3. Neuroleptic malignant
syndrome.
• Neuroleptic malignant syndrome (NMS) is a life-
threatening neurologic emergency associated with the
use of antipsychotic (neuroleptic) agents and
characterized by a distinctive clinical syndrome of mental
status change, rigidity, fever, and dysautonomia.
4. INTRODUCTION
• Incidence rates for NMS range from 0.02
to 3 percent among patients taking
antipsychotic agents
• Additionally, young males are particularly
susceptible and the male : female ratio has
been reported to be as high as 2:1
5. 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.
8. Neuroleptic and Nonneuroleptic Medications Associated With Neuroleptic Malignant
Syndrome
A. Neuroleptics B. Nonneuroleptics with antidopaminergic activity
(1) Typical
a. Haloperidol (1) Metoclopramide
b. Fluphenazine (2) Tetrabenazine
c. Chlorpromazine (3) Reserpine
d. Prochlorperazine (4) Droperidol
e. Trifluoperazine (5) Promethazine
f. Thioridazine (6) Amoxapine
g. Thiothixene (7) Diatrizoate
h. Loxapine C. Dopaminergics (withdrawal)
i. Perphenazine
j. Bromperidol (1) Levodopa
k. Clopenthixol (2) Dopamine agonists
l. Promazine (3) Amantadine
(2) Atypical (4) Tolcapone
a. Clozapine D. Others
b. Risperidone (1) Lithium
c. Olanzapine (2) Phenelzine
d. Quetiapine (3) Dosulepin
e. Ziprasidone (4) Desipramine
f. Aripiprazole (5) Trimipramine
9. •Pathophysiology:
• The mechanism is commonly thought to depend on decreased
levels of dopamine activity due to:
• Dopamine receptor blockade
• Genetically reduced function of dopamine receptor D2
• 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.
10. • Another system that also appears to play a role in the signs
and symptoms of NMS is the peripheral skeletal muscle
system. Release of calcium has been shown to be increased
from the sarcoplasmic reticulum of muscle cells with
antipsychotic usage, possibly leading to increased muscle
contractility and rigidity, breakdown of muscle, and
hyperthermia. To date, however, none of the theories put
forth as the underlying cause of NMS have been able to
explain why only a small fraction of patients exposed to
neuroleptics develop the condition. Furthermore, it remains
unknown why patients who develop NMS are usually able to
continue being treated with similar medications and, at times,
even the same offending agent
11. Mechanism of action of First
generation Antipsychotic
drugs:
• The mechanism of action of all first-generation
antipsychotics (FGAs) appears to be postsynaptic
blockade of brain dopamine D2 receptors. Evidence
supporting this mechanism includes strong antagonism
of D2 receptors in both cortical and striatal areas .
12. Mechanism of action of 2nd
generation Anti psychotic
drugs:
• The mechanism of action of second-generation
antipsychotics SGAs) appears to be postsynaptic
blockade of brain dopamine D2 receptors.
• They also block 5HT2 recepotors.
15. • CLINICAL MANIFESTATIONS: NMS is defined by its association with a class of
medications that block dopamine transmission and a tetrad of distinctive clinical
features: fever, rigidity, mental status changes, and autonomic instability .
Typical symptoms — The tetrad of NMS symptoms typically evolves over one to
three days. Each feature is present in 97 to 100 percent of patients:
●Mental status change is the initial symptom in 82 percent of patients [40]. It is not
surprising, given the usual psychiatric comorbidity of the typical patient, that its
significance is often underappreciated. This often takes the form of an agitated
delirium with confusion rather than psychosis. Catatonic signs and mutism can be
prominent. Evolution to profound encephalopathy with stupor and eventual coma
is typical
●Muscular rigidity is generalized and is often extreme. The increased tone can be
demonstrated by moving the extremities and is characterized by "lead-pipe
rigidity" or stable resistance through all ranges of movement. Superimposed
tremor may lead to a ratcheting quality or a cogwheel phenomenon. Other motor
abnormalities include tremor (seen in 45 to 92 percent), and less commonly,
dystonia, opisthotonus, trismus, chorea, and other dyskinesias. Patients can also
have prominent sialorrhea, dysarthria, and dysphagia.
