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NEUROLEPTIC MALIGNANT SYNDROME –
CURRENT APPROACH TO DIAGNOSIS AND
MANAGEMENT
Cristian Mihãilescu1
Abstract:
The neuroleptic malignant syndrome (NMS) represents an
infrequent but serious condition, an idiosyncratic reaction
to a neuroleptic medication. It concerns mainly patients
under psychiatric treatment, occuring even after the
emergence of the so-called lower-risk atypical
neuroleptics. Currently, little is known about risk factors
and susceptibility for developing NMS which can
practically occur at any age and irrespective of gender and
comorbidities. NMS is feared due underdiagnosis and to
its poor prognosis, especially when left untreated when it
could lead to serious complications and fatalities. An
increased level of alertness is necessary for enabling an
earlier diagnosis, hence an earlier treatment that can
improve its prognosis.
Keywords: neuroleptic, malignant, atypical, levodopa,
pathogeny, treatment.
Rezumat:
Sindromul neuroleptic malign (SNM) reprezintã o
afecþiune rarã dar gravã, o reacþie idiosincraticã la
neuroleptice. Poate sã aparã în special la pacienþi aflaþi
sub tratament psihiatric, chiar ºi dupã apariþia
neurolepticelor atipice considerate cu risc mai redus de
SNM. În prezent, sunt puþine date cu privire la factorii de
risc ºi susceptibilitatea pentru a dezvolta SNM ce se poate
manifesta practic la orice vârstã ºi indiferent de sex ºi
comorbiditãþi. SNM este redutabil datoritã dificultãþii
diagnostice ºi prognosticului sãu nefavorabil, mai ales în
lipsa tratamentului, când poate conduce la complicaþii
severe ºi chiar deces. Este necesarã creºterea nivelului de
alertã pentru a facilita diagnosticul mai precoce, deci ºi
introducerea mai precoce a tratamentului ceea ce îi poate
ameliora prognosticul.
Cuvinte-cheie: neuroleptic, malign, atipic, levodopa,
patogenie, tratament.
atypical, are able to precipitate the syndrome
INTRODUCTION
(1,2).
Delay used this term for the first time in 1960.
According to the current conception, the neuroleptic
malignant syndrome (NMS) is a rare, but life-threatening,
idiosyncratic reaction to a neuroleptic medication. The
clinical presentation consists of fever, extrapyramidal
signs and symptoms, altered mental status and
dysautonomia.
EPIDEMIOLOGY
The frequency follows closely the rate of
antipsychotic medication use, without geographic
variations nor related to race. Prospective studies and
pooled data from the literature report an incidence of 0.070.2% (1). The awareness regarding NMS has increased,
hence probably a lower incidence now than in the past.
The incidence is higher in men, with a men to
women ratio of 2:1 (1, 2). NMS has been diagnosed in ages
ranging from 3 to 80 years, reaching a peak before 40 years
of age (the maximal incidence of neuroleptic treatment) (2,
3).
ETIOLOGY AND PATHOGENY
Originally, only the older generation, more potent
neuroleptics (eg, haloperidol, fluphenazine) were
considered to be able to trigger NMS. Recently, it was
aknowledged that all antipsychotic agents, typical and
The dopaminergic blockade hypothesis is
widely accepted nowadays since medications implicated
in NMS have dopamine D2-receptor antagonist
properties (1). Pros and cons have been formulated about
this hypothesis. Previous studies have induced catalepsy
in animals with D2-receptor antagonists. There are also
overlapping features of catatonia and NMS (4-6), the
former being recognized as a risk factor for NMS. But
most convincing for the implication of the dopaminergic
blockade in NMS is the occurence of the syndrome after
suddenly withdrawing treatment with dopamine,
dopamine agonists or Amantadine in patients suffering
from Parkinson's disease and the reversal after the
reintroduction of such medication.
