Neuroleptic Malignant Syndrome (NMS)

Neuroleptic Malignant Syndrome (NMS) is a rare but life-threatening idiosyncratic reaction caused primarily by dopamine receptor blockade, usually due to antipsychotic drugs or sudden withdrawal of dopaminergic medications.

It is characterized by:

• Hyperthermia
• Severe muscle rigidity
• Altered mental status
• Autonomic instability

NMS is a medical emergency with mortality historically >30%, now reduced to ~5–10% with early recognition and ICU care.

Pathophysiology

• Central dopamine D2 receptor blockade
• Especially in:
• Hypothalamus → temperature dysregulation
• Nigrostriatal pathways → rigidity
• Spinal cord/basal ganglia → muscle hypermetabolism

Additional Mechanisms

1. Skeletal Muscle Dysfunction

• Excessive calcium release from sarcoplasmic reticulum
• Similarities with malignant hyperthermia
• Causes:
• Rigidity
• Rhabdomyolysis
• Heat generation

2. Sympathetic Hyperactivity

Causes:

• Tachycardia
• Labile BP
• Diaphoresis
• Arrhythmias

3. Hypermetabolic State

Leads to:

• Increased oxygen consumption
• Lactate production
• Metabolic acidosis

Causative Drugs

A. Antipsychotics (Most Common)

Typical Antipsychotics

Highest risk:Haloperidol—Fluphenazine—Chlorpromazine

Atypical Antipsychotics

Lower risk but still important:Olanzapine—Risperidone—Clozapine—Quetiapine—Ziprasidone

B. Antiemetics With Dopamine Blockade

• Metoclopramide
• Prochlorperazine
• Droperidol

C. Withdrawal of Dopaminergic Drugs

Especially in Parkinson disease:

• Levodopa withdrawal
• Amantadine withdrawal

This may produce:“Parkinsonism-hyperpyrexia syndrome”

Risk Factors

Patient Related

• Dehydration
• Physical restraint
• Malnutrition
• Parkinson disease

Environmental

• Hot weather
• Infection
• ICU setting

Clinical Features

Classic tetrad:

1. Hyperthermia
2. Rigidity
3. Mental status changes
4. Autonomic dysfunction

Time Course

Usually:Develops over 1–3 days

• Most cases within:First 2 weeks of neuroleptic therapy/After dose increase

Slower onset than serotonin syndrome.

1. Hyperthermia

• Often >38.5°C
• May exceed 41°C

Due to:Muscle heat production/Hypothalamic dysregulation

2. Muscle Rigidity

“Lead-pipe rigidity” is classic.

Features:

• Generalized severe rigidity
• Hyporeflexia or normal reflexes
• Tremor
• Dysphagia
• Dysarthria

Rigidity may be so severe that:

• CK becomes massively elevated.

3. Altered Mental Status

Range:Agitation—Confusion—Delirium—Mutism—Stupor—Coma

4. Autonomic Instability

Major feature.

Manifestations:

• Tachycardia
• Labile hypertension
• Hypotension
• Tachypnea
• Diaphoresis
• Arrhythmias
• Sialorrhea
• Urinary incontinence

Laboratory Findings

Creatine Kinase (CK)

Most characteristic abnormality.

• Usually >1000 IU/L—May exceed 100,000 IU/L

Due to:Rhabdomyolysis

Leukocytosis-Often 10,000–40,000/mm³

Electrolyte Abnormalities

May include:

• Hyperkalemia
• Hypocalcemia
• Hyperphosphatemia

Metabolic Acidosis

Due to:Lactic acidosis—-Muscle breakdown

Liver Enzymes-Elevated AST/ALT

Renal Dysfunction

From:Myoglobinuria/AKI

Other Findings

• Low serum iron
• Elevated LDH
• Elevated aldolase

Diagnostic Criteria

No single definitive test exists.

