Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS) is a rare, idiosyncratic, and potentially life-threatening reaction to antipsychotic Antipsychotic Antipsychotics, also called neuroleptics, are used to treat psychotic disorders and alleviate agitation, mania, and aggression. Antipsychotics are notable for their use in treating schizophrenia and bipolar disorder and are divided into 1st-generation antipsychotics (FGAs) and atypical or 2nd-generation antipsychotics. First-Generation Antipsychotics drugs. Neuroleptic malignant syndrome presents with ≥ 2 of the following cardinal symptoms: fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, altered mental status, muscle rigidity, and autonomic dysfunction. It is important to promptly identify this condition because of its high morbidity and mortality rates. Diagnosis is based on positive clinical and laboratory findings, along with the exclusion of other possible causes. Management involves discontinuing antipsychotic Antipsychotic Antipsychotics, also called neuroleptics, are used to treat psychotic disorders and alleviate agitation, mania, and aggression. Antipsychotics are notable for their use in treating schizophrenia and bipolar disorder and are divided into 1st-generation antipsychotics (FGAs) and atypical or 2nd-generation antipsychotics. First-Generation Antipsychotics medication, supportive care, and pharmacologic options.

Last update:

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp

Overview

Definition

Neuroleptic malignant syndrome (NMS) is a life-threatening neurologic disorder associated with the use of antipsychotics that presents as a classic tetrad:

  • Fever
  • Altered mental status
  • Autonomic instability
  • Muscle rigidity

Epidemiology

  • Incidence 0.01%–0.07% of people taking antipsychotics
  • 10% mortality rate if left untreated
  • If renal failure is present, the mortality rate increases to 50%.

Etiology

  • NMS is an idiosyncratic reaction to neuroleptic ( antipsychotic Antipsychotic Antipsychotics, also called neuroleptics, are used to treat psychotic disorders and alleviate agitation, mania, and aggression. Antipsychotics are notable for their use in treating schizophrenia and bipolar disorder and are divided into 1st-generation antipsychotics (FGAs) and atypical or 2nd-generation antipsychotics. First-Generation Antipsychotics) drugs.
  • Antipsychotics primarily modulate the dopamine (D2) pathway.
  • Typical antipsychotics have a greater likelihood of leading to NMS than atypical antipsychotics:
    • Common 1st-generation “typical” antipsychotics:
      • Haloperidol (Haldol)
      • Droperidol
      • Chlorpromazine (Thorazine)
    • Common 2nd-generation “atypical” antipsychotics:
      • Risperidone (Risperdal)
      • Olanzapine (Zyprexa)
      • Quetiapine (Seroquel)
      • Clozapine (Clozaril)
      • Ziprasidone (Geodon)
      • Aripiprazole (Abilify)
  • Other medications that can trigger NMS:
    • Amoxapine, dosulepin ( tricyclic antidepressants Tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications used in the management of mood disorders, primarily depression. These agents, named after their 3-ring chemical structure, act via reuptake inhibition of neurotransmitters (particularly norepinephrine and serotonin) in the brain. Tricyclic Antidepressants)
    • Droperidol, metoclopramide ( antiemetics Antiemetics Antiemetics are medications used to treat and/or prevent nausea and vomiting. These drugs act on different target receptors. The main classes include benzodiazepines, corticosteroids, atypical antipsychotics, cannabinoids, and antagonists of the following receptors: serotonin, dopamine, and muscarinic and neurokinin receptors. Antiemetics)
    • Diatrizoate (contrast agent)
    • Promethazine (antihistamine)
    • Tetrabenazine (treatment of hyperkinetic movement disorders) 
    • Lithium
    • Phenelzine (monoamine oxidase inhibitor)
    • Sudden withdrawal of dopaminergic drugs (antiparkinson medications such as levodopa)

Pathophysiology and Clinical Presentation

Pathophysiology

  • Exact underlying mechanism remains unclear.
  • Sudden decrease in the central dopaminergic activity:
    • Significant D2 receptor blockage
    • Abrupt withdrawal of D2 receptor agonist
  • D2 blockade in various structures of the nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System causes the characteristic symptoms:
    • Hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
    • Nigrostriatal pathways → rigidity
    • Spinal cord → rigidity and tremor

Clinical presentation

Cardinal features of the neuroleptic malignant syndrome include:

  • Fever (> 40°C)
  • Alteration in the level of consciousness:
    • Encephalopathy
    • Delirium Delirium Delirium is a medical condition characterized by acute disturbances in attention and awareness. Symptoms may fluctuate during the course of a day and involve memory deficits and disorientation. Delirium
    • Stupor
    • Coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma
  • Autonomic dysregulation:
    • Diaphoresis (excessive sweating)
    • Tachycardia, tachypnea, or hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
    • Sialorrhea (excessive salivation)
    • Hypoxemia
  • Severe muscular rigidity, also known as “lead pipe rigidity”