The clinical syndrome is thought to be
secondary to decreased dopamine activity in the central
nervous system (CNS), as a result of dopamine D2receptors antagonism or of decreased dopamine
availability. Blockade of dopamine neurotransmission in
the striatum results in muscular rigidity which leads to
pyrexia. At the level of the hypothalamus, the blockade
results in altered thermoregulation and reduction of heat
dissipation, by interference with the normal role of
dopamine as an inhibitor of heat production, process
stimulated by serotonin. Blockade at several other levels
within CNS (mesocortex, basal ganglia, spinal cord) has
been implicated in the occurence of mental status
alterations and autonomic disturbancies noted in NMS.
11
Internal Medicine, Senior M.D., Psychiatry Clinical Hospital ”Prof. Dr. Alexandru Obregia”, Integrated Outpatient Clinic, Berceni Road No.10-12,
sector 4, Bucharest, Romania, Email: [email protected]
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Cristian Mihãilescu: Neuroleptic Malignant Syndrome – Current Approach To Diagnosis And Management
The peripheral effects include a direct myotoxic
effect resulting in an increase of calcium release from the
sarcoplasmic reticulum (7), contributing to the increased
contractility and to hyperthermia. Dopamine is also
known to directly inhibit the skeletal muscle contraction,
the dopaminergic blockade resulting in the opposite
effect.
There are several facts speaking against a single
pathogenic hypothesis in NMS. Among these, the fact that
NMS occurs after Clozapine (no D2-blocking properties)
(8) or after non-neuroleptic medications. Furthermore
NMS can have heterogeneous presentations, atypical
NMS not including development of rigidity nor fever (1).
One particular aspect involves the atypical neuroleptics,
associated with a lower risk of NMS. They display less
dopaminergic antagonism, reflected in the lower rate of
extrapyramidal side effects than the conventional
antipsychotics. Even so, their administration doesn't seem
to entirely eliminate the risk of NMS (9-15).
It has also been claimed that the sympathetic
nervous system activation or dysfunction may be involved
significantly in the pathogenesis of NMS (1, 16).
Normally, the sympathetic nervous system coordinates
thermoregulation and represents the main regulator of
muscular contraction and thermogenesis. The
sympatoadrenal hyperactivity observed on NMS can also
be accounted for by the dopaminergic blockade which
leads to a reduction in the tonic inhibition of the
sympathetic nervous system (16).
Other hypotheses for the pathogenesis of NMS
include GABA hypoactivity at the level of the GABAA
receptor, also based on a similarity with catatonia and on
the benefit of benzodiazepines in NMS, increased
serotoninergic activity at the 5-HT1A receptors and
decreased at the 5-HT2A receptors (17, 18) and
glutamatergic hypoactivity at the NMDA receptors (19). A
low level of serum iron has been reported as a risk factor
for NMS (20), predicting the conversion of malignant
catatonia to NMS (21). Furthermore, anomalies of the
muscle membrane (7, 22) have been described as a
possible substrate for the peripheral manifestations of
NMS.
The most important risk factor for the
development of NMS is represented by the treatment with
typical neuroleptics (e.g. haloperidol, chlorpromazine,
fluphenazine, levomepromazine) but also, even to a lesser
degree, the atypical neuroleptics (e.g. clozapine,
quetiapine, olanzapine, aripiprazole risperidone,
perospirone, zuclopenthixol) (9-15, 23). Development of
NMS was observed even with the use of non-neuroleptic
drugs like metoclopramide, amoxapine, lithium and some
antidepressants which can block central dopaminergic
pathways. Approximately 17% of NMS cases develop
within 25 hours from the start of antipsychotic treatment,
66% within the first week and almost all cases within 30
days (1). The risk remains high even in the first 22 days
after withdrawal of the causing drug (1) and was not
associated with the serum level of the drug which was
considered therapeutic (3). There is still uncertainty
surrounding the association of NMS with a recent increase
in dosage, high dosages, the duration of exposure and the
type of neuroleptic (long-acting versus short-acting) (3).
