Neuroleptic Malignant Syndrome

Primary Category

Neuromuscular

P-Category

Secondary Category

S-Category

Authors:

Umair Hamid MD,
Danish Batti MD

Introduction

Neuroleptic Malignant Syndrome (NMS) is a life-threatening neurological disorder requiring emergent care.

It is associated with the use of antipsychotic agents also called neuroleptics

The incidence rate for NMS in patients taking antipsychotics is 0.02 to 3%

Characterized by muscle rigidity, fever, dysautonomia, and changes in cognitive functions

The incidence of NMS was 0.2-3.2% in the last century; dropped to 0.01-0.02% recently

A decreasing trend of mortality has been seen in recent years (mortality rates: 25% before 1984 and 5.6% in 2011)

Pathophysiology

Two major theories explain the pathogenesis of NMS

Central dopamine receptor blockade in the hypothalamus and/or basal ganglia is most commonly accepted theory
Another less favored theory proposes NMS may be caused by a spectrum of inherited defects in genes responsible for a variety of calcium regulatory proteins within sympathetic neurons. According to this theory, NMS is considered as a neurogenic form of malignant hyperthermia

Etiology

NMS is exclusively seen as an adverse effect of medications with dopamine receptor-antagonist properties

Most often associated with high-potency first-generation antipsychotic drugs
Implication with other classes of antipsychotic drug has been noted including low potency and second-generation antipsychotic drugs
Antiemetic drugs have also been associated with NMS
Although association of NMS with antipsychotic agents is idiosyncratic, usual pattern of NMS onset is seen within the first 2 weeks of drug therapy
Another common pattern of NMS is seen in the re-introduction of anti-dopaminergic therapy after sudden withdrawal (such as patient started on full dose of medications after few days of vomiting).

NMS is also seen in removal of dopaminergic medications

Settings of withdrawal or dose reduction of Parkinson medication L-Dopa or dopamine agonist or switching to other agent
Sometimes considered as a separate syndrome called neuroleptic malignant-like syndrome or parkinsonism hyperpyrexia syndrome

Risk Factors

History of previous NMS occurrence is one of the strongest risk factors (15-20 percent in reported cases)

Antipsychotic dose association

Parenteral route
Higher titration rates
Total dose of drug administration

Certain psychiatric conditions like acute catatonia or extreme agitation

Systemic factors

Preexisting abnormalities of CNS dopamine activity or receptor function
Infection
Surgery

Metabolic factors

Dehydration
Physical exhaustion
Iron deficiency

Clinical Manifestations

Variable onset after starting antipsychotic therapy

16% of cases develop within 24 hours
66% develop within first week
Almost 100% cases develop within 30 days

Tetrad of symptoms mostly evolve over 1-3 days of onset

Mental status change (82% prevalence)

Agitated delirium
Confusion
Catatonic signs
Mutism

Motor abnormalities may include

Muscle rigidity
Lead-pipe rigidity
Cogwheel phenomenon
Myoclonic Tremors
Dystonias
Opisthotonus
Trismus
Chorea
Other dyskinesias
Sialorrhea
Dysarthria
Dysphagia

Hyperthermia

Typically >38ºC
Can increase more than 40ºC
Less consistent in NMS associated with second-generation antipsychotic agents

Autonomic instability

Tachycardia (88%)
High Blood pressure (61%)
Tachypnea (73%)

Investigations

Elevated serum creatine kinase levels

High specificity in NMS
>1000 IU/L; can go up to 100,000 IU/L

WBC - 10,000 to 40,000/mm3

Mildly elevated lactate dehydrogenase, Alk. phos., liver transaminases

Myoglobinuria secondary to rhabdomyolysis

Low serum iron concentration

CSF analysis is normal in 95% of cases

Neuroimaging studies are normal

EEG may show generalized slowing consistent with metabolic encephalopathy

Diagnostic Criteria

Many diagnostic criteria for NMS have been proposed but had unresolved differences between them

One study developed a criteria using the Delphi Method; the criteria consists of signs and symptoms with their respective priority scores

Exposure to dopamine antagonist, or withdrawal from dopamine agonist within past 72 hours
Hyperthermia (>40ºC or >38ºC on at least 2 occasions, measured orally)
Mental status alteration
Raised CK levels (4x the normal limit)
Sympathetic nervous system lability, defined by at least 2 of the following

BP elevation (systolic or diastolic ≥25% above baseline)
BP fluctuation (≥20 mm Hg diastolic change or ≥25 mm Hg systolic change within 24 hours)
Diaphoresis
Urinary incontinence

