CONTENTS

• Pathophysiology
• Epidemiology
• Clinical features
• Laboratory abnormalities
• Differential diagnosis & evaluation
• Diagnostic criteria
• Management
  • Supportive care
  • Bromocriptine
  • Dantrolene
  • Electroconvulsive therapy
• Podcast
• Questions & discussion
• Pitfalls

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pathophysiology

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As its name implies, NMS is often related to neuroleptic agents (i.e., antipsychotic medications) and is manifest by mental status changes, hyperthermia, rigidity, and autonomic dysfunction. It can present as a life-threatening emergency, and is often challenging to diagnose.

Neuroleptic malignant syndrome seems to result from a deficiency of signaling via D2 dopamine receptors in the brain:

• Dopamine deficiency within striatal dopamine pathways in the basal ganglia may cause Parkinsonian-type symptoms (e.g., lead-pipe rigidity).
• Dopamine deficiency in the hypothalamus may cause autonomic dysfunction.
• Dopamine alterations within the reticular activating system may cause alterations in consciousness (e.g., mutism, coma).(28144147)

A combination of excess motor tone plus dysautonomia may precipitate other features of neuroleptic malignant syndrome, including rhabdomyolysis and hyperthermia.

Treatment involves both augmentation of D2 signaling in the brain, as well as providing muscle relaxants to reduce peripheral muscle tone.

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epidemiology

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causative agents

• Antipsychotics are the most common cause:
  • NMS can occur with typical or atypical agents (especially clozapine).
  • ⏰ NMS usually presents within a month of initiating treatment (most often within two weeks), but it can emerge during chronic therapy (often triggered by another illness).
• Antiemetics that block the dopamine receptor:
  • Prochlorperazine.
  • Promethazine.
  • Metoclopramide.
• Withdrawal of dopaminergic Parkinson's medications.

risk factors

• Personal or family history of NMS.
• Aspects of antipsychotic therapy:
  • Rapid up-titration of neuroleptic.
  • Higher doses of antipsychotic.
  • First-generation (“typical”) antipsychotics have greater risk than atypical antipsychotics. Clozapine and quetiapine have the lowest risk.(Shutter, 2019)
  • Multiple antipsychotic agents, coadministration with lithium.
• Underlying dopamine deficiency:
  • Parkinson's disease or Lewy body dementia.(28144147)
  • Active withdrawal of dopaminergic stimulation (e.g., cessation of chronic cocaine use).(28660166)
  • Other medications that deplete dopamine (e.g., tetrabenazine).(Frucht 2022)

epidemiology

• The risk of NMS is on the order of ~0.01-0.04% among people exposed to antipsychotics.(32659853)
• There doesn't appear to be any dramatic age or sex predominance.(30743298) Historical trends towards higher rates among young men may simply represent patients treated with higher doses of neuroleptics.
• There are a few case reports of NMS arising within the ICU, as a nosocomial complication of antipsychotic administration. Diagnosis of nosocomial NMS is challenging (e.g., the development of fever and altered mental status may initially be attributed to sepsis).

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clinical features

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Symptoms usually develop gradually over 1-3 days, but timing is extremely variable. NMS likewise takes a while to improve, with resolution usually occurring over two weeks.

four features classically present in order

Clinical presentations vary. Mental status changes and extrapyramidal symptoms often precede hyperthermia and autonomic instability. Initially, many patients will only have mental status changes and extrapyramidal features – which may render early diagnosis challenging.

#1/4: mental status changes in ~70%

• These may be variable. Agitation may occur initially, with later evolution into mutism, catatonia, and coma.(30459031, 30743298)
• These symptoms may be obscured in patients who are intubated and sedated, or in patients with poorly controlled schizophrenia (in whom these symptoms may blend into the symptoms of schizophrenia).

