10/15/2015

Neuroleptic Malignant Syndrome: Practice Essentials, Background,

Pathophysiology

Neuroleptic Malignant Syndrome

Author: Theodore I Benzer, MD, PhD Chief Editor: Asim Tarabar, MD
more... Updated: Feb 12, 2015

Practice Essentials
Neuroleptic malignant syndrome (NMS) is a rare, but lifethreatening, idiosyncratic
reaction to neuroleptic medications that is characterized by fever, muscular
rigidity, altered mental status, and autonomic dysfunction. NMS often occurs
shortly after the initiation of neuroleptic treatment, or after dose increases.

Signs and symptoms

The key to diagnosis is that NMS occurs only after exposure to an neuroleptic
drug. On average, onset is 414 days after the start of therapy 90% of cases occur
within
10 days. However, NMS can occur years into therapy. Once the syndrome starts,
it usually evolves over 2472 hours.
Cardinal features are as follows:
Severe muscular rigidity
Hyperthermia (temperature
>38C) Autonomic instability
Changes in the level of consciousness
A summary of the clinical features of neuroleptic malignant syndrome includes
the following:
Muscular rigidity (typically, lead pipe
rigidity) Hyperthermia (temperature >38C)
Diaphoresis
Pallor
Dysphagia
Dyspnea
Tremor
Incontinence
Shuffling gait
Psychomotor agitation
Delirium progressing to lethargy, stupor, coma
Other general examination findings indicative of autonomic dysregulation
include the following:
Diaphoresis
Sialorrhea
Tachycardia
Tachypnea, respiratory distress (31% of
cases) Increased or labile blood pressure
Hypoxemia (low pulse oximeter
reading) See Clinical Presentation for more
detail. Diagnosis
No laboratory test result is diagnostic for NMS. Laboratory studies are used to
assess severity and complications or rule out other diagnostic possibilities. A
summary of the laboratory abnormalities that may be found in neuroleptic
malignant syndrome includes the following:
Increased LDH
Increased creatine kinase (50100% of cases)
Increased AST and ALT
Increased alkaline
phosphatase Hyperuricemia
Hyperphosphatemia
Hyperkalemia
Myoglobinemia
Leukocytosis (7098% of cases)
Thrombocytosis
Proteinuria
Decreased serum iron
[1]
Increased CSF
protein Hypocalcemia
Myoglobinuria
Metabolic acidosis
See Workup for more detail.

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Management
Treatment of NMS is mainly supportive it is directed toward controlling the rigidity
and hyperthermia and preventing complications (eg, respiratory failure,
rhabdomyolysis, renal failure). The value of other interventions, such as
dantrolene, amantadine, bromocriptine, and electroconvulsive therapy, is
uncertain. [2] Monitoring and management in an ICU is recommended.
What deters female physicians from
The most important
becoming leaders?
intervention is to discontinue
all neuroleptic agents. In
V iew our 2015 Wom en as P hysician Leaders
most cases, symptoms will
report t o f ind out >
resolve in 12 weeks.
Episodes precipitated by
longacting depot injections
of neuroleptics can last as long as a month.
See Treatment and Medication for more detail.

