Neuroleptic Malingmant Syndrome (NMS, Antipsychotics: Signs, Syndromes, Treatment)

Rapid heart rate also occurs in NMS. Mydriasis, which is widening of the pupil, is another sign that is

sometimes seen in NMS. The pupil is the black circle in the middle of each eye that responds to light.

Seizures can also occur in NMS patients. Seizures are involuntary muscle movements and/or decreased

awareness of the environment due to overexcitement of nerve cells in the brain.

Another sign of NMS that is sometimes seen is fluttering of the eyes. Liver and kidney failure can occur in

NMS. The liver is the largest organ in the body and is responsible for filtering (removing) harmful chemical

substances, producing important chemicals for the body, and other important functions. The kidneys are

two organs located on each side of the spine, behind the stomach. The kidneys remove wastes from the

blood.

WHAT ARE THE LABORATORY FINDINGS IN NEUROLEPTIC MALIGNANT SYNDROME?

There are some lab findings associated with NMS, but these lab findings occur in other conditions too. As

mentioned above, one of the laboratory findings in NMS is leukocytosis (an abnormal increase in the

number of white blood cells.

Approximately 75% of NMS patients have a high level of white blood cells and a high level of creatine

kinase in the blood. Creatine kinase is an enzyme found in the muscles, brain, and other tissues. Creatine

kinase helps store energy. An enzyme is a type of protein that helps produce chemical reactions in the

body. Creatine kinase levels are often extremely high (100 to 200 times the normal level) in NMS patients

due to massive rhabdomyloysis. Rhabdomyolysis is a suddenly occurring disease that causes destruction

of muscle tissue connected to bones.

Other laboratory indications of muscle damage and the death of muscle tissue include high levels of

alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH).

ALT, AST, and LDH are all types of enzymes. An enzyme is a type of protein that helps produce chemical

reactions in the body. Among other things, ALT and AST help form amino acids, which are groups of

chemical substances that are an important component of muscles. LDH is an enzyme found in many body

tissues and organs. Injury to organs and tissues often cause a release of LDH into the blood, which

raises the level of this enzyme on blood tests.

An increased level of alkaline phosphatase can also be found in some NMS patients. Alkaline

phosphatase is an enzyme that is present in all tissues. This enzyme is also released when tissues are

damaged. High levels of uric acid can be found in the blood in NMS patients. Uric acid is a waste product

that is produced from the breakdown of nucleic acids. Nucleic acids are substances found in all living

things that play a major role in the continuation of life.

An increased level of phosphates can be found in the blood of NMS patients. Phosphates are a type of

salt that play an important role in living cells in terms of storing and using energy. High levels of myoglobin

can be found in the blood and/or urine (pee) in NMS patients. Myoglobin is a protein that is responsible for

the red color of muscle and stores oxygen.

Approximately 95% of NMS patients have a low level of oxygen in the blood. An abnormal level of

electrolytes is another finding that occurs in NMS. Electrolytes are chemical substances that are able to

conduct electricity after they are melted or dissolved in water. They are important to normal bodily

functioning. Low levels of iron and/or calcium can be found in the blood in NMS patients. Increased levels

of catecholamines can also be found in the blood. Catecholamines are types of chemical substances that

are released in the body in response to stress. An example of a type of catecholamine is adrenaline.

Another lab finding in NMS can be the presence of metabolic acidosis. Acidosis is when there is too much

acid in the blood. Metabolic acidosis is when excess acid is in the body fluids or bicarbonate is lost from

them. Bicarbonate is a substance in the blood that prevents it from becoming too acidic or too alkaline

(non-acidic). Another laboratory finding in NMS is thrombocytosis. Thrombocytosis is a bleeding disorder

caused by a large decrease in the number of platelets in the blood. Platelets are cells that help stop

bleeding by changing the blood from a liquid to solid form.

On a test used to measure electric brain waves (known as an electroencephalography or EEG), slowed

brain waves are found in about half of NMS cases. These EEG findings are usually consistent with

encephalopathy. Encephalopathy means any disease or disorder of the structure or function of the brain,

especially those that are destructive, worsening, or chronic. Chronic means to last or frequently reoccur

over a long period of time.

