al, 2021). Hosseini and Elyasi (2017) suggest that malnutrition and dehydration are risk factors that raise the risk of mortality. The use of physical restraints is also likely to increase the likelihood of death as this raises the risk of the development and exacerbation of rhabdomyolysis secondary to this action (Wadoo et al, 2021).

Signs and symptoms

Hyperthermia, generalised muscle rigidity (often described as ‘lead pipe rigidity’), autonomic dysfunction resulting in increases to heart rate, respiration rate and blood pressure, along with mental status changes including irritability, agitation, delirium and differences in behaviour, such as refusing to talk or move, as well as an altered level of consciousness are all signs and symptoms of neuroleptic malignant syndrome (Dolp et al, 2020; Grant et al, 2021; Guinart et al, 2021a). Hyperthermia with a temperature above 38°C is common, with temperatures higher than 40°C reported in approximately 40% of cases (Sharman, 2020).

It is not uncommon for patients taking antipsychotic medications to experience temperatures rising above the accepted normothermic baseline, and Wadoo et al (2021) pointed out that an elevated temperature in the absence of generalised muscular rigidity does not indicate neuroleptic malignant syndrome.

The extent to which specific symptoms are seen in cases of neuroleptic malignant syndrome are detailed in Table 2.

Mental status changes are usually the first symptom to appear, with muscular rigidity, autonomic instability and, finally, hyperthermia following (Wadoo et al, 2021). The syndrome may not be immediately recognisable and can be challenging to diagnose, particularly in the emergency out-of-hospital care setting. In the initial stages of the syndrome, patients may present with mild muscle rigidity, mild diaphoresis, mild increases in heart rate and agitation or delirium (Gall-Ojurongbe and Williams, 2015; Wilson et al, 2016).

While symptoms can manifest at any time during treatment with antipsychotic medication, in approximately 96% of cases, they begin to manifest within the first week. All symptoms of neuroleptic malignant syndrome will manifest within 30–40 days of a patient starting antipsychotic medication or a change being made in the their medication (Wilson et al, 2016; Wadoo et al, 2021).

Assessment and diagnosis

As the condition needs to be identified early on, paramedics should have a high index of suspicion for neuroleptic malignant syndrome in their assessment of patients presenting with hyperthermia, muscle rigidity and an altered mental status. Dolp et al (2020), Guinart et al (2021a; 2021b) and Grover et al (2022) all highlighted the need for neuroleptic malignant syndrome to be recognised early to minimise the risk of potential complications, organ failure and death.

Box 1.Red flags for neuroleptic malignant syndrome

• Recent cessation of a dopamine agonist or antagonist
• Past medical history of neuroleptic malignant syndrome
• Recent diagnosis of psychotic disorder
• Taking any antipsychotic medication
• A recent change to antipsychotic medication including alteration in dose or commencement or cessation of a drug of this type
• Development of muscle rigidity even in the absence of autonomic instability
• Overdose of antipsychotic medication

Box 2.Variation in vital signs from baseline

• Increase in blood pressure of >25%
• Diastole increase of >20 mmHg
• Systole >25 mmHg
• Increased heart rate/tachycardia >25%
• Increased respiration rate >50%
• Temperature >38°C

Box 3.Differential diagnoses

• Acute psychosis
• Severe depression
• Serotonin syndrome
• Infection/sepsis
• Excited catatonia
• Parkinsonism
• Alcohol or sedative withdrawal, including delirium tremens
• Heatstroke
• Anticholinergic poisoning
• Dystonic reaction
• Acute behavioural disturbance
• Encephalitis
• Malignant hyperthermia
• Meningitis
• Non-convulsive status epilepticus
• Strychnine poisoning
• Tetanus
• Thyroid storm

Paramedics must gather a detailed history from all patients to determine if any of the red flags listed in Box 1 are present. To effectively identify neuroleptic syndrome early in the patient assessment phase, it is imperative that any history of recent changes to antipsychotic medication are considered, including alternations in dose, starting a new antipsychotic medication or cessation of such a drug in the presence of hyperthermia, muscle rigidity, tachycardia, dystonia, autonomic instability and altered mental status.