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A genetic predisposition was observed (1) in homozygots
for mutations of the citochrome P4502D.
Further risk factors are male gender (NMS is
twice as frequent in men), dehydration (7), concomitant
medication, exposure to cocaine, possible concomitant
illnesses and/or debilitated state, hyponatremia, stress,
malnutrition, cerebral trauma and organic disorders (3). In
our experience, alcohol withdrawal may also be a
contributing factor to development of NMS. There is still
controversy regarding the impact of high environmental
temperature and humidity as risk factors for NMS (20).
DIAGNOSIS
Symptoms usually set in insidiously over days,
although occasional fulminant onsets have been reported
(20). The clinical presentation includes hyperthermia,
extrapyramidal effects and signs of autonomic
dysfunction.
The diagnosis of NMS is difficult because
manifestations are very nonspecific, and is only made by
corroborating history, clinical criteria and laboratory
findings together with a thorough differential diagnosis. A
multispeciality team approach, including a careful
neurological and psychiatric examination, is usually
needed,
Relevant to diagnosis is a history of neuroleptic
treatment, in the last 1 to 4 weeks for oral agents and 2 to 4
weeks for long-acting, depot agents. Physical
examination reveals generalised lead-pipe muscular
rigidity and pyrexia (usually above 38C, in the absence of
another known cause). Also, more than 5 of the following
features have to be fulfilled for making the diagnosis of
NMS: alterations of the mental status, tachycardia,
hypertension or hypotension, tachypnea or hypoxia,
diaphoresis and sialorrhea, tremor, incontinence,
increased levels of creatine-kinase or myoglobinuria,
leukocytosis and metabolic acidosis (1, 2, 3).
NMS with atypical presentations have also to be
taken into account. Muscular rigidity and hyperthermia
are not always present at onset and may set in later or not at
all (1, 2).
Other associated signs and symptoms and
laboratory findings (including those from
electromyography, electroencephalography, cerebral
computed tomography, muscular biopsy) may be helpful
especially with the differential diagnosis but do not
contribute significantly to the diagnosis of NMS (3).
DIFFERENTIAL DIAGNOSIS
A detailed presentation of the differential
diagnosis in NMS is beyond the scope of this article. A list
of possible differential diagnoses can be found in table 1.
The most common causes of NMS-like
symptoms, and thus most frequently needing
differentiation from NMS are: Parkinson's disease,
meningitis, encephalitis, delirium, depression / mania
with catatonic features, catatonic schizophrenia /
psychosis, serotonin syndrome, drug-induced
extrapyramidal reactions, anticholinergic poisoning, heat
stroke.
Romanian Journal of Psychiatry, vol. XII, No.3, 2010
Neuromuscular
Parkinson's disease
Meningitis
Encephalitis (especially acute viral)
Multiple system atrophy (Shy-D rager syndrome)
Epilepsy and status epilepticus
Stroke
Space-occupying lesions, including CNS neoplasm
Cerebral vasculitis
Malignant hyperthermia
Severe dystonia
Stroke
Metabolic
Hyperthyroidism (thyrotoxicosis)
Hypocalcemia
Hypomagnesemia
Pheochromocytoma
Infectious
Rabies
Sepsis
Tetanus
Botulism
Psychiatric
Delirium
Depression / mania with catatonic features
Catatonic schizophrenia / psychosis
Lethal catatonia
Toxic exposures
Heat stroke
Amphetamines
Anticholinergic agents
Cocaine
Excess serotonin (serotonin syndrome)
Extrapyramidal drug reactions
Monoamine oxidase inhibitors
Salicylates (Aspirin overdose)
Heavy metal poisoning (e.g. lead, arsenic)
Strychnine
Side-effects associated with atypical antipsychotics
Rapid withdrawal of dopaminergic medications (e.g.,
L-dopa)
Dopamine depleting medications (e.g., reserpine,
tetrabenazine)
Lithium toxicity
Allergic drug reactions
Phencyclidine intoxication
Alcohol / sedative (benzodiazepine, barbiturate)
withdrawal
Strychnine poisoning
Miscellaneous
Acute intermittent porphyria
Systemic lupus erythematosus
Table 1. Differential diagnosis of NMS.