It is worth noting however, that procedures used to take pictures of the brain do not reveal abnormalities

in brain structure that can be attributed to NMS. Studies of the cerebrospinal fluid (CSF) usually do not find

any abnormalities, however sometimes there can be increased levels of proteins in the CSF. The CSF is

a cushiony fluid that protects the brain and spine. High levels of protein may also be found in the urine in

patients with NMS. Evaluations for infections do not usually turn up anything of significance.

WHAT ARE THE EARLY SIGNS OF NEUROLEPTIC MALIGNANT SYNDROME?

NMS can begin quickly (in hours) or it may begin slowly (over several days). The early signs are typically

high body temperature, muscle rigidity, and a change in mental status (such as confusion). The muscle

rigidity can lead to the high body temperature. The high body temperature tends to begin before the

changes in blood pressure and rapid heart beat. After this, the changes in mental status usually begins.

Insensitivity to pain or unpleasant feelings can also occur early. Catatonia is another early sign. Catatonia

is a condition characterized by a lack of movement, rigid muscles, and agitation. Difficulty swallowing,

difficulty controlling the ability to pee and poop, unstable blood pressure, rapid heart beat, rapid or

abnormal breathing (in about 78% of cases), excessive saliva (too much spit), drooling, sweating, and

dysarthria are other early signs of NMS. Dysarthria is a type of speech difficulty that results from an

impaired ability to control the muscles involved in speech.

Other early NMS signs include rash, tremor (uncontrollable shaking movements), myoclonus (one or more

jerking contractions [shortenings] of a group of muscles), low fevers, and high levels of creatine kinase in

the blood (see previous section).

It is important to realize that the presence of these early signs do not always mean that NMS is present or

that NMS is going to occur. They are warning signs that the clinician needs to look out for, however, when

antipsychotic medications are prescribed.

WHEN CAN NEUROLEPTIC MALIGNANT SYNDROME OCCUR?

Neuroleptic malignant syndrome can occur at any time during treatment with antipsychotic medications,

even years after treatment began. The average case of NMS begins 4 to 14 days after antipsychotics are

administered. One study that evaluated cases of NMS found that 16% developed NMS within 24 hours of

using antipsychotics for the first time, 66% developed it within one week, 90% develop it within 2 weeks,

and almost all cases developed NMS within the first 30 days. Remember that this does not mean that all

patients who use antipsychotics will develop NMS within 30 days. It means that research has shown that

of the patients who do develop NMS, almost all of the cases occurred within 30 days of starting

antipsychotics.

Once signs of NMS begin, they develop quickly and peak within 3 days. However, the progression of NMS

can vary from as little as 45 minutes to 65 days. NMS can occur in patients with a wide variety of mental

illnesses, provided they are taking antipsychotics. NMS can even occur in patients who are prescribed

antipsychotics to prevent nausea and vomiting or to calm them down. Antipsychotics have calming effects

on the body.

WHAT CAUSES NEUROLEPTIC MALIGNANT SYNDROME?

Neuroleptic malignant syndrome appears to be caused by a sudden withdrawal in the activation of

dopamine receptors or by a decreased availability of dopamine. Dopamine is a chemical messenger in the

brain that is important for slowing down movements, causing pleasurable sensations, and other important

functions. Dopamine receptors are areas on nerve cells that receive dopamine so that dopamine can

exert its effect. There are different types of dopamine receptors in the brain and each type is given a

different number. For example, there is the dopamine-1 receptor, the dopamine-2 receptor, and the

dopamine-3 receptor.

Too much dopamine in the brain can lead to psychosis (see above), whereas too little can lead to

Parkinson's disease. Parkinson's disease is a type of brain disorder that leads to serious difficulties with

muscle movements.

