Neuroleptic malignant syndrome (NMS) is a rare
but life-threatening reaction that can occur in response to
neuroleptic or antipsychotic medication.
Symptoms include
high fever, confusion, rigid muscles, variable blood pressure, sweating, and fast heart rate.
[ Complications may include rhabdomyolysis, high blood potassium, kidney failure, or ]seizures
An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with los ...
.
Any medications within the family of neuroleptics can cause the condition, though typical antipsychotics appear to have a higher risk than atypicals, specifically first generation antipsychotics like haloperidol. Onset is often within a few weeks of starting the medication but can occur at any time. Risk factors include dehydration, agitation, and catatonia
Catatonia is a complex neuropsychiatric behavioral syndrome that is characterized by abnormal movements, immobility, abnormal behaviors, and withdrawal. The onset of catatonia can be acute or subtle and symptoms can wax, wane, or change during ...
.[
Rapidly decreasing the use of ]levodopa
-DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOPA ...
or other dopamine agonists, such as pramipexole, may also trigger the condition. The underlying mechanism involves blockage of dopamine receptors. Diagnosis is based on symptoms.
Management includes stopping the triggering medication, rapid cooling, and starting other medications.[ Medications used include dantrolene, bromocriptine, and diazepam.][ The risk of death among those affected is about 10%.] Rapid diagnosis and treatment is required to improve outcomes.[ Many people can eventually be restarted on a lower dose of antipsychotic.][
As of 2011, among those in ]psychiatric hospitals
Psychiatric hospitals, also known as mental health hospitals, behavioral health hospitals, are hospitals or wards specializing in the treatment of severe mental disorders, such as schizophrenia, bipolar disorder, eating disorders, dissociati ...
on neuroleptics about 15 per 100,000 are affected per year (0.015%).[ In the second half of the 20th century rates were over 100 times higher at about 2% (2,000 per 100,000).][ Males appear to be more often affected than females.][ The condition was first described in 1956.][
]
Signs and symptoms
NMS symptoms include:[
]
* Increased body temperature >38 °C (>100.4 °F), or
* Confused or altered consciousness[
* ]Excessive sweating
Hyperhidrosis is a condition characterized by abnormally increased sweating, in excess of that required for regulation of body temperature. Although primarily a benign physical burden, hyperhidrosis can deteriorate quality of life from a psychologi ...
* Rigid muscles[
* Autonomic imbalance][
The first symptoms of neuroleptic malignant syndrome are usually muscle cramps and tremors, ]fever
Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using val ...
, symptoms of autonomic nervous system instability such as unstable blood pressure
Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressur ...
, and sudden changes in mental status (agitation, delirium
Delirium (also known as acute confusional state) is an organically caused decline from a previous baseline of mental function that develops over a short period of time, typically hours to days. Delirium is a syndrome encompassing disturbances ...
, or coma
A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to respond normally to painful stimuli, light, or sound, lacks a normal wake-sleep cycle and does not initiate voluntary actions. Coma patients exhi ...
). Once symptoms appear, they may progress rapidly and reach peak intensity in as little as three days.[ These symptoms can last anywhere from eight hours to forty days.][
Symptoms are sometimes misinterpreted by doctors as symptoms of mental illness which can result in delayed treatment. NMS is less likely if a person has previously been stable for a period of time on antipsychotics, especially in situations where the dose has not been changed and there are no issues of noncompliance or consumption of psychoactive substances known to worsen ]psychosis
Psychosis is a condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are incoherent speech and behavior ...
.
Causes
NMS is usually caused by antipsychotic drug use, and a wide range of drugs can result in NMS. Individuals using butyrophenones (such as haloperidol and droperidol
Droperidol (Inapsine, Droleptan, Dridol, Xomolix, Innovar ombination with fentanyl">fentanyl.html" ;"title="ombination with fentanyl">ombination with fentanyl is an antidopaminergic medication, drug used as an antiemetic (that is, to prevent o ...
) or phenothiazines (such as promethazine
Promethazine is a first-generation antihistamine, antipsychotic, sedative, and antiemetic used to treat allergies, insomnia, and nausea. It may also help with some symptoms associated with the common cold and may also be used for sedating pe ...
and chlorpromazine) are reported to be at greatest risk. However, various atypical antipsychotics such as clozapine
Clozapine is a psychiatric medication and is the first atypical antipsychotic (also called second-generation antipsychotic). It is primarily used to treat people with schizophrenia and schizoaffective disorders who have had an inadequate resp ...