In completing a comprehensive physical examination of a patient suspected of presenting with neuroleptic malignant syndrome, paramedics should be looking for signs and symptoms such as an altered mental status, drowsiness, confusion or coma, hyperthermia, muscle rigidity and autonomic instability (Strawn et al, 2007). In some instances, where a patient is agitated, it may not be possible to obtain baseline vital signs, making it difficult to assess for changes in autonomic stability (Wadoo et al, 2021). Wilson et al (2016) encouraged the use of a mobility assessment, as patients will present with ‘robot like’ movements because of muscle rigidity.

Where neuroleptic malignant syndrome is suspected, it is imperative that paramedics err on the side of caution and, if they suspect neuroleptic malignant syndrome, they should start supportive medical treatment in accordance with their service guidelines.

Box 2 provides a guide to the vital sign changes that should help paramedics make a provisional diagnosis of neuroleptic malignant syndrome.

A provisional diagnosis of neuroleptic malignant syndrome may also be made through the exclusion of other causes such as hyperglycaemia, status epilepticus and heatstroke. An important consideration in the diagnosis of neuroleptic malignant syndrome is that it manifests at normal environmental temperatures although the patient will be hyperthermic at 38°C or above. Once medical causes of the presentation have been ruled out, a number of differential diagnoses need to be eliminated to make a provisional diagnosis of neuroleptic syndrome (Box 3). It is also possible to eliminate several differential diagnoses, for example alcohol or sedative withdrawal, through a comprehensive history.

The presentation of neuroleptic malignant syndrome is similar to both serotonin syndrome and excited delirium syndrome, with all three collectively falling under the diagnosis of acute behavioural disturbance. Serotonin toxicity is often misdiagnosed as neuroleptic malignant syndrome; serotonin syndrome can be distinguished from neuroleptic malignant syndrome based on history and presenting clinical features. The signs and symptoms of serotonin toxicity start to appear around 6 hours after a change in serotonergic medications (Quinn and Stern, 2009), whereas the onset of symptoms in neuroleptic malignant syndrome is hours or days after exposure to a causative medication (Berman, 2011). The onset of the signs and symptoms of excited delirium syndrome is also rapid (Takeuchi et al, 2011).

Neuromuscular signs can also be used to distinguish between serotonin syndrome and neuroleptic malignant syndrome and excited delirium syndrome, as serotonin syndrome and excited delirium syndrome display neuromuscular hyperactivity whereas neuroleptic malignant syndrome produces slow, neuromuscular responses (Boyer and Shannon, 2005).

As neuroleptic malignant syndrome is mostly a diagnosis by elimination, a thorough and comprehensive history will assist in diagnosing this condition and excluding serotonin syndrome and excited delirium syndrome.

Measuring blood creatinine kinase (CK) levels is a definitive diagnostic test in the diagnosis of neuroleptic malignant syndrome and, while not all paramedic skill levels or ambulance services use CK testing, there may be services where this is an option at an advanced practice level. CK levels rise because of damage to muscles caused by extreme muscle rigidity (Sharman, 2020). Normal CK levels are <200 units/litre, while patients with neuroleptic malignant syndrome may have levels more than four times the upper limit of normal (>800 units/litre) (Wilson et al, 2016; Dolp et al, 2020).

Complications of neuroleptic malignant syndrome

If neuroleptic malignant syndrome is not recognised early, there is potential for significant organ damage or long-term effects such as kidney damage and renal failure secondary to rhabdomyolysis, or ventricular dysrhythmias such as a prolonged Q-T interval (Gall-Ojurongbe and Williams, 2015; Stroup and Gray, 2018).

Patients with neuroleptic malignant syndrome may deteriorate rapidly and other complications such as pneumonia, seizures, cardiac arrest, increased propensity for thrombus formation (including pulmonary embolism), and respiratory failure may result (Guinart et al, 2021a).

Given the potential for rapid deterioration and the significance of the complications, paramedics must have a high index of suspicion for neuroleptic malignant syndrome when treating any patient with a mental health history presenting with agitation and muscle rigidity to reduce morbidity and mortality from this condition.