Antipsychotic medications generally work by blocking specific types of dopamine receptors. When a nerve

cell's dopamine receptors are blocked, dopamine cannot exert its effect on that nerve cell. The overall

effect of blocked dopamine receptors is a decrease in the amount of dopamine stimulation in the brain. If a

large number of the dopamine receptors suddenly become blocked or deactivated at any point in

treatment, NMS can result.

Almost all drugs that block the dopamine-2 receptor can cause NMS. All antipsychotics block the

dopamine-2 receptor. NMS typically occurs when the levels of antipsychotic medication in the body are in

the high end of the normal range. However, NMS is not usually the result of an overdose.

Evidence to support the view that suddenly reducing the activation of dopamine receptors can lead to an

NMS-like condition comes from work with Parkinson's disease patients. Remember that Parkinson's

disease is caused by too little dopamine in the brain. This condition is sometime treated with the drug,

levodopa. Levodopa is a chemical that the brain turns into dopamine. Thus, giving patients levodopa

increases the amount of dopamine in the brain. This, in turn, increases the activation of dopamine

receptors.

If levodopa is suddenly withdrawn from Parkinson's disease patients, NMS symptoms result. Suddenly

withdrawing levodopa would suddenly withdraw the activation of dopamine receptors. This is what can

occur if this medication is suddenly discontinued. Suddenly blocking off dopamine receptors in a patient

with Huntington's disease has also led to NMS symptoms. Huntington's disease is a motor disorder that

results in chorea and deterioration of mental functioning. Chorea is involuntary, irregular, dance-like

movements of the arms, legs, and face.

Blocking dopamine receptors in the hypothalamus leads to abnormally high body temperatures. The

hypothalamus is an area in brain that is important for many bodily functions such as sleep, appetite, and

temperature control. Blocking dopamine receptors in the spine and nigrostriatal pathway can lead to rigid

muscles and tremors. The nigrostriatal pathway is a pathway in the brain that connects the substantia

nigra with the striatum. The substantia nigra is a dark area in the lower part of the brain that contains

dopamine, a chemical messenger that is important for movement. The striatum is an area in the lower part

of the brain that is important for movement. The nigrostriatal pathway was given its name because it

connects these two areas.

Antipsychotics can also cause a release of calcium from a network of very tiny tubes in the muscles

known as the sarcoplasmic reticulum. Calcium is a natural element that is very important in bone

formation. The increased calcium in the muscles causes them to contract (shorten). This contributes to

rigid muscles. Rigid muscles and high body temperatures contribute to muscle damage and the death of

muscle tissue in NMS.

The muscle impairments in NMS indicate that an abnormality in the muscle membrane occurs. A

membrane is a thin layer of flexible tissue that covers something. The unstable blood pressure and rapid

heart rate in NMS indicate that this condition is also partly caused by an impaired sympathetic nervous

system. The sympathetic nervous system is a system that generally excites the body by doing things such

as increasing both the heart rate and blood pressure. The blockage of dopamine-2 receptors may remove

the ability of the body to slow down the effects of the sympathetic nervous system.

CAN MEDICATIONS BESIDES NEUROLEPTICS LEAD TO NEUROLEPTIC MALIGNANT SYNDROME?

Interestingly, the answer is yes. Some NMS cases, including ones that lead to death, have been reported

with drugs that prevent nausea and vomiting, such as prochlorperazine (Compazine) or droperidol

(Inapsine). NMS has been reported in anti-allergy medications, such as promethazine (Phenergan). NMS

has also been reported in medications that improve peristalsis in the stomach and intestines, such as

Metoclopramide (Reglan). Peristalsis is a series of wavelike, coordinated contractions and relaxations of

a tube-like structure in the body that forces the contents of the tubes onwards. The intestine is a tube

shaped structure that is part of the digestive tract.

HOW MANY PEOPLE DEVELOP NEUROLEPTIC MALIGNANT SYNDROME?

NMS is a rare occurrence. Anywhere from .02 to 2.2% of patients that are given antipsychotic

medications develop NMS.

ARE THERE RISK FACTORS FOR NEUROLEPTIC MALIGNANT SYNDROME?

