Neuroleptic Malignant Syndrome

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 upto 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

Table 2: Proposed Treatment Algorithm for NMS Spectrum-Related Symptoms

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

Further Reading

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

Bibliography

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

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

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

4. 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.

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