Management

Paramedic management of neuroleptic malignant syndrome is by necessity supportive in nature and aimed at reducing the potential for rapid deterioration, morbidity and mortality. Supportive care should be provided in accordance with the paramedic's specific clinical practice guidelines (e.g. JRCALC, local guidelines).

General supportive care measures such as airway management and oxygenation should be given to patients with a decrease in consciousness level to maintain cerebral and central perfusion status. The use of fluids to maintain hydration and prevent damage to the kidneys secondary to rhabdomyolysis should be considered (Chavez et al, 2016). Autonomic stability should be monitored in accordance with the patient's presentation and individual service clinical practice guidelines. Cooling of the patient should be considered to reduce hyperthermia.

Increasingly, ambulance services are opting for the use of sedation in the management of agitated patients experiencing a mental health emergency when this is clinically indicated. Sedation can be a useful adjunct in the management of agitation to prevent injury to the patient or others including paramedics. The use of sedation can also assist with calming the patient to allow for assessment and obtaining vital signs in cases where other approaches to calming the patient have been unsuccessful.

Droperidol, midazolam and/or olanzapine are the sedative agents of choice for most ambulance services that have approved the use of sedation in the management of agitated patients.

Droperidol is in the same drug class as haloperidol, acting as a dopamine D2 antagonist, with both having been linked to cases of neuroleptic malignant syndrome (Wilson et al, 2016). Given that droperidol is a dopamine D2 antagonist, caution is required in cases where the patient is presenting with neuroleptic malignant syndrome to prevent further deterioration because of an increased dopamine blockade. Stroup and Gray (2018) note that droperidol should not be administered in cases where neuroleptic malignant syndrome is suspected as the use of any form of dopamine blocker should be considered an absolute contraindication in neuroleptic malignant syndrome.

Olanzapine, a second-generation antipsychotic medication used by some ambulance services, has also been linked to neuroleptic malignant syndrome (Hosseini and Elyasi, 2017). Unlike droperidol and haloperidol, olanzapine is both a dopamine and serotonin antagonist, although its low affinity with dopamine D2 receptors means it comes with a lower risk of neuroleptic malignant syndrome compared to first-generation antipsychotic medications (Thomas and Saadabadi, 2023). Despite its low affinity with dopamine D2 receptors, olanzapine should be considered an absolute contraindication in patients presenting with neuroleptic malignant syndrome.

Stroup and Gray (2018) and Huebinger et al (2020) suggested benzodiazepines such as midazolam as the preferred frontline pharmacology for the management of agitation. The use of physical restraints in the management of agitated patients with neuroleptic malignant syndrome has the potential to increase symptoms, with the best evidence suggesting that benzodiazepines should be used instead of physical restraint (Wadoo et al, 2021).

Clinical practice guidelines in ambulance services tend to recommend droperidol, with midazolam approved only in patients aged under 14 years (St John Ambulance New Zealand, 2024a; 2024b). Some ambulance services have approved the use of midazolam for agitated delirium if droperidol is unavailable or ineffective. Olanzapine, given orally in tablet form, is used in some services when a patient is aged over 14 years, is presenting with a mild-to-moderate risk to safety and can tolerate oral medication (St John Ambulance New Zealand, 2017). The use of olanzapine is listed in the guidelines as a contraindication in antipsychotic overdose; however, there is no mention of neuroleptic malignant syndrome being a contraindication for olanzapine, despite it being an atypical antipsychotic and dopaminergic agent, which is likely to increase dopamine levels and worsen the patient's presentation (St John Ambulance New Zealand, 2024c).

The definitive care approach to the management of neuroleptic malignant syndrome in hospital is based upon a hierarchy of both clinical severity and diagnostic certainty (Caroff et al, 1998; Velamoor, 1998; Wijdicks, 2022), with severe cases requiring intensive care monitoring and treatment (Wijdicks, 2022). Admission to intensive care is required because of the intensive nature of the monitoring and supportive care required for these patients. Wijdicks (2022) also recognised the significance of aggressive and supportive care in neuroleptic malignant syndrome, indicating that this is essential and uncontroversial.