, olanzapine, risperidone, quetiapine
Quetiapine, sold under the brand name Seroquel among others, is an atypical antipsychotic medication used for the treatment of schizophrenia, bipolar disorder, and major depressive disorder. Despite being widely used as a sleep aid due to its ...
, and ziprasidone have also been implicated in cases.
NMS may also occur in people taking dopaminergic
Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate do ...
drugs (such as levodopa
-DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOPA ...
) for Parkinson's disease, most often when the drug dosage is abruptly reduced. In addition, other drugs with anti-dopaminergic activity, such as the antiemetic metoclopramide, can induce NMS. Tetracyclics with anti-dopaminergic activity have been linked to NMS in case reports, such as the amoxapines. Additionally, desipramine, dothiepin
Dosulepin, also known as dothiepin and sold under the brand name Prothiaden among others, is a tricyclic antidepressant (TCA) which is used in the treatment of depression. Dosulepin was once the most frequently prescribed antidepressant in the ...
, phenelzine, tetrabenazine, and reserpine
Reserpine is a drug that is used for the treatment of high blood pressure, usually in combination with a thiazide diuretic or vasodilator. Large clinical trials have shown that combined treatment with reserpine plus a thiazide diuretic reduces m ...
have been known to trigger NMS. Whether lithium
Lithium (from el, λίθος, lithos, lit=stone) is a chemical element with the symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard conditions, it is the least dense metal and the least dense solid ...
can cause NMS is unclear. However, concomitant use of lithium is associated with a higher risk of NMS when the patient starts on a neuroleptic drug e.g. anti-psychotics.
At the molecular level, NMS is caused by a sudden, marked reduction in dopamine activity, either from withdrawal of dopaminergic agents or from blockade of dopamine receptors.
Risk factors
One of the clearest risk factors in the development of NMS is the course of drug therapy chosen to treat a condition. Use of high-potency neuroleptics, a rapid increase in the dosage of neuroleptics, and use of long-acting forms of neuroleptics (such as haloperidol) are all known to increase the risk of developing NMS. There appears to be no relationship between duration of therapy and the development of NMS.
Use of the following agents is most commonly associated with the development of NMS[:
* Typical Neuroleptics: e.g. haloperidol, chlorpromazine.
* Atypical Neuroleptics: e.g. Olanzapine, clozapine, risperidone
* Anti-dopaminergic antiemetics: e.g. Droperidol
* Withdrawal of Dopaminergic Agents: ]levodopa
-DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOPA ...
, amantadine
It has been purported that there is a genetic risk factor for NMS. In one study, identical twins presented with NMS, and a mother and two of her daughters have presented with NMS in another case.
Demographically, it appears that males, especially those under forty, are at greatest risk for developing NMS, although it is unclear if the increased incidence is a result of greater neuroleptic use in men under forty.[ It has also been suggested that postpartum women may be at a greater risk for NMS.
An important risk factor for this condition is Lewy body dementia. These patients are extremely sensitive to neuroleptics. As a result, neuroleptics should be used cautiously in all cases of dementia.
]
Pathophysiology
The mechanism is commonly thought to depend on decreased levels of dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 8 ...
activity due to:
* Dopamine receptor
Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through diffe ...
blockade
* Genetically reduced function of dopamine receptor D2
*Sympathoadrenal hyperactivity and autonomic dysfunction
It has been proposed that blockade of D2-like (D2, D3 and D4) receptors induce massive glutamate release, generating catatonia, neurotoxicity and myotoxicity. Additionally, the blockade of diverse serotonin receptors by atypical antipsychotics and activation of 5HT1 receptors by certain of them reduces GABA release and indirectly induces glutamate release, worsening this syndrome.
The muscular symptoms are most likely caused by blockade of the dopamine receptor D2, leading to abnormal function of the basal ganglia
The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an extern ...
similar to that seen in Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
.