●Hyperthermia is a defining symptom according to many diagnostic criteria.
Temperatures of more than 38°C are typical (87 percent), but even higher
temperatures, greater than 40°C, are common (40 percent) [5]. Fever may be a less
consistent symptom in patients with NMS associated with second-generation
antipsychotic agents .
●Autonomic instability typically takes the form of tachycardia (in 88 percent), labile
or high blood pressure (in 61 to 77 percent), and tachypnea (in 73 percent)
Dysrhythmias may occur. Diaphoresis is often profuse.
16. LABORATORY ABNORMALITIES
• Characteristic laboratory findings seen in NMS include elevated
creatinine phosphokinase (CPK) due to rhabdomyolysis and
leukocytosis, but these are neither specific for the syndrome nor
present in all cases.
• When rhabdomyolysis is present, it can be severe enough to cause
renal failure, requiring hemodialysis.
• Additional common laboratory abnormalities include a metabolic
acidosis and iron deficiency.
• The cerebrospinal fluid (CSF) and imaging studies are usually
normal, but an electroencephalogram (EEG) may show
nongeneralized slowing
22. Other Differential Diagnosis
• CNS
INFECTIONS(Meningitis,
Encephalitis)
• Systemic infection(
Pneumonia, Sepsis)
• Heat stroke
• Tetanus
• Drug
intoxication(phencyclidin
e, Ecstasy,
cocaine,lithium).
• Methylenedioxymetham
phetamine(MDMA)
intoxication
• Thyrotoxicosis
• Withdrawal states.
23.
24.
25. • Malignant catatonia — Most problematic in the
differential diagnosis of NMS, malignant catatonia shares
clinical features of hyperthermia and rigidity with NMS.
However, in this syndrome, there is usually a behavioral
prodrome of some weeks that is characterized by
psychosis, agitation, and catatonic excitement. The motor
symptoms are also characterized by more positive
phenomena (dystonic posturing, waxy flexibility, and
stereotyped repetitive movements) than are described in
NMS
• Laboratory values are more typically normal.
• The two syndromes may overlap; many case descriptions
exist of NMS arising in patients with malignant catatonia
27. TREATMENT
• The management of patients with NMS should be based upon a hierarchy of clinical
severity and diagnostic certainty . When manifestations are severe, intensive care unit
monitoring and treatment are required
• Stop causative agent — Removal of the causative agent is the single most
important treatment in NMS. Other potential contributing psychotropic agents (lithium,
anticholinergic therapy, serotonergic agents) should also be stopped if possible. When
the precipitant is discontinuation of dopaminergic therapy, it should be reinstituted.
• Supportive care — The need for aggressive and supportive care in NMS is essential
and uncontroversial . Complications are common and severe, even fatal. These include:
●Dehydration
●Electrolyte imbalance
●Acute renal failure associated with rhabdomyolysis
●Cardiac arrhythmias, including torsades de pointes and cardiac arrest
●Myocardial infarction
●Cardiomyopathy
●Respiratory failure from chest wall rigidity, aspiration pneumonia, pulmonary embolism
●Deep venous thrombophlebitis
●Thrombocytopenia
●Disseminated intravascular coagulation
●Deep venous thrombosis
●Sepsis
28. • The intensive nature of the required monitoring and supportive treatment is such that
admission to the intensive care unit is required. The following supportive treatment should
be provided:
Discontinue any antipsychotic agent or precipitating drug.
Maintain cardiorespiratory stability. Mechanic ventilation, antiarrhythmic agents, or pacemakers
may be required
Maintain euvolemic state using intravenous fluids. Insensible fluid loss from fever and from
diaphoresis should also be considered.
If creatine kinase (CK) is very elevated, high-volume intravenous fluids with urine alkalinization
may help prevent or mitigate renal failure from rhabdomyolysis.
Lower fever using cooling blankets. More aggressive physical measures may be required: ice
water gastric lavage and ice packs in the axilla. The use of acetaminophen or aspirin may have a
role in reducing temperature in NMS, but it is not established.
Lower blood pressure if markedly elevated. The use of any specific agent over another is not
supported by clinical data. Clonidine is effective in this setting . Nitroprusside may have
advantages by also facilitating cooling through cutaneous vasodilation .