Background
Neuroleptic malignant syndrome (NMS) is a rare, but lifethreatening, idiosyncratic
reaction to neuroleptic medications that is characterized by fever, muscular rigidity,
altered mental status, and autonomic dysfunction. The syndrome was first
described by Delay and colleagues in 1960, in patients treated with highpotency
antipsychotics. [3]
Neuroleptic drugs are primarily used to treat schizophrenia and other psychotic
states. Traditional agents (eg, chlorpromazine, haloperidol) act through inhibition of
dopaminergic receptors, whereas the secondgeneration (atypical) agents work by
causing blockade of serotonin receptors. These agents also have dopamineblocking
properties, though not as potent as those of the traditional agents, and while they
are not classified accurately as neuroleptics they can cause NMS. Atypical
antipsychotic drugs that may cause NMS include the following:
Olanzapine
Risperidone
Paliperidone
Aripiprazole
Ziprasidone
Amisulpride
Quetiapine
The secondgeneration antipsychotic agent clozapine may also be associated with
the development of NMS. However, it appears to be less likely to produce
extrapyramidal features, including rigidity and tremor.[4]
In general, over the past 30 years, NMS has been associated with a variety of
drugs that lead to decreased dopamine receptor activation. [5] A drug's potential for
inducing NMS seems to parallel its antidopaminergic activity.
NMS frequently occurs shortly after the initiation of neuroleptic treatment. The
mean onset is 10 days after starting the new medication. Onset of NMS may also
follow dose increases of an established medication. No clear relationship has
been established between neuroleptic dosage and risk of developing neuroleptic
malignant syndrome, however. Of note, NMS has also been precipitated by the
abrupt withdrawal of antiParkinson medication, which effectively decreases the
domaminergic activity of the brain.
While some clear risk factors for NMS have been identified, the low incidence of
this syndrome and the consequent difficulty in studying it in a controlled,
prospective manner make clinical features, predisposing conditions, treatment, and
prognosis difficult to define. Successful treatment requires prompt recognition,
withdrawal of neuroleptic agent, exclusion of other medical conditions, aggressive
supportive care, and administration of certain pharmacotherapies (see Treatment
and Medication).
See Neuroleptic Agent Toxicity for discussion of the range of adverse effects
seen with therapeutic doses and overdoses of these drugs.

Pathophysiology
The most widely accepted mechanism by which antipsychotics cause neuroleptic
malignant syndrome is that of dopamine D2 receptor antagonism. In this model,
central D2 receptor blockade in the hypothalamus, nigrostriatal pathways, and
spinal cord leads to increased muscle rigidity and tremor via extrapyramidal
pathways.
Hypothalamic D2 receptor blockade results in an elevated temperature set point
and impairment of heatdissipating mechanisms (eg, cutaneous vasodilation,
sweating), while nigrostriatal blockade results in muscular rigidity. Peripherally,
antipsychotics lead to increased calcium release from the sarcoplasmic reticulum,
resulting in increased contractility, which can contribute to hyperthermia, rigidity,
and muscle
cell breakdown.

Beyond these direct effects, D2 receptor blockade might cause neuroleptic

malignant syndrome by removing tonic inhibition from the sympathetic nervous
system. [6, 7] The resulting sympathoadrenal hyperactivity and dysregulation leads
to

autonomic dysfunction. This model suggests that patients with baseline high levels
of sympathoadrenal activity might be at increased risk. While that has not been
proven in controlled studies, several such states have been proposed as risk
factors for neuroleptic malignant syndrome.[8]
Direct muscle toxicity also has been proposed as a mechanism of
neuroleptic malignant syndrome.

Etiology
All classes of antipsychotics have been associated with neuroleptic malignant
syndrome, including lowpotency neuroleptics, highpotency neuroleptics, and the
newer (or atypical) antipsychotics. Neuroleptic malignant syndrome has been
reported most frequently in patients taking haloperidol and chlorpromazine.
Lithium at toxic levels may also reportedly cause neuroleptic malignant syndrome.
[9]

The clearest risk factors for neuroleptic malignant syndrome relate to the
time course of therapy. Strongly associated factors are as follows[10] :
Highpotency neuroleptic use
Highdose neuroleptic use
Rapid increase in neuroleptic dose
Depot injectable (longacting) neuroleptic use (ie, fluphenazine decanoate,
fluphenazine enanthate, haloperidol decanoate, risperdal consta)
Prior episodes of neuroleptic malignant syndrome
Recent episode of catatonia [11]
A number of demographic features have been implicated, including male sex (2:1
ratio) and age younger than 40 years. However, those features may simply
indicate the higher usage of potent neuroleptics in this population.
Other potential risk factors include the following:
Dehydration [12]
Agitation [12]
Exhaustion
Malnutrition
Organic brain syndromes
Nonschizophrenic mental illness
Lithium use
Past history of electroconvulsive
therapy Warm and humid environments
Inconsistent use of neuroleptics
Postpartum period [13]
Genetic factors also might play a role. Case reports have been published on
neuroleptic malignant syndrome occurring in identical twins as well as in a
mother and two of her daughters. [14]
In patients who have experienced an episode of neuroleptic malignant syndrome,
the risk of recurrence is strongly related to the elapsed time between the episode
and restarting antipsychotics.[43] Delaying reintroduction of antipsychotic medication
until at least 2 weeks after the resolution of symptoms is typically recommended.
[45]