Supportive treatment should include maintaining cardiorespiratory stability using antiarrhythmic agents, pacemakers and mechanical ventilation if necessary (Parry et al, 1994; Wijdicks, 2022).

A euvolaemic state should be maintained with intravenous fluids, with a consideration of insensible fluid loss from fever and diaphoresis (Guzé and Baxter, 1985). In presentations where CK is very elevated, high-volume intravenous fluids with urine alkalinisation should be considered to assist in preventing or mitigating renal failure secondary to rhabdomyolysis (Lappa et al, 2002).

Fever can be reduced with the use of cooling blankets; however, in some cases, it may be necessary to use more aggressive physical measures such as ice water gastric lavage or ice packs in the axilla (Wijdicks, 2022).

There is no evidence supporting the use of antipyretics in the supportive management of neuroleptic malignant syndrome (Wijdicks, 2022). In presentations where the patient is markedly hypertensive, nitroprusside may be advantageous as this agent will also facilitate cooling through cutaneous vasodilation (Blue et al, 1986).

Prophylactic use of heparin or low molecular weight heparin is indicated for the prevention of deep vein thrombosis, with benzodiazepines indicated for the management of agitation if necessary (Caroff et al, 1998).

Most neuroleptic malignant syndrome episodes resolve within 2 weeks, with average recovery times being 7–11 days (Rosebush and Stewart, 1989; Velamoor, 1998), with most patients recovering without neurologic sequelae. However, in cases where there has been severe hypoxia for extended periods or grossly elevated temperatures over an extended period of time, there is an increased risk of these consequences (Wijdicks, 2022).

Conclusion

Despite the move away from the use of first-generation antipsychotics, neuroleptic malignant syndrome has been reported with the use of all second-generation antipsychotics and paramedics should maintain a high degree of suspicion regarding neuroleptic malignant syndrome in presentations with a history of antipsychotic use and hyperthermia.

While paramedic management options for hyperthermia are limited, paramedic management of symptoms should be a priority as neuroleptic malignant syndrome is a medical emergency. As commencement or cessation of antipsychotic medication is outside the scope of paramedic practice, the management of neuroleptic malignant syndrome in the paramedic setting is symptomatic in nature.

Sedation is the primary paramedic management approach for agitated patients, with the use of droperidol being favoured by ambulance services that authorise the use of sedation. However, droperidol may exacerbate the dopamine blockade that triggers neuroleptic malignant syndrome, leading to an exacerbation of symptoms and increasing the risk of mortality. Benzodiazepines such as midazolam should be considered for the management of agitated patients when neuroleptic malignant syndrome is suspected. Paramedics who are not authorised to administer sedation should consider making an early request for support from higher-level clinicians who may have this authority.

Key Points

• Neuroleptic malignant syndrome should be suspected in any patient presenting with a history of taking a dopamine receptor-blocking medication and pyrexia or an altered mental status.
• Patients with Parkinson's disease who have sudden reductions in anti-Parkinson disease medications may present with a neuroleptic malignant-like syndrome
• Neuroleptic malignant syndrome may be difficult to distinguish from infection, especially as they can occur at the same time, particularly if the infection was present when the patient started an antipsychotic medication, as infection increases the risk of developing neuroleptic malignant syndrome
• Neuroleptic malignant syndrome has been reported with each of the atypical antipsychotics, occuring most commonly with the use of clozapine

CPD Reflection Questions

• Reflect upon your approach to history-taking in cases where the patient presents with agitation, hyperthermia, tachypnoea and muscle rigidity. Have you ever considered the possibility of neuroleptic malignant syndrome, and specifically asked about the use of antipsychotic medication?
• Consider the pharmacological agents available for the management of agitated patients in your service. Are any of these contraindicated for use in cases where neuroleptic malignant syndrome could be a provisional diagnosis?
• How confident would you be in provisionally diagnosing neuroleptic malignant syndrome in the prehospital care setting based on presentation and history?