Prescribe heparin or low molecular weight heparin for prevention of deep venous thrombosis.
Use benzodiazepines (eg: lorazepam 0.5 to 1 mg) to control agitation, if necessary .
29. •Specific treatments
• Medical therapy — Medications are often used in patients with
moderate or severe clinical manifestations of NMS.
Recommendations for specific medical treatments in NMS are
based upon case reports and clinical experience, not upon data
from clinical trials. Their efficacy is unclear and disputed .
Commonly used agents are dantrolene, bromocriptine, and
amantadine. We are more likely to use these agents in more severe
cases and escalate treatment if there is no effect or the patient
worsens. A reasonable approach is to start with benzodiazepines
(lorazepam or diazepam) along with dantrolene in cases with
moderate to severe muscle rigidity with elevated CK; bromocriptine
or amantadine may also be added for patients with moderate to
severe illness
• Electroconvulsive therapy — Electroconvulsive therapy (ECT) is
generally reserved for patients not responding to other treatments
or in whom nonpharmacologic psychotropic treatment is needed.
30. PROGNOSIS
• The prognosis 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.[34] 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
31. Recurrence of NMS after
resuming Antipsychotic drugs:
• Possible risk factors for recurrent NMS are administration
of high-potency neuroleptics and reintroduction of
neuroleptics before the initial episode of NMS has
completely resolved. Bipolar disorder and concomitant
use of lithium may predispose to NMS and therefore
could also heighten the risk of recurrence.
32. Things to consider before
resuming antipsychotic drugs:
• ●Wait at least two weeks before resuming therapy, or
longer if any clinical residua exist.
• ●Use lower- rather than higher-potency agents.
• ●Start with low doses and titrate upward slowly.
• ●Avoid concomitant lithium.
• ●Avoid dehydration.
• ●Carefully monitor for symptoms of NMS.
33. SUMMARY AND
RECOMMENDATIONS
●Causes – Neuroleptic malignant syndrome (NMS) is a life-threatening neurologic emergency associated
with the use of dopamine antagonists, and less commonly with dopamine agonist withdrawal. First-generation
antipsychotic agents are most commonly implicated, but NMS can occur with any antipsychotic agent and also
with antiemetic drugs . (See 'Associated medications' above.)
●Clinical manifestations – Cardinal clinical and laboratory features include :
•Mental status change, which may take the form of an agitated or hypoactive delirium
•Muscular rigidity, which is characterized by generalized, "lead-pipe" rigidity
•Hyperthermia with temperatures typically above 38°C, sometimes higher
•Dysautonomia manifesting as tachycardia, labile blood pressure, tachypnea; arrhythmias may occur
•Elevated creatine kinase, the severity of which mirrors muscular rigidity, typically more than 1000
international units/L
34. ●Differential diagnosis – Important considerations in the differential diagnosis
include meningitis, encephalitis, systemic infections, heat stroke, and other drug-induced
dysautonomias.
●Evaluation and diagnosis – NMS is a clinical diagnosis; no laboratory test can
confirm the diagnosis. Testing is performed to rule out other conditions
•Antipsychotic agents should be withheld if there is suspicion for NMS. Patients should
have close inpatient monitoring of clinical signs and laboratory values
•Patients with significant hyperthermia and rigidity should be admitted to an intensive care
unit setting and undergo aggressive supportive care as outlined above, as well as
monitoring for potential dysautonomia and other complications.
•For patients with creatine kinase (CK) elevations or hyperthermia on presentation and
those who do not respond to withdrawal of medication and supportive care within the first
day or two, we suggest medical therapy . Benzodiazepines are typically initiated first to
mitigate agitation and/or muscle rigidity; dantrolene and/or bromocriptine may be added
depending on symptom severity.
•Electroconvulsive therapy (ECT) is an option in patients not responding to medical therapy
in the first week, those in whom residual catatonia persists after other symptoms have
resolved, and those in whom lethal catatonia is suspected as an alternative or concomitant
disorder.
●Resuming antipsychotic therapy – The risk of recurrent NMS following resumption of
antipsychotic agents is uncertain. If antipsychotic medication is required, we attempt to
minimize risk by following some general guidelines.