The majority of patients who develop neuroleptic malignant syndrome will be able to
tolerate an antipsychotic at some point in the future. [43, 44] Given the potentially life
threatening nature of neuroleptic malignant syndrome, reintroduction of
antipsychotic treatment must be approached cautiously. The risk of recurrence
may be reduced by switching to a different antipsychotic class and, if possible,
using an atypical antipsychotic rather than a traditional agent.

Epidemiology
In the United States, neuroleptic malignant syndrome has been variably reported as
occurring in 0.072.2% of patients taking neuroleptics. [15] Data largely come from
case control studies rather than prospective randomized trials. Because of
increased awareness of this syndrome and efforts at prevention, the incidence is
probably
lower now than in the past. [16]
The frequency of neuroleptic malignant syndrome internationally parallels the use
of antipsychotics, especially neuroleptics, in a given region. No data suggest
geographic or racial variation. The one large randomized trial conducted in China
showed an incidence of 0.12% in patients taking neuroleptics. [17] A retrospective
study conducted in India showed an incidence of 0.14%. [18]
Onset of neuroleptic malignant syndrome ranges from 144 days after initiation of
neuroleptic drug therapy mean onset is 10 days. Lazarus et al reported neuroleptic
malignant syndrome occurring in 67% of patients within 1 week and 96% of
patients within 30 days following administration of neuroleptics. [19, 20]

Sex and agerelated variations in incidence

Neuroleptic malignant syndrome has been reported to be more common in
males, although that most likely reflects greater neuroleptic usage rather than
greater susceptibility. The maletofemale ratio is 2:1.

The reported mean age of patients experiencing neuroleptic malignant syndrome is

40 years, but the syndrome may occur in patients of any age who are receiving
neuroleptics or other precipitating medications. [20] Differential incidence simply
might reflect a population that has a high rate of antipsychotic usage. Some
small
case series suggest that onset in elderly patients might occur after a longer
duration of antipsychotic use.
Although NMS is rare in children, studies suggest that clinicians should maintain a
high level of suspicion in children. Symptoms of NMS in children are consistent
with those described in adults. [21]

Prognosis
The prognosis in patients with neuroleptic malignant syndrome depends on how
promptly treatment is instituted and on the presence of associated complications.
In the absence of rhabdomyolysis, renal failure, or aspiration pneumonia, and with
good supportive care, the prognosis for recovery is good.
In patients who develop neuroleptic malignant syndrome after taking an oral agent,
the syndrome may last 710 days after discontinuation of the drug. In those who
have received depot neuroleptics (eg, fluphenazine), the syndrome may last up to
a month.
The mortality rate in patients with neuroleptic malignant syndrome, once reported at
2030%, is now estimated at 511.6%. The mortality rate rises to about 50% if
neuroleptic malignant syndrome is complicated by renal failure.
Patients who have previously experienced episodes of neuroleptic malignant
syndrome are at risk for recurrences, especially if antipsychotics are restarted
shortly afterward. However, the majority of these patients will be able to tolerate
another antipsychotic, which is very important because most patients taking
neuroleptics require them to maintain a reasonable functional status.

Complications
Complications of neuroleptic malignant syndrome include dehydration from poor
oral intake, acute renal failure from rhabdomyolysis, and deep venous thrombosis
and pulmonary embolism from rigidity and immobilization.
Avoiding antipsychotics can cause complications related to uncontrolled
psychosis. Most patients taking antipsychotic medicines are being treated for a
severe and persistent psychiatric disorder a high likelihood exists that a patient
will relapse while off antipsychotics.
A summary of the potential complications of neuroleptic malignant
syndrome includes the following:
Rhabdomyolysis
Renal failure
Cardiovascular arrhythmias and collapse
Aspiration pneumonia
Respiratory failure
Seizure
Pulmonary embolism and deep venous thrombosis
(DVT) Hepatic failure
Disseminated intravascular coagulation (DIC)
Decompensation of psychiatric disease following the withdrawal
of neuroleptics