Hypermetabolism consisting of

Raised heart-rate ≥25% above baseline
Respiratory rate ≥50% above baseline

Negative work-up for infectious, toxic, metabolic, or neurologic causes

DSM-IV-TR research criteria require following be present after recent administration of an antipsychotic

Severe muscle rigidity
Elevated temperature
As well as two associated signs, symptoms, or laboratory findings that are not better accounted for by a substance-induced, neurological, or general medical condition

Table 1: Differential Diagnosis

Differential Diagnosis

Infectious

Meningitis or encephalitis
Postinfectious encephalomyelitis syndrome
Brain abscess
Sepsis

Psychiatric

Idiopathic malignant catatonia
Agitated delirium

Neurologic

Benign extrapyramidal side effects
Nonconvulsive status epilepticus
Structural lesions, particularly involving the midbrain

Toxic or pharmacologic

Anticholinergic delirium
Salicylate poisoning
Malignant hyperthermia

Inhalation anesthetics
Succinylcholine

Serotonin syndrome

Monoamine oxidase inhibitors
Triptans
Linezolid

Substances of abuse

Amphetamines
Hallucinogens

Withdrawal

Dopamine agonists
Baclofen
Sedative-hypnotics
Alcohol

Endocrine

Thyrotoxicosis
Pheochromocytoma

Environmental

Heatstroke

Management

Supportive care

Always start with the ABCs (airway, circulation and breathing support)
Stop causative agent
Start and maintain rehydration with IV fluids
Passive and active cooling, as needed, to resolve febrile state
Maintain blood pressure
DVT prophylaxis
Benzodiazepines for agitation

Mainstay treatment

Bromocriptine (often treatment of choice)

Dopamine agonist
Administered through a nasogastric tube
2.5 mg 6-8 hourly
Maximum of 40 mg/day
Continue till 10 days after NMS is controlled; then taper slowly

Carbidopa-Levodopa (Sinemet)

Alternative to Bromocriptine
Treatment of choice in patients with concerns of Parkinsonism started on antipsychotic medications
Has to be given oral or via NG tube. Can mix in acidic solutions (orange juice or cranberry juice)
Usual starting dose is 25-100 mg every 6-8 hours.
Should be tapered off slowly

Benzodiazepines (better option in transient and mild situations)

Lorazepam - 1-2 mg IM/IV 4-6 hourly
Diazepam - 10 mg IV 8 hourly

Dantrolene

Direct acting muscle relaxant
1-2.5 mg/kg IV
Maximum dose of 10mg/kg/day
Adverse effects

Hepatotoxicity
Should be avoided if LFTs are very abnormal

Continue till 10 days after NMS is controlled; then taper slowly

Amantadine (not routinely used at this point)

Dopaminergic and anticholinergic effects
Alternative to bromocriptine
100 mg initially
Titrated upward to a maximum dose of 200 mg 12 hourly

How to restart antipsychotics after recovery from NMS

Wait at least 2 weeks
Using lower potency agents and newer antipsychotics
Avoid dehydration or concomitant lithium
Carefully monitoring of NMS symptoms

Adapted from 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

Prognosis

Average period of resolution is 2 weeks

Persistence of residual catatonia and motor signs up to 6 months has been seen

Most patients recover without sequelae

Mortality rate is 5-20%

Strongest predictors of mortality are disease severity and complications

Duration of NMS episodes may be prolonged when long-acting depot antipsychotics are implicated

Bibliography

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

Neuroleptic Malignant Syndrome; Strawn JR, Keck Jr PE, Caroff SN; Am J; Psychiatry, 2007

Adnet, P. (2000). Neuroleptic malignant syndrome. British Journal of Anaesthesia. 85(1): 129-35. DOI: 10.1093/bja/85.1.129

Modi S, Dharaiya D, Schultz L, Varelas P (2016). "Neuroleptic Malignant Syndrome: Complications, Outcomes, and Mortality". Neurocrit Care. 24 (1): 97–103. doi:10.1007/s12028-015-0162-5. PMID 26223336.

Shalev A, Hermesh H, Munitz H (1989). "Mortality from neuroleptic malignant syndrome". J Clin Psychiatry. 50 (1): 18–25. PMID 2562951.

Berman, B.D. (2011). Neuroleptic Malignant Syndrome: A Review for Neurohospitalists. Neurohospitalist. 1(1): 41-47. doi: 10.1177/1941875210386491

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