#2/4: extrapyramidal symptoms, which may include:

• Tremor (similar to Parkinson's disease), chorea.
• Oculogyric crises (gaze may be fixated upwards).
• Dystonia (which may be refractory to anticholinergic therapies).
• Dysphagia or dysarthria may occur.
• Rigidity is the most common and hallmark extrapyramidal symptom:
  • The most severe manifestation is lead-pipe rigidity (stable resistance throughout the range of motion; see video below). However, patients may also have a superimposed tremor on top of the lead pipe rigidity, which creates a pattern of cogwheel rigidity.

#3/4: hyperthermia

• Not all patients have hyperthermia:
  • ~87% of patients have temperatures >38C.
  • ~40% of patients have temperatures >40C (so frank hyperthermia is often absent).
• Delayed onset of hyperthermia may promote diagnostic confusion.
• Similar to other forms of hyperthermia, this is usually not associated with chills, nor responsive to antipyretic therapy.

#4/4: autonomic instability with sympathetic activation

• These features seem to be the least frequent:(30459031)
  • Sinus tachycardia and other arrhythmias (~62%).
  • Labile hypertension (~42%).
  • Diaphoresis (~44%).
  • Urinary incontinence.

complications are responsible for the ~10% mortality associated with NMS

• Most common complications:(32659853)
  • Aspiration, pneumonia, and respiratory failure may occur. This may relate in some cases to dysphagia and hypersalivation caused by NMS.
  • Renal failure due to rhabdomyolysis occurs commonly.
  • Venous thromboembolic events may result from immobility and systemic inflammation.
• Takotsubo cardiomyopathy may result from autonomic instability.
• Disseminated intravascular coagulation and multiorgan failure may ultimately evolve, secondary to the above processes.

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laboratory abnormalities

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• Creatinine kinase is often >1,000 U/L.
  • Creatinine kinase may be normal early in the disease course, before rigidity emerges. One literature review found a CK level above 300 IU/L in 94% of patients.(32659853)
  • For a differential diagnosis of the causes of elevated creatinine kinase, see the chapter on rhabdomyolysis here. There are numerous causes of creatinine kinase elevation, but marked elevation without another explanation might point to NMS in the appropriate clinical context.
• Leukocytosis (as high as 40,000), with left shift and elevated neutrophil/lymphocyte ratio. C-reactive protein is often also elevated.

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differential diagnosis & evaluation

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differential diagnosis

• Toxicological
  • Serotonin syndrome, which may be sorted out since:
    • These two disorders are caused by different medications.
    • Serotonin syndrome is marked by clonus and hyperreflexia.
    • If present, nausea, vomiting, diarrhea point towards serotonin syndrome.
  • Malignant hyperthermia (usually caused by inhalational anesthetics or succinylcholine, more rapid onset than NMS).
  • Muscle relaxant withdrawal (e.g., intrathecal baclofen, carisoprodol).(27625493)
  • Sympathomimetic, anticholinergic, or phencyclidine intoxication.
  • Ethanol or sedative withdrawal.
  • Lithium intoxication.
• Infection
  • Meningitis, encephalitis.
  • Sepsis of any etiology.
• Neurologic
  • Stroke involving the brainstem and basal ganglia.(28144147)
  • Nonconvulsive status epilepticus.
  • Acute Parkinsonism.
  • Extrapyramidal side effect of a medication (e.g., isolated dystonic reaction or oculogyric crisis).
• Hyperthyroidism (may cause tremor, but shouldn't cause extrapyramidal motor abnormalities).
• Environmental heat stroke, which can be aggravated by neuroleptics. Heat stroke shouldn't cause rigidity or diaphoresis.
• Malignant catatonia – Neuroleptic malignant syndrome is actually one form of malignant catatonia which is triggered by neuroleptics. Thus, neuroleptic malignant syndrome is often indistinguishable from other forms of malignant catatonia. Other potential triggers of catatonia should therefore be considered. Features that may suggest an additional or alternative cause of catatonia may include:
  • Behavioral prodrome for weeks involving psychosis, agitation, or apathy.(28144147)
  • More positive motor symptoms (e.g., waxy flexibility, stereotyped repetitive movements, automatisms).

evaluation will vary, but may involve the following:

• Neurological examination and measurement of core temperature.
• Creatinine kinase level.
• Complete blood count with differential.
• Thyroid stimulating hormone (if features of possible thyrotoxicosis).
• Evaluation for infection (e.g., blood cultures, chest X-ray).
• Depending on the context, neuroimaging and lumbar puncture might be considered.