DSM-5 Criteria

Requires:

• Exposure to dopamine antagonist
• Severe rigidity
• Fever

Plus ≥2:

• Diaphoresis
• Dysphagia
• Tremor
• Incontinence
• Altered consciousness
• Mutism
• Tachycardia
• Elevated/labile BP
• Leukocytosis
• Elevated CK

Levenson Criteria(3 major OR 2 major + 4 minor)

Major

• Fever
• Rigidity
• Elevated CK

Minor

• Tachycardia
• Abnormal BP
• Tachypnea
• Altered consciousness
• Diaphoresis
• Leukocytosis

In patients where the diagnosis is less clear, neuroimaging and lumbar puncture may be necessary to exclude structural and infectious diagnosis from the differential. Additional laboratory testing such as a lithium level and screening for drugs of abuse may be helpful in selected cases.

Differential Diagnosis

NMS vs Serotonin Syndrome

NMS vs Malignant Hyperthermia

Complications

• Rhabdomyolysis(Most common severe complication)
• Acute Kidney Injury(Due to:Myoglobinuria/Hypovolemia)
• Respiratory Failure(Causes:Rigidity—Aspiration—ARDS)
• DIC
• Arrhythmias
• Venous Thromboembolism
• Aspiration Pneumonia
• Multiorgan Failure

Management

1. Stop Offending Drug(MOST IMPORTANT STEP)

Discontinue:Antipsychotics/Dopamine antagonists

2. ICU Admission

Indications:

• Hyperthermia
• Autonomic instability
• CK elevation
• Organ dysfunction

Supportive Care

This is the cornerstone of therapy.

Airway and Breathing

May require:

• Intubation
• Mechanical ventilation

Indications:

• Severe rigidity
• Hyperthermia
• Reduced consciousness
• Respiratory failure

Circulation

IV Fluids

Aggressive hydration:Prevent AKI—-Treat rhabdomyolysis

Targets:Urine output >200 mL/hr in severe rhabdomyolysis

Cooling Measures(Avoid shivering.)

Aggressive temperature control.

Methods:

• Cooling blankets
• Ice packs
• Cold IV saline(15–30 mL/kg IV(1–2 liters)of 4°C normal saline,Usually infused over:30–60 minutes)
• Evaporative cooling

Cold gastric lavage was historically used as an internal cooling method in severe hyperthermic states such as:

• Neuroleptic Malignant Syndrome (NMS)
• Heat stroke
• Malignant hyperthermia

However, in modern critical care practice, it is rarely recommended routinely because evidence is limited and safer/more effective cooling techniques are available.

Electrolyte Management

Correct:Hyperkalemia—Acidosis—Hypocalcemia (if symptomatic)

DVT Prophylaxis

Because:Immobility—Catatonia—ICU stay

Specific Pharmacologic Therapy

Evidence mostly observational.

1. Bromocriptine

Mechanism-Dopamine agonist.

Dose

• 2.5–5 mg orally/NG every 6–8 hr
• Gradually titrate
• Max:~45 mg/day

Benefits

• Reduces rigidity
• Reduces hyperthermia

Adverse Effects

• Hypotension
• Nausea
• Psychosis

2. Dantrolene

Mechanism-Peripheral skeletal muscle relaxant.

Reduces:Calcium release/Muscle rigidity/Heat production

Dose

Initial-1–2.5 mg/kg IV

Repeat until response.

Maximum-Up to 10 mg/kg/day

Uses

Most useful in:

• Severe rigidity
• Severe hyperthermia

3. Benzodiazepines

Useful especially when:Agitation/Catatonia

Agents:Lorazepam/Diazepam

4. Amantadine

Alternative dopamine agonist.

Dose-100–200 mg orally twice daily

Role of ECT

Electroconvulsive Therapy

May be lifesaving in:

• Refractory NMS
• Severe catatonia
• Persistent symptoms

Prognosis

Recovery

Usually:2–14 days after stopping drug

Longer with depot antipsychotics.

Restarting Antipsychotics After NMS

Wait at least:

• 2 weeks after complete recovery
• Longer for depot drugs

Use:

• Low-potency atypical agent
• Low dose
• Slow titration

Avoid:

• Dehydration
• Polypharmacy

Monitor carefully.

REFERENCES

1.Simon LV, Hashmi MF, Callahan AL. Neuroleptic Malignant Syndrome. [Updated 2023 Apr 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482282/

2.Irwin & Rippe’s Intensive Care Medicine 9th edition

3.ICU Protocols 3rd Edition