Since NMS occurs so infrequently, it has been difficult to identify risk factors for the condition. That is, it is

almost impossible to figure out who will develop NMS before treatment with antipsychotics begins.

Although the following factors are possible risk factors, doctors do not typically eliminate the possibility of

giving antipsychotics if one or more of the following risk factors are present.

A history of developing NMS increases the risk that one will develop it again. It has been proposed that

patients with disorders that affect structures deep in the brain may be predisposed to develop NMS. Being

a young male is thought to be a risk factor for NMS. The reason that males are more likely than females to

develop NMS is because males are prescribed antipsychotics more often. For the same reason, people

younger than age 40 have a higher rate of NMS than people over age 40. That is, people younger than

age 40 are more likely to be given antipsychotic medications. Males may also be more likely to be given

antipsychotic medications because if they are agitated they may be perceived as more threatening than

females. After a woman has given birth (if she is using antipsychotics), she is at risk for NMS.

The presence of catatonia is also seen as a risk factor for NMS. Catatonia is a psychological condition

characterized by a lack of movement, rigid muscles, and agitation. General agitation can be a risk factor

for NMS, as can mood disorders, exhaustion, poor nutrition, brain damage, increased room temperature,

and dehydration (an excessive loss of water from body tissues). Prior electroconvulsive therapy (also

known as ECT or shock therapy) may be a risk factor for NMS. Electroconvulsive therapy is the process

of causing convulsions (abnormal, severe, involuntary muscle movements) by passing controlled levels of

electricity through the brain.

Approximately 17% of patients who develop NMS have experienced a similar episode at some point

earlier in treatment with antipsychotics. Rapidly changing the dose of antipsychotics appears to put

patients at risk for NMS. More injections of antipsychotics, high doses of antipsychotics, using very

powerful antipsychotics, and using antipsychotics inconsistently are all risk factor for NMS. Combining the

antipsychotic medication, Haldol, with the mood stabilizing medication, Lithium, can increase the risk of

NMS. The use of depot neuroleptics is a risk factor for NMS. Depot neuroleptics are an injected form of an

antipsychotic drug that stays in the muscle and slowly releases itself overtime.

Hyponatremia is a risk factor for NMS. Hyponatremia is a decreased level of sodium (salt) in the blood.

Thyrotoxicosis is also seen as a risk factor for NMS. Thyrotoxicosis is a poisonous condition that results

from an overactive thyroid gland. The thyroid gland is a butterfly-shaped organ located in front of the neck

that produces certain chemicals that are important for growth and metabolism. Metabolism is a term for

the chemical actions in cells that release energy from nutrients or that use energy to create other

substances.

WHICH ANTIPSYCHOTIC MEDICATIONS ARE MOST LIKELY TO CAUSE NEUROLEPTIC MALIGNANT

SYNDROME?

The two antipsychotic medications that are most likely to cause NMS are haldoperidol (Haldol),

trifluoperazine (Stelazine), and chlorpromazine (Thorazine). An explanation for Haldol causing the most

cases of NMS may be that it is one of the most frequently prescribed antipsychotic medications,

especially for agitated psychotic patients.

HOW SERIOUS IS NEUROLEPTIC MALIGNANT SYNDROME?

NMS is potentially a very serious condition and in most cases represents an emergency. The high body

temperatures that sometimes occur can lead to brain damage if not decreased immediately. The rigidity in

the muscles causes them to wear away. The heart, lungs, and or kidneys can stop working and cause

death. Abnormal heart rhythms and seizures can lead to death as well. Seizures are involuntary muscle

movements and/or decreased awareness of the environment due to overexcitement of nerve cells in the

brain.

Other causes of death in NMS patients include infections, blood clots (a collection of a mass of blood),

and pulmonary embolism. A pulmonary embolism is a blockage of an artery (a type of blood vessel that

carries blood away from the heart) that goes from the heart to the lungs. The blockage is due to a blood

clot. The condition can be life threatening because it can lead to the inability to breathe.