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diagnostic criteria

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There's no gold-standard diagnostic test to establish the presence of NMS. Consequently, there is no scientific approach to establish a set of diagnostic criteria. The criteria below were developed by a panel of experts, as a way to predict whether another expert would deem that the patient had NMS. This strategy is bereft with circular logic, so it may well be missing the mark entirely.

Regardless, the criteria are listed below. A validation study found that a cutoff of at least 74 points total (out of 100) could be used to determine the presence of NMS (with 70% sensitivity and 90% specificity, compared to expert adjudication).(28027111)

• Exposure to a dopamine antagonist or withdrawal of a dopamine agonist in the prior 72 hours: 20 points
• Hyperthermia (>100.4 F or >38C) on at least two occasions, measured orally: 18 points
• Rigidity: 17 points
• Mental status alteration (reduced or fluctuating level of consciousness): 13 points
• Creatinine kinase elevation at least four times the upper limit of normal: 10 points
• Sympathetic nervous system lability, defined as at least two of the below: 10 points
  • Blood pressure elevation (systolic or diastolic >25% above baseline)
  • Blood pressure fluctuation (>25% systolic or >20% diastolic change in 24 hours)
  • Diaphoresis
  • Urinary incontinence
• Hypermetabolic state (defined as heart rate increase >25% above baseline and respiratory rate increase >50% above baseline): 5 points
• Negative evaluation for other toxic, metabolic, infectious, or neurologic causes: 7 points

As with many diagnostic scoring systems in critical care, the value of this score to dictate clinical management is dubious. Ideally, we would like to identify NMS and initiate treatment before the full-blown syndrome is present, at a time point when patients might not meet the above criteria.

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supportive care

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discontinue offensive medication(s)

• Stop any antipsychotics.
• Avoid antiemetics that antagonize the dopamine receptor (e.g., metoclopramide, promethazine, prochlorperazine).
• If the episode was triggered by withdrawal of Parkinson's medications, restart these medications immediately.
  • Have a low threshold to consult with a neurologist regarding optimization of Parkinson's medications. Among sicker patients who are unable to take tablets orally, this can get tricky.

supportive care for hyperthermia

• General supportive care for the hyperthermic patient is discussed in the chapter on hyperthermia here.
• Physical cooling measures may be required (e.g., cooling blankets, ice packs, evaporative cooling).
• Antipyretics are not helpful.

manage fluid, electrolytes, and rhabdomyolysis

• Rhabdomyolysis is common; its treatment is discussed further here.
• Electrolytes should be monitored and treated appropriately.
• There is a high risk of renal failure, so nephrotoxins should be avoided.
• Volume depletion may result from insensible losses and inability to tolerate oral intake – monitor and treat this accordingly.

benzodiazepines

• Benzodiazepines are widely used in the supportive care of patients with neuroleptic malignant syndrome and malignant catatonia. They may help control agitation and also promote muscle relaxation.
• A usual dose may be ~2 mg IV q8hr of lorazepam.
• The response to treatment should be noted (in some patients this may cause significant improvement).
• There is a risk that benzodiazepines could cause or promote the development of delirium.

management of agitation

• This may be challenging in patients with underlying psychosis. Of course, antipsychotics need to be avoided.
• Treatment options may include:
  • Central alpha 2 agonists (e.g., dexmedetomidine or clonidine).
  • Valproate is probably a reasonable treatment for hyperactive delirium in this context. Some case reports have questioned whether valproate might promote NMS, but valproate alone doesn't cause NMS.(28138117)