Mortality/morbidity
Mortality from neuroleptic malignant syndrome is very difficult to quantify, because
the literature on this subject consists largely of case reports and because the
diagnostic parameters used have been inconsistent. In some series, mortality
rates as high as 76% have been reported. Most series suggest, however, that the
mortality rate is 1020%. When reporting bias is factored in, the true rate of
mortality from neuroleptic malignant syndrome might be much lower.
Studies have also found that the mortality rate has been decreasing over the past
2 decades. Currently, the mortality rate is estimated at 511.6%. Mortality is caused
by one or more complications (eg, respiratory failure, cardiovascular collapse, renal
failure, arrhythmias, thromboembolism, DIC). [22] Renal failure is associated with a
50% mortality rate.
No consistent longterm physical, neurological, cognitive, or laboratory sequelae
have been attributed to neuroleptic malignant syndrome alone, although
sequelae may result from such secondary complications as prolonged hypoxia or
ischemic encephalopathy. Researchers have noted sporadic cases of prolonged
rigidity and longterm neuropsychological deficits.

Patient Education
When prescribing neuroleptic medications, clinicians should explain and educate
the patient and caretakers about possible adverse effects of the medications. After
an episode of neuroleptic malignant syndrome, educational approaches can help
patients and their relatives to understand what has happened to the patient, why

the neuroleptic malignant syndrome has developed in the past, and the possibility
of recurrence if antipsychotic therapy is restarted.
This education may help patients and their relatives to decide about giving consent
to restart antipsychotics. If they give consent, they have to be aware of the early
signs of neuroleptic malignant syndrome (eg, rigidity, hyperthermia, and changes
of consciousness) and the importance of immediately seeking medical care if
these arise.
For patient education information, see Neuroleptic Malignant Syndrome. Helpful
Web sites for patients include the following:
Neuroleptic Malignant Syndrome Information Service
NINDS Neuroleptic Malignant Syndrome Information Page (National
Institute of Neurological Disorders and Stroke)
Clinical Presentation

Contributor Information and Disclosures

Author
Theodore I Benzer, MD, PhD Assistant Professor in Medicine, Harvard Medical School Director of the
ED Observation Unit, Director of Toxicology, Chair of Quality and Safety, Department of Emergency
Medicine, Massachusetts General Hospital
Theodore I Benzer, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American
College of Emergency Physicians
Disclosure: Nothing to
disclose. Coauthor(s)
Mary C Mancini, MD, PhD, MMM Professor and Chief of Cardiothoracic Surgery, Department of
Surgery, Louisiana State University School of Medicine in Shreveport
Mary C Mancini, MD, PhD, MMM is a member of the following medical societies: American Association for
Thoracic Surgery, American College of Surgeons, American Surgical Association, Society of Thoracic
Surgeons, Phi Beta Kappa
Disclosure: Nothing to
disclose. Chief Editor
Asim Tarabar, MD Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale
University School of Medicine Consulting Staff, Department of Emergency Medicine, YaleNew Haven Hospital
Disclosure: Nothing to
disclose. Acknowledgements
Iqbal Ahmed, MBBS, FRCPsych (UK) Faculty, Department of Psychiatry, Tripler Army Medical Center
Clinical Professor of Psychiatry, Uniformed Services University of the Health Sciences Clinical Professor of
Psychiatry, Clinical Professor of Geriatric Medicine, University of Hawaii, John A Burns School of Medicine
Iqbal Ahmed, MBBS, FRCPsych (UK) is a member of the following medical societies: Academy of
Psychosomatic Medicine, American Association for Geriatric Psychiatry, American Neuropsychiatric
Association, American Psychiatric Association, American Society of Clinical Psychopharmacology, and Royal
College of Psychiatrists
Disclosure: Nothing to disclose.
Michael J Burns, MD Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth
Israel Deaconess Medical Center
Michael J Burns, MD is a member of the following medical societies: American Academy of Clinical Toxicology,
American College of Emergency Physicians, American College of Medical Toxicology, and Society for
Academic Emergency Medicine
Disclosure: Nothing to disclose.
G Patricia Cantwell, MD, FCCM Professor of Clinical Pediatrics, Chief, Division of Pediatric Critical Care
Medicine, University of Miami, Leonard M Miller School of Medicine Medical Director, Palliative Care Team,
Director, Pediatric Critical Care Transport, Holtz Children's Hospital, Jackson Memorial Medical Center Medical
Manager, FEMA, Urban Search and Rescue, South Florida, Task Force 2 Pediatric Medical Director, Tilli Kids
Pediatric Initiative, Division of Hospice Care Southeast Florida, Inc
G Patricia Cantwell, MD, FCCM is a member of the following medical societies: American Academy of
Hospice and Palliative Medicine, American Academy of Pediatrics, American Heart Association, American
Trauma Society, National Association of EMS Physicians, Society of Critical Care Medicine, and Wilderness
Medical Society
Disclosure: Nothing to disclose.
Timothy E Corden, MD Associate Professor of Pediatrics, CoDirector, Policy Core, Injury Research
Center, Medical College of Wisconsin Associate Director, PICU, Children's Hospital of Wisconsin
Timothy E Corden, MD is a member of the following medical societies: American Academy of Pediatrics, Phi
Beta Kappa, Society of Critical Care Medicine, and Wisconsin Medical Society
Disclosure: Nothing to disclose.
Girish G Deshpande, MD, MBBS, FAAP Associate Professor of Pediatrics, Interim Director and Division
Chief of Critical Care Medicine, Department of Pediatrics, University of Illinois College of Medicine at Peoria