In the past, research and clinical studies seemed to corroborate the D2 receptor blockade theory in which antipsychotic drugs were thought to significantly reduce dopamine activity by blocking the D2 receptors associated with this neurotransmitter. The introduction of atypical antipsychotic drugs, with lower affinity to the D2 dopamine receptors, was thought to have reduced the incidence of NMS. However, recent studies suggest that the decrease in mortality may be the result of increased physician awareness and earlier initiation of treatment rather than the action of the drugs themselves.[ NMS induced by atypical drugs also resembles "classical" NMS (induced by "typical" antipsychotic drugs), further casting doubt on the overall superiority of these drugs.
However, the failure of D2 dopamine receptor antagonism, or dopamine receptor dysfunction, do not fully explain the presenting symptoms and signs of NMS, as well as the occurrence of NMS with ]atypical antipsychotic
The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs (antipsychotic drugs in general are also known as major tranquilizers and ne ...
drugs with lower D2 dopamine activity. This has led to the hypothesis of sympathoadrenal hyperactivity (results from removing tonic inhibition from the sympathetic nervous system
The sympathetic nervous system (SNS) is one of the three divisions of the autonomic nervous system, the others being the parasympathetic nervous system and the enteric nervous system. The enteric nervous system is sometimes considered part of ...
) as a mechanism for NMS. Release of calcium is increased from the sarcoplasmic reticulum with antipsychotic usage. This can result in increased muscle contractility, which can play a role in the breakdown of muscle, muscle rigidity, and hyperthermia. Some antipsychotic drugs, such as typical neuroleptics, are known to block dopamine receptors; other studies have shown that when drugs supplying dopamine are withdrawn, symptoms similar to NMS present themselves.[
In support of the sympathoadrenal hyperactivity model, it has been hypothesized that a defect in calcium regulatory proteins within the sympathetic neurons may bring about the onset of NMS. This model of NMS strengthens its suspected association with ]malignant hyperthermia
Malignant hyperthermia (MH) is a type of severe reaction that occurs in response to particular medications used during General anaesthesia, general anesthesia, among those who are susceptible. Symptoms include tetany, muscle rigidity, hyperthermia ...
in which NMS may be regarded as a neurogenic form of this condition which itself is linked to defective calcium-related proteins.
There is also thought to be considerable overlap between malignant catatonia and NMS in their pathophysiology, the former being idiopathic and the latter being the drug-induced form of the same syndrome.
The raised white blood cell count and creatine phosphokinase (CPK) plasma concentration seen in those with NMS is due to increased muscular activity and rhabdomyolysis (destruction of muscle tissue). The patient may experience hypertensive crisis and metabolic acidosis
Metabolic acidosis is a serious electrolyte disorder characterized by an imbalance in the body's acid-base balance. Metabolic acidosis has three main root causes: increased acid production, loss of bicarbonate, and a reduced ability of the kidne ...
. A non-generalized slowing on an EEG is reported in around 50% of cases.
The fever seen with NMS is believed to be caused by hypothalamic dopamine receptor blockade. The peripheral problems (the high white blood cell and CPK count) are caused by the antipsychotic drugs. They cause an increased calcium release from the sarcoplasmic reticulum
The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the smooth endoplasmic reticulum in other cells. The main function of the SR is to store calcium ions (Ca2+). Calcium ion levels are kep ...
of muscle cells which can result in rigidity and eventual cell breakdown. No major studies have reported an explanation for the abnormal EEG, but it is likely also attributable to dopamine blockage leading to changes in neuronal pathways.[
]
Diagnosis
Differential diagnosis
Due to the comparative rarity of NMS, it is often overlooked. Immediate treatment for the syndrome should not be delayed as it has a high mortality of between 10-20%. Differentiating NMS from other neurological disorders can be very difficult. It requires expert judgement to separate symptoms of NMS from other diseases.
The diagnosis is suggested on patients with an accurate history of drug exposure to the most common inducing agents such as strong antidopaminergic medication. The differential diagnosis includes serotonin syndrome
Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain serotonergic medications or drugs. The degree of symptoms can range from mild to severe, including a potentiality of death. Symptoms in mild cases include h ...
, encephalitis
Encephalitis is inflammation of the Human brain, brain. The severity can be variable with symptoms including reduction or alteration in consciousness, headache, fever, confusion, a stiff neck, and vomiting. Complications may include seizures, hal ...