TREATMENT
NMS represents a medical emergency where
time to diagnosis and treatment is of the essence. In order
to achieve these goals, due to the complexity and severity
of manifestations, NMS requires a multidisciplinary
approach. The proposed medical treatment of the
syndrome is: elimination of neuroleptic treatment, general
measures as supportive therapy and pathogenic, specific
treatment.
Initially, general measures address the lowering
of body temperature in order to fight hyperthermia. In case
of rhabdomyolysis, special attention must be paid to
hydration (7), urine alkalinization and correction of
electrolytic disorders. In some cases with life-threatening
hiperkalemia, acidosis, uremic encephalopathy and fluid
overload, dialysis may become an option even if it would
not influence the serum levels of myoglobin. Other
measures may include circulatory support consisting of an
adequate hydration, cardiac monitoring and even
hemodynamic support, sometimes intubation with
ventilation and venous thromboembolism prophylaxis
with heparins.
Controversies remain with regard to the efficacy
and value of particular specific NMS treatments. This is
due to the fact that NMS is a fairly rare, life-threatening
condition and difficult to diagnose due to its well-known
mimicry. All these features didn't allow the conduct of
double-blind or placebo-controlled clinical trials in order
to identify the most appropriate treatment. As a result,
current practice is based on case-studies and no treatment
protocol exist so far. The main drugs used in NMS are the
dopaminergic medication, benzodiazepines, Amantadine
and peripheral myorelaxants. The indicated doses may
vary significantly from one case to another, therefore they
are adapted and personalized for each particular case.
There is no proof that combinations of drugs are
associated with an increased efficacy, therefore they
cannot be routinely recommended.
Another challenge in NMS treatment is the route
of administration since the use of the usual oral products is
limited by trismus and the general condition of the
patients. Especially in the acute phases, the parenteral
route is advisable or the use of dispersible formulations
that can be readily administered orally.
The use of dopaminergic drugs reflects the
essential role of the dopaminergic blockade in the
pathogenesis of NMS. The most widely used
dopaminergic agonists are apomorphine, bromocriptine.
Apomorphine administered subcutaneously is considered
first-line therapy, useful even as monotherapy (13).
Bromocriptine acts by the activation of the postsynaptic
dopaminergic D2 receptors, thus increasing the
production of dopamine and contributing mainly to the
improvement of an altered mental status and of rigidity. It
may be associated with side effects like hypotension,
nausea, psychosis. It is administered with caution in renal
and liver diseases and it's contraindicated in ischemic
heart disease and peripheral arterial disease.
Levodopa is usually administered in
combination with carbidopa or benserazide. There is
recent information and is also our experience that a
levodopa-based treatment may be effective as a first-line
treatment in NMS, irrespective of the severity of
presentation, by addressing most of the NMS features.
There have also been reports concerning the
presence of active glucocorticoid receptors within the
ventral tegmental area and substantia nigra.
Glucocorticoid medication can benefit NMS patients
through an increase of the dopaminergic activity but also
through their well-known lysosome membrane
stabilization effect (24).
Benzodiazepines are supposed to act through
potentiation of the GABAergic activity and by indirectly
increasing the dopaminergic activity through their actions
at the level of basal ganglia and substantia nigra (26).
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Cristian Mihãilescu: Neuroleptic Malignant Syndrome – Current Approach To Diagnosis And Management
They don't have a preventative effect (20, 26) but their use,
mainly parenterally but also orally, reduces rigidity,
improves the mental status and reduces psychomotor
agitation. Dysautonomia, including diaphoresis, and
pyrexia are not influenced by their use.