Consulting Staff, Division of Critical Care Medicine, Children's Hospital of Illinois at OSF St Francis Medical
Center
Girish G Deshpande, MD, MBBS, FAAP is a member of the following medical societies: American Academy of
Pediatrics
Disclosure: Nothing to disclose.
Barry J Evans, MD Assistant Professor of Pediatrics, Temple University Medical School Director of
Pediatric Critical Care and Pulmonology, Associate Chair for Pediatric Education, Temple University
Children's Medical Center
Barry J Evans, MD is a member of the following medical societies: American Academy of Pediatrics, American
College of Chest Physicians, American Thoracic Society, and Society of Critical Care Medicine
Disclosure: Nothing to disclose.
Alan D Schmetzer, MD Professor Emeritus, Interim Chairman, Department of Psychiatry, Indiana University
School of Medicine Addiction Psychiatrist, Roudebush VA Medical Center
Alan D Schmetzer, MD is a member of the following medical societies: American Academy of Addiction
Psychiatry, American Academy of Clinical Psychiatrists, American Academy of Psychiatry and the Law,
American College of Physician Executives, American Medical Association, American Neuropsychiatric
Association,
American Psychiatric Association, and Association for Convulsive Therapy
Disclosure: Nothing to disclose.
Darius P Sholevar, MD Fellow, Cardiovascular Disease, Albert Einstein Medical Center
Disclosure: Nothing to disclose.
Mark S Slabinski, MD, FACEP, FAAEM Vice President, EMP Medical Group
Mark S Slabinski, MD, FACEP, FAAEM is a member of the following medical societies: Alpha Omega
Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, American
Medical Association, and Ohio State Medical Association
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center
College of Pharmacy EditorinChief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Joseph Tonkonogy, MD, PhD Clinical Professor of Psychiatry, University of Massachusetts Medical
School Consulting Staff, Departments of Psychiatry, University of Massachusetts Medical School
Joseph Tonkonogy, MD, PhD is a member of the following medical societies: American Academy of Neurology,
American Medical Association, American Neuropsychiatric Association, International Neuropsychological
Society, Massachusetts Medical Society, Royal Society of Medicine, Society for Neuroscience, and United
Council for Neurologic Subspecialties, Certification Behavioral Neurology and Neuropsychiatry
Disclosure: Nothing to disclose.
John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals
John T VanDeVoort, PharmD is a member of the following medical societies: American Society of
Health System Pharmacists
Disclosure: Nothing to disclose.
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of
Pharmacy EditorinChief, Medscape Drug Reference
Disclosure: Nothing to disclose.

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