, toxic encephalopathy, status epilepticus
Status epilepticus (SE), or status seizure, is a single seizure lasting more than 5 minutes or 2 or more seizures within a 5-minute period without the person returning to normal between them. Previous definitions used a 30-minute time limit. The s ...
, heat stroke
Heat stroke or heatstroke, also known as sun stroke, is a severe heat illness that results in a body temperature greater than , along with red skin, headache, dizziness, and confusion. Sweating is generally present in exertional heatstroke, ...
, catatonia
Catatonia is a complex neuropsychiatric behavioral syndrome that is characterized by abnormal movements, immobility, abnormal behaviors, and withdrawal. The onset of catatonia can be acute or subtle and symptoms can wax, wane, or change during ...
and malignant hyperthermia
Malignant hyperthermia (MH) is a type of severe reaction that occurs in response to particular medications used during General anaesthesia, general anesthesia, among those who are susceptible. Symptoms include tetany, muscle rigidity, hyperthermia ...
. Drugs such as cocaine
Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Am ...
and amphetamine
Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...
may also produce similar symptoms. Features which distinguish NMS from serotonin syndrome include bradykinesia, muscle rigidity, and a high white blood cell count.
Treatment
NMS is a medical emergency and can lead to death if untreated. The first step is to stop the antipsychotic medication and treat the hyperthermia
Hyperthermia, also known simply as overheating, is a condition in which an individual's body temperature is elevated beyond normal due to failed thermoregulation. The person's body produces or absorbs more heat than it dissipates. When extreme ...
aggressively, such as with cooling blankets or ice packs to the axillae and groin. Supportive care in an intensive care unit capable of circulatory and ventilatory support is crucial. The best pharmacological treatment is still unclear. Dantrolene has been used when needed to reduce muscle rigidity, and more recently dopamine pathway medications such as bromocriptine have shown benefit.
Amantadine is another treatment option due to its dopaminergic and anticholinergic effects.
Apomorphine may be used however its use is supported by little evidence.[ ]Benzodiazepine
Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...
s may be used to control agitation. Highly elevated blood myoglobin
Myoglobin (symbol Mb or MB) is an iron- and oxygen-binding protein found in the cardiac and skeletal muscle tissue of vertebrates in general and in almost all mammals. Myoglobin is distantly related to hemoglobin. Compared to hemoglobin, myoglobi ...
levels can result in kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; bloo ...
damage, therefore aggressive intravenous hydration with diuresis may be required. When recognized early NMS can be successfully managed; however, up to 10% of cases can be fatal.[
Should the affected person subsequently require an antipsychotic, trialing a low dose of a low-potency atypical antipsychotic is recommended.][
]
Prognosis
The prognosis
Prognosis (Greek: πρόγνωσις "fore-knowing, foreseeing") is a medical term for predicting the likely or expected development of a disease, including whether the signs and symptoms will improve or worsen (and how quickly) or remain stabl ...
is best when identified early and treated aggressively. In these cases NMS is not usually fatal. In earlier studies the mortality rates from NMS ranged from 20%–38%, but by 2009 mortality rates were reported to have fallen below 10% over the previous two decades due to early recognition and improved management. Re-introduction to the drug that originally caused NMS to develop may also trigger a recurrence, although in most cases it does not.
Memory impairment is a consistent feature of recovery from NMS, and is usually temporary though in some cases may become persistent.
Epidemiology
Pooled data suggest the incidence of NMS is between 0.2%–3.23%. However, greater physician awareness coupled with increased use of atypical anti-psychotics have likely reduced the prevalence of NMS.[ Additionally, young males are particularly susceptible and the male:female ratio has been reported to be as high as 2:1.][
]
History
NMS was known about as early as 1956, shortly after the introduction of the first phenothiazines.[ ] NMS was first described in 1960 by French clinicians who had been working on a study involving haloperidol. They characterized the condition that was associated with the side effects of haloperidol "''syndrome malin des neuroleptiques''", which was translated to neuroleptic malignant syndrome.[
]
References
External links
NINDS Neuroleptic Malignant Syndrome Information Page
NIH.
{{DEFAULTSORT:Neuroleptic Malignant Syndrome
*
Extrapyramidal and movement disorders
Medical emergencies
Syndromes
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