Other signs and symptoms are as follows:

  • Dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia (trouble swallowing)
  • Dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea
  • Symptoms of Parkinson’s disease (e.g., tremors, bradykinesia, rigidity)
  • Sustained feeling of motion/restlessness
  • Uncontrollable, repetitive, stereotypical writhing movements, usually of the tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Oral Cavity: Lips and Tongue
  • Urinary incontinence Urinary incontinence Urinary incontinence (UI) is involuntary loss of bladder control or unintentional voiding, which represents a hygienic or social problem to the patient. Urinary incontinence is a symptom, a sign, and a disorder. The 5 types of UI include stress, urge, mixed, overflow, and functional. Urinary Incontinence

Diagnosis and Management

Laboratory findings in NMS

The diagnosis of NMS is mainly clinical. Laboratory investigations are performed to rule out other conditions or complications.

Laboratory findings associated with NMS:

  • Leukocytosis (increased WBCs)
  • Elevated CK, due to the severe muscle rigidity
  • Elevated potassium 
  • Abnormal liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver function
  • Myoglobinuria

Management

NMS is an acute medical emergency and should be treated as such.

The 1st step should be to stop the antipsychotic Antipsychotic Antipsychotics, also called neuroleptics, are used to treat psychotic disorders and alleviate agitation, mania, and aggression. Antipsychotics are notable for their use in treating schizophrenia and bipolar disorder and are divided into 1st-generation antipsychotics (FGAs) and atypical or 2nd-generation antipsychotics. First-Generation Antipsychotics agent or restart the dopamine agent.

  • Control fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever:
    • Antipyretics 
    • Cooling blankets
    • Ice packs
  • Medical therapy:
    • Benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines: 1st-line for agitation and seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
    • Dantrolene:
      • Treats muscular rigidity
      • Inhibits the ryanodine receptor
      • Prevents release of Ca2+ from the sarcoplasmic reticulum of skeletal muscle
      • Leads to muscle relaxation
    • Dopamine agonists (bromocriptine, amantadine)
  • Supportive care, such as admitting the patient to the ICU
  • Symptoms should start subsiding immediately after the discontinuation of the causative agent and resolve within 10 days.
  • Different antipsychotics can be safely re-administered in most cases after 2 weeks.

Differential Diagnosis

The most relevant differential diagnoses for NMS are serotonin syndrome Serotonin syndrome Serotonin syndrome is a life-threatening condition caused by large increases in serotonergic activity. This condition can be triggered by taking excessive doses of certain serotonergic medications or taking these medications in combination with other drugs that increase their activity. Serotonin Syndrome and malignant hyperthermia Malignant hyperthermia An important complication of anesthesia is malignant hyperthermia, an autosomal dominant disorder of the regulation of calcium transport in the skeletal muscles resulting in a hypermetabolic crisis. Malignant hyperthermia is marked by high fever, muscle rigidity, rhabdomyolysis, and respiratory and metabolic acidosis. Malignant Hyperthermia, and it is important to distinguish between them.

  • Serotonin syndrome: characterized by fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, autonomic dysfunction, and rigidity/spasticity related to overdoses by selective serotonin reuptake inhibitors Serotonin Reuptake Inhibitors Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Serotonin Reuptake Inhibitors and Similar Antidepressant Medications (SSRIs) or some other antidepressant Antidepressant Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Serotonin Reuptake Inhibitors and Similar Antidepressant Medications. Serotonin syndrome presents with more GI symptoms (e.g., nausea, vomiting). Management is nearly the same as for NMS. 
  • Malignant hyperthermia: rare complication triggered by certain inhaled anesthetics Inhaled anesthetics Inhaled anesthetics are chemical compounds that can induce and maintain general anesthesia when delivered by inhalation. Inhaled anesthetics can be divided into 2 groups: volatile anesthetics and gases. Volatile anesthetics include halothane, isoflurane, desflurane, and sevoflurane. Inhaled Anesthetics or paralytics. Suspect in the operating room or during anesthesia Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts procedure. Management is nearly the same as for NMS and is clinically indistinguishable except for the specific drugs that trigger the syndrome.