Another cause of death in NMS is aspiration pneumonia. Pneumonia is inflammation of the lungs due to

infection. Aspiration pneumonia is pneumonia that develops from the presence of fluids or fluid-like

contents in the airways of the lungs. Approximately 5 to 11.6% of people with NMS die from it. This is a

decrease from death rates that used to be as high as 30%. Death rates tend to be higher in patients with

severe muscle loss. Severe muscle loss can lead to kidney failure.

HOW IS NEUROLEPTIC MALIGNANT SYNDROME TREATED?

Some cases of NMS are mild and go away without treatment in one to two weeks. With treatment,

however, NMS can go away within days. Drug treatment of NMS begins by taking the patient off the

antipsychotic medications. This is considered the most important step to treating NMS and usually stops

the condition within 7 to 10 days. Research has shown that about 63% of NMS patients recover in one

week after the antipsychotics are discontinued and that almost all cases recover in 30 days. These

percentages refer to patients who take antipsychotics in pill form (by mouth). For patients who receive

depot neuroleptics, the recovery time can be twice as long, but is usually about 21 days. Depot

neuroleptics are an injected form of an antipsychotic drug that stays in the muscle and slowly releases

itself overtime.

The symptoms that the patient presents with must be treated intensely. This treatment will vary depending

on the individual case. If the patient's body temperature is high, treatment begins by lowering the

temperature with cooling blankets, ice packs. adequate levels of cooled fluids, and medications to

decrease fever. Electrolytes that have been lost are replaced. Electrolytes are chemical substances that

are able to conduct electricity after they are melted or dissolved in water. They are important to normal

bodily functioning.

If the patient is having difficulty breathing, they may need breathing assistance. In cases of kidney failure,

dialysis may be necessary. Dialysis is a technique in which one is hooked up to a machine that performs

the functions of the kidneys, removing wastes and extra water from the blood.

Some medications are used by doctors to treat NMS. Dantroline (Dantrium) is a medication sometimes

used to treat NMS. Dantrium works directly on relaxing the muscles. This helps to treat the rigid muscles.

Dantrium also works to decrease high body temperatures rather quickly. Dantrium is typically administered

through the veins. Veins are blood vessels that carry blood to the heart.

Lorazepam (Ativan) is another medication sometimes used to treat NMS. Lorazepam belongs to a class of

relaxing, antianxiety drugs known as benzodiazepines. Benzodiazepines are useful in treating catatonia,

which can occur in NMS. Catatonia is a psychological condition characterized by a lack of movement,

rigid muscles, and agitation.

Bromocriptine (Parlodel) and amantadine (Symadine) are also used to treat NMS. Bromocriptine and

Symadine increase the activation of dopamine receptors. Increasing the activation of dopamine receptors

helps to overcome the deactivation of dopamine receptors caused by antipsychotic medications. Other

drugs that perform this function are sometimes used to treat NMS. See the section on causes of NMS to

learn more about dopamine receptors.

The above medications (Dantrium, Ativan, Symadine, and Parlodel) are especially useful during the first

few days of treatment. Many doctors will start by giving the patient Bromocriptine (in pill form, by mouth)

and Dantrium (see three paragraphs ago). When the signs of NMS begin to go away, doctors usually take

patients off of Dantrium and keep them on Bromocriptine. Drug treatment can last from approximately 10

days (if the patients were using antipsychotics by mouth) to 3 weeks (if the patients were using an

injected form of antipsychotics).

Rarely, electroconvulsive therapy (also known as ECT or shock therapy) has been used to treat NMS,

although its use is controversial. Electroconvulsive therapy is the process of causing convulsions

(abnormal, severe, involuntary muscle movements) by passing controlled levels of electricity through the

brain. Some research has shown that ECT helps to rapidly treat NMS. It is not fully understood why ECT is

effective, but is have even been shown to work late in the course of NMS. ECT is usually used after the

previously mentioned interventions have failed. In other words, it is a last resort. ECT seems to be

especially useful in patients with catatonia (see two paragraphs ago). However, some patients have

experienced heart attacks and heart problems after trying ECT.

