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Neuroleptic Malignant Syndrome (NMS)

Definition: Rare adverse reaction to dopamine receptor antagonists leading to autonomic dysfunction and can be fatal if not recognized early (Harrison & McErlane, 2008).

Most commonly associated with typical antipsychotics:

• haloperidol (Serenace)

• fluphenazine (Modecate)

• chlorpromazine (Largactil)

Can occur with atypicals:

• quetiapine (Seroquel)

• risperidone (Risperdal)

• olanzapine (Zyprexa)

• aripiprazole (Abilify)

• amisulpride (Solian)

• ziprasidone (Zeldox)

and dopamine receptor antagonists:

• prochlorperazine (Stemetil)

• metoclopramide (Maxalon)

• promethazine (Phenergan)

Pathophysiology

Not fully understood

Probably dopaminergic blockade or depletion in the central nervous system (CNS)

May be a drug induced malignant catatonia (? same underlying pathophysiology) (Fink, 1996, as cited in Strawn, Keck & Caroff, 2007).

Genetics may be involved

Incidence

0.5% to 3% of all patients treated with traditional antipsychotics

Haloperidol in 50% of cases (potency, widespread use)

Recent 0.01% to 0.02%, ? due to increasing use of atypicals (Stubner, 2004, as cited in Strawn, Keck & Caroff, 2007).

Death in 11% to 30% of earlier cases - decreased now to 10% due to early detection/management (Strawn, Keck & Caroff, 2007).

Risk factors

• previous history of NMS/EPSE

• dehydration

• withdrawal of antiparkinsonian medications

• history of organic brain syndrome (delirium)

• use of high potency agents

• iron deficiency

Onset

At any time - can develop rapidly

Most cases when drug started, dosage increased or rapidly titrated

Clinical manifestations

Mild to severe depending on individual

Early signs and symptoms: sudden change in mental status, fever, and muscle rigidity

Sudden changes in mental status: “clouding” of consciousness, ranging from confusion to stupor or coma, agitation, delirium, and catatonia. Mental state changes precede other signs in 80% of cases.

Hyperpyrexia > 38 °C of unknown origin (? caused by dopamine blockade in hypothalamus causing temp dysregulation and profuse sweating)

Dystonia abrupt onset stiffening and rigidity in large muscles (especially head & neck)

Severe muscle rigidity produces excess body heat contributing to hyperpyrexia

Difficulty swallowing or a sensation of tongue thickening that rapidly worsens

Other

• EPSEs parkinsonian tremors, akathisia

• elevated or labile blood pressure

• tachycardia, tachypnea, tremor, and urinary incontinence

• As the syndrome progresses, increasing muscle rigidity can lead to diminished chest wall compliance, hypoventilation, and even respiratory failure.

Laboratory

• Raised Creatine kinase (muscle enzyme)

• Raise Myoglobinuria (muscle protein)

Creatine kinase rises 2 – 4 hours after muscle injury (indicator degree muscle damage) Continued rise may indicate onset rhabdomyolysis.

Rhabdomyolysis (skeletal muscle break down) releases myoglobin into circulation.

Once myoglobin in kidneys, it precipitates in renal tubules causing kidney damage and subsequent renal failure.

Other

• proteinuria secondary to stress/tissue damage.

• elevated white blood cell count

• Arterial blood gas analysis - assess for adequate oxygenation and metabolic acidosis

Prevention

Conservative use of antipsychotics

Reduction of risk factors

Early diagnosis

Prompt discontinuation of offending medications

Medical management

Depending on symptom severity and complications (see table).

Dantrolene acts directly on muscle to produce relaxation, which decreases rigidity.

Bromocriptine's primary action is to activate D2 receptors and it also stimulates dopamine production (Strawn, Keck, & Caroff, 2007).

Neuroleptic Malignant Syndrome (NMS) Management Table

|Stage |Clinical Presentation |Supportive Care |First Line Interventions |Second Line Interventions |

|Stage I: drug-induced |Rigidity; tremor |Reduce or switch |Anticholinergic agents | |

|parkinsonism | |antipsychotics | | |

|Stage II: drug-induced |Rigidity; mutism; |Discontinue, reduce, or |Lorazepam (1–2 mg IM or IV | |

|catatonia |stupor |switch antipsychotics |every 4–6 hr) not available| |

| | | |in Australia | |

|Stage III: mild, early |Mild rigidity; |Discontinue |Lorazepam (1–2 mg IM or IV | |

|NMS |catatonia or |antipsychotics, |every 4–6 hr)- not available| |

| |confusion; temperature |carefully monitor for |in Australia | |

| |≤38°C; heart rate ≤100 |progression, correct risk| | |

| |bpm |factors | | |

|Stage IV: moderate NMS |Moderate rigidity; |Discontinue |Lorazepam (1–2 mg IM or IV. |Consider electroconvulsive |

| |catatonia or confusion;|antipsychotics, |every 4–6 hr), not |therapy (6–10 bilateral |

| |temperature 38–40°C; |manage fluids, initiate |available in Australia |treatments) |

| |heart rate 100–120 bpm |cooling measures, correct|bromocriptine | |

| | |risk factors, |(2.5–5 mg orally or by | |

| | |provide intensive care |nasogastric tube every 8 | |

| | | |hr), or amantadine (100 mg | |

| | | |orally or by NG tube every 8| |

| | | |hr) | |

|Stage V: severe NMS |Severe rigidity; |Discontinue |Dantrolene (1–2.5 mg/kg |Consider electroconvulsive |

| |catatonia or coma; |antipsychotics, |body weight IV every 6 hr |therapy (6–10 bilateral |

| |temperature ≥40°C; |manage fluids, initiate |for 48 hr, tapered), |treatments) |

| |heart rate ≥120 bpm |cooling measures, correct|bromocriptine (2.5–5 mg | |

| | |risk factors, |orally or by NG tube every 8| |

| | |provide intensive care |hr), | |

| | | |or amantadine (100 mg orally| |

| | | |or by NG tube every 8 hr) | |

Woodbury & Woodbury, 1992 cited in Strawn, J. R., Keck, P. E., & Caroff, S. N. (2007). Neuroleptic malignant syndrome. American Journal of Psychiatry, 164(6), 870-876, p. 874.

Antipsychotic use following NMS - 30% risk of developing again

• Check reports on previous episodes for accuracy

• Clearly documented indications for antipsychotics

• Consider alternative medications

• Reduce risk factors

• Rechallenge after at least 2 weeks to elapse after recovery from NMS

• Use low doses of low-potency conventional antipsychotics or atypical antipsychotics and titrate gradually after a test dose

• Monitor patients for early signs of NMS

• Obtain informed consent from patients/family regarding benefits of antipsychotic versus risk recurrence (Strawn, Keck, & Caroff, 2007).

Resources on NMS

Neuroleptic Malignant Syndrome Information Service



References

Harrison, P. A., & McErlane, K. S. (2008 ). Neuroleptic malignant syndrome American Journal of Nursing, 108(7), 35-38.

Strawn, J. R., Keck, P. E., & Caroff, S. N. (2007). Neuroleptic malignant syndrome. American Journal of Psychiatry, 164(6), 870-876.

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