Other conditions that present with altered mental status, autonomic dysfunction, and fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever:

  • Meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis: infection of the meninges Meninges The brain and the spinal cord are enveloped by 3 overlapping layers of connective tissue called the meninges. The layers are, from the most external layer to the most internal layer, the dura mater, arachnoid mater, and pia mater. Between these layers are 3 potential spaces called the epidural, subdural, and subarachnoid spaces. Meninges, the protective membranes around the brain, most often caused by Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus pneumoniae or Haemophilus Haemophilus Haemophilus is a genus of Gram-negative coccobacilli, all of whose strains require at least 1 of 2 factors for growth (factor V [NAD] and factor X [heme]); therefore, it is most often isolated on chocolate agar, which can supply both factors. The pathogenic species are H. influenzae and H. ducreyi. Haemophilus influenzae. Meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis presents with fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, stiff neck, and headache. Diagnosis is by lumbar puncture for CSF evaluation. Management consists of the rapid administration of antibiotics.
  • Encephalitis Encephalitis Encephalitis is inflammation of the brain parenchyma caused by an infection, usually viral. Encephalitis may present with mild symptoms such as headache, fever, fatigue, and muscle and joint pain or with severe symptoms such as seizures, altered consciousness, and paralysis. Encephalitis: inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of the brain, usually caused by viral agents. Often presents as only mild flu-like signs and symptoms, such as a fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever or headache, or no symptoms at all. Diagnosis is by spinal tap and brain imaging. Management consists of antiviral medications and supportive care, such as bed rest, fluid therapy, and antiinflammatory drugs.
  • Toxic encephalopathy: neurologic disorder caused by exposure to neurotoxic organic solvents, such as heavy metals, neurotoxic drugs, or cyanotoxins. The clinical presentation is varied, including altered mental status, memory loss, and visual problems. Diagnosis is made by exclusion, and management is mainly supportive. 
  • Heatstroke Heatstroke Heatstroke is an illness characterized as a core body temperature exceeding 40°C (104°F) with accompanying neurological symptoms including ataxia, seizures, and/or delirium. Heatstroke is usually due to the body's inability to regulate its temperature when challenged with an elevated heat load. Heatstroke: elevation of core body temperature above the normal diurnal range of 36ºC–37.5ºC due to the failure of thermoregulation. Heatstroke Heatstroke Heatstroke is an illness characterized as a core body temperature exceeding 40°C (104°F) with accompanying neurological symptoms including ataxia, seizures, and/or delirium. Heatstroke is usually due to the body's inability to regulate its temperature when challenged with an elevated heat load. Heatstroke presents as severe neurologic dysfunction, marked elevated core temperature, absent sweating, hot and flushed skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, tachycardia, hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension, tachypnea, and nausea. Management involves volume resuscitation and rapid cooling of the patient. 
  • Status epilepticus: medical emergency characterized by a single seizure lasting > 5 minutes or ≥ 2 seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures within a 5-minute period without a return to a normal lucid state. EEG supports the diagnosis, and management includes antiseizure drugs (e.g., diazepam, lorazepam, phenytoin).
  • Thyrotoxicosis Thyrotoxicosis Thyrotoxicosis refers to the classic physiologic manifestations of excess thyroid hormones and is not synonymous with hyperthyroidism, which is caused by sustained overproduction and release of T3 and/or T4. Graves' disease is the most common cause of primary hyperthyroidism, followed by toxic multinodular goiter and toxic adenoma. Thyrotoxicosis and Hyperthyroidism: classic physiologic manifestations of excess thyroid hormones Thyroid hormones The 2 primary thyroid hormones are triiodothyronine (T3) and thyroxine (T4). These hormones are synthesized and secreted by the thyroid, and they are responsible for stimulating metabolism in most cells of the body. Their secretion is regulated primarily by thyroid-stimulating hormone (TSH), which is produced by the pituitary gland. Thyroid Hormones Thyrotoxicosis Thyrotoxicosis Thyrotoxicosis refers to the classic physiologic manifestations of excess thyroid hormones and is not synonymous with hyperthyroidism, which is caused by sustained overproduction and release of T3 and/or T4. Graves' disease is the most common cause of primary hyperthyroidism, followed by toxic multinodular goiter and toxic adenoma. Thyrotoxicosis and Hyperthyroidism presents as signs of an increased metabolic rate and overactivity of the sympathetic nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System. Diagnosis is made by measuring the levels of thyroid-stimulating hormone (TSH) and free thyroxine (T4) and triiodothyronine (T3). Management depends on the cause but may be pharmacologic, surgical, or with radioiodine.

References

  1. Berman BD BD Blount’s disease (BD) is an orthopedic childhood disorder characterized by outward bowing of the leg due to abnormal ossification of the medial aspect of the tibial epiphysis. Blount’s disease mostly affects children of African descent and tends to debut at approximately 1–3 years of age. Blount’s Disease (BD). (2011). Neuroleptic malignant syndrome: a review for neurohospitalists. The Neurohospitalist 1(1):41–47. https://doi.org/10.1177/1941875210386491
  2. Simon LV, Hashmi MF, Callahan AL. (2020). Neuroleptic malignant syndrome. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK482282/
  3. Wijdicks EFM. (2019). Neuroleptic malignant syndrome. UpToDate. Retrieved February 1, 2021, from https://www.uptodate.com/contents/neuroleptic-malignant-syndrome

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

¡Hola!

Esta página está disponible en Español.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.

Details