Although some doctors will restart antipsychotic medications at some point (see next section for details)

another strategy has been to prescribe other medications besides antipsychotics or besides the ones that

caused the problem. In patient's with Parkinson's disease that develop NMS, the treatment basically

remains the same except that they are usually restarted on the anti-parkinsonian medication as soon as

possible.

WHAT IS THE PROGNOSIS FOR PEOPLE THAT SURVIVE TREATMENT FOR NEUROLEPTIC

MALIGNANT SYNDROME?

The prognosis is generally good for people that survive after receiving treatment for NMS. Persistent

signs of NMS are rare in patients that have recovered from it. However, some patients have reportedly

experienced amnesia (memory loss), brain damage, dementia, and catatonia. Dementia is a mental

disorder characterized by a significant loss of intellectual and cognitive abilities without impairment of

perception or consciousness. Catatonia is a psychological condition characterized by a lack of

movement, rigid muscles, and agitation. The catatonia may occur, however, in patients with pre-existing

brain disorders.

Muscle abnormalities, such as muscle weakness and/or muscle wasting, have been reported in some

NMS survivors. Peripheral neuropathy (damage to nerve fibers outside of the brain or spine) has also

been reported in some NMS cases, as have contractures. A contracture is a deformity caused by

shrinkage of scar tissue in the skin, shortening of muscles, connective tissues, or tendons. Connective

tissues are tissues that connect other tissues and body parts. Tendons are groups of fibers that attach

muscles to bones. The shrinkage of the muscles and tendons is irreversible.

It should also be mentioned that of those patients that survive NMS, approximately 30% will develop this

condition again if antipsychotics are readministered when more than 2 weeks have passed after

recovery. If the antipsychotics are given in less than 2 weeks after recovery, 63% of patient will develop

it again. Thus, these patients need to be closely monitored if given antipsychotics after recovering from

NMS. In patients that take antipsychotics by mouth, doctors typically wait 2 weeks after recovery from

NMS before administering them again. When the antipsychotics are readministered, they are done so in

low doses and the dosage is increased slowly.

In patients that received the injectable form of antipsychotics, doctors typically wait 6 weeks after

recovery from NMS before administering them again. However, some doctors recommend avoiding using

the injectable form of antipsychotics at all after NMS has occurred because it is a high risk factor for

developing the condition.

CAN NEUROLEPTIC MALIGNANT SYNDROME BE PREVENTED?

To some degree, NMS can be prevented. This can be done by prescribing the lowest effective amount of

antipsychotic medications. In addition, antipsychotic medications with anticholinergic side effects appear

to be less likely to cause NMS. Anticholinergic side effects are side effects that result from blocking

acetylcholine receptors. Acetylcholine is a chemical messenger in the body that is important for memory

and muscle movements. Common anticholinergic side effects include dry mouth, constipation (difficulty

pooping), blurry vision, and difficulty initiating urination (peeing).

WHEN WAS NEUROLEPTIC MALIGNANT SYNDROME FIRST DESCRIBED?

NMS was first described in 1960 by J. Delay after early trials of the antipsychotic medication, haloperidol

(Haldol). The first report of NMS in the English literature was in 1968. The reference for this article is as

follows: Delay J, Deniker P. (1968) Drug induced extrapyramidal syndromes. In: Vinkin PJ, Bruyn GW

(eds). Handbook of Clinical Neurology: diseases of the Basal Ganglia, Vol 6. New York, American

Elsevier/North Holland Publishing. 248-66. NMS was not focused on to a significant degree until 1980

when hundreds of case studies began to appear in the literature.

WHAT IS THE ORIGIN OF THE TERM, NEUROLEPTIC MALIGNANT SYNDROME?

Neuroleptic malignant syndrome comes from the Greek word "neuron" meaning "nerve," the Greek word

"lepsis" meaning "seizure," the Latin word "malignus" meaning "bad disposition," the Greek word "syn"

meaning "together," and the Greek word "dromos" meaning "course." Put the words together and you have

"nerve seizure (and) bad disposition (that) course together."