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bromocriptine is 1st line

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general 💊

• Bromocriptine is a dopamine agonist, which should reverse the antidopaminergic effect of antipsychotic medications.
• There is no high-quality evidence for any therapy in NMS. However, enhancing dopamine signaling is a rational strategy that should improve the underlying pathophysiology, and is supported by some case-report level evidence. A systematic literature review suggested that NMS-specific therapy (e.g., bromocriptine and dantrolene) might reduce mortality in severe cases, when compared to purely symptomatic therapy with benzodiazepines.(32659853)

dosing of bromocriptine

• Starting dose is 2.5 mg PO q8hr, may titrate up to 5-10 mg q6-8hr.
• Maximal dose is 40 mg/day (10 mg q6hr).
• Continue for 10 days after NMS resolution to avoid recurrence, then taper off very gradually.

potential side-effects

• Psychosis, including exacerbation of the patient's underlying psychiatric illness.
• Dyskinesia.
• Hypotension.
• Nausea/emesis.

alternative dopaminergic agent: amantadine

• Amantadine also has dopaminergic effects and may be used as an alternative dopaminergic agent, if bromocriptine is contraindicated. The initial dose is 100 mg q8-q12hr, with a potential to increase to 200 mg BID.
• For severe and refractory NMS, amantadine could be combined with bromocriptine.(33896535)

other situations where bromocriptine may be useful

• Neurogenic fever. 📖
• Paroxysmal sympathetic hyperactivity (PSH) 📖
  • Bromocriptine may be used for refractory hyperthermia.
  • The starting dose is 1.25 mg PO q12hr, with up-titration to a maximal cumulative dose of 40 mg/day.(Naidech 2022)

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dantroline is 2nd line

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general 💊

• Dantrolene is a direct-acting muscle relaxant. It should rapidly reduce heat production and rigidity.
• Dantrolene shouldn't be used as monotherapy for NMS, but may be helpful in moderate/severe cases in combination with bromocriptine.
• One advantage of dantrolene is that if the diagnosis is wrong and the patient has another related form of rigidity, dantrolene may still be beneficial.

dosing

• The ideal dose is unclear. The dosing range is 1-2.5 mg/kg q6-8hr hours IV (with a maximal daily dose of 10 mg/kg/day).
• Once the patient stabilizes (usually after a few days), IV dantrolene may be transitioned to oral dantrolene (e.g., 1 mg/kg q6hr).(28144147)
• There is disagreement about how rapidly this should be discontinued. Dantrolene may typically be weaned off over several days, to avoid recurrence of NMS.

contraindications, cautions & adverse events

• Adverse effects are rare when used for short-term treatment of NMS.
  • Combination of dantrolene with calcium channel blockers is contraindicated.
  • Dantrolene can cause liver injury, so it's contraindicated in patients with cirrhosis or acute liver injury.
  • It's unclear whether dantrolene may reduce diaphragmatic strength, but theoretically higher doses might.(28660166)

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electroconvulsive therapy

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• Electroconvulsive therapy (ECT) has been used for NMS, analogous to its use in malignant catatonia in general.
• For patients with severe NMS refractory to medical therapy, ECT could be considered. For patients with underlying schizophrenia or psychotic depression, ECT could be particularly helpful (since it may treat the NMS and the underlying disorder).

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podcast

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Don't assume that absence of fever excludes NMS. There is no single symptom nor laboratory abnormality which is present in 100% of cases, so NMS is a challenging diagnosis. The diagnosis must be based upon recognizing a constellation of features, as well as excluding alternative possibilities.
• Among patients with NMS, make sure to avoid any drugs that may inhibit the dopamine receptors (e.g., metoclopramide, promethazine, and prochlorperazine).
• NMS may be extremely difficult to diagnose in the context of poorly controlled psychiatric disorders (e.g., it may be extremely difficult to diagnose delirium on the background of a baseline psychotic state).(32968424)

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