Amantadine mainly reduces hyperthermia and
acts as an antagonist of the NMDA receptor and is thought
to facilitate dopamine release from intact dopaminergic
terminals, increasing dopamine concentration at
dopaminergic terminals.
Peripheral myorelaxants are mainly used to
correct the increased muscle tone and hyperthermia.
Dantrolene sodium is supposed to bind and shut down the
ryanodine receptors within the sarcoplasmic reticulum,
thereby decreasing the calcium release (3). In the acute
phase it should be administered intravenously, then orally.
It can be associated with liver toxicity, therefore it's
contraindicated in advanced liver disease,
photosensitivity. Caution is warranted in heart failure and
pulmonary conditions. It's value has been challenged with
regard to its real therapeutic value and safety (1,25). Other
intravenous myorelaxants have been proposed and used in
the treatment of NMS (pancuronium, rocuronium,
mivacurium).
Electroconvulsive therapy (ECT) represents an
alternative in cases where the medications detailed above
failed, in severe NMS with a high risk of complications,
when NMS is manifested mainly through or cannot be
differentiated from catatonic syndrome, in case of
persistent residual catatonia and parkinsonism after
resolution of the acute metabolic symptoms of NMS (1) or
in patients with high risk of relapse after the reintroduction
of neuroleptics (27). ECT influences favorably
hyperthermia, diaphoresis, mental status, conscioussness
and the underlying psychiatric pathology when patients
can no longer take neuroleptics but has no impact on
delirium and should not be used in clinically unstable
patients and with high risk of cardiac arrest or ventricular
fibrillation (27).
After treating NMS, especially in patients that
need ongoing neuroleptic treatment, secondary
prophylaxis measures become essential. Firstly, these
patients have to be informed that they will continue to
have an increased risk of NMS recurrence. When possible
neuroleptics have to be avoided or, in cases where reexposure to neuroleptics is deemed necessary, it would be
better to avoid depot neuroleptics and use a class of
neuroleptics different from that of the causing drug. The
new neuroleptic has to be started approximately 2 weeks
after the NMS resolution (3,20), with the lowest possible
dose and with subsequent slow gradual uptitrating, under
close monitoring and avoiding dehydration.
EVOLUTION
The complications associated with NMS are
usually severe and unpredictable and are the ones
responsible for its poor prognosis (see table 2).
Rhabdomyolysis can induce hydroelectrolytic disorders
like hyperkalemia, hyperphosphatemia and hypocalcemia
and can contribute to the occurence of acute renal failure.
The development of acute renal failure represents a factor
of poor prognosis, being associated with a 50% mortality
rate (1). Acute respiratory failure can be explained by
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pulmonary embolism, aspiration pneumonia,
acute pulmonary edema or the occurence of acute
respiratory distress syndrome. (1, 3).
Rhabd omyolysis
Acu te renal failure
Acu te resp iratory failure
Myo cardial in farction
Brain lesio ns
Seizu res
Hep atic failure
Disseminated intrav ascular coagulatio n
Escherichia coli fasciitis
Sep sis
Table 2. The most frequent complications of NMS
Other possible complications have been
reported: gastrointestinal bleeding as a consequence of
commonly accepted medical treatments (especially the
use of cyclooxygenase inhibitors as antipyretic agents)
and NMS-induced changes in blood coagulation status
(28), diffuse intravascular coagulation, lactic acidosis,
arrhythmias, cardiac arrest, liver failure, muscular and
peripheral nerves lesions. Also, the psychiatric illnesses
treated with neuroleptics may decompensate after their
withdrawal.
The development of NMS complications
adversely impact the evolution and prognosis. Thus, they
need special attention and a case-by-case approach to
treatment.
In case of an early diagnosis and treatment and in
the absence of complications, NMS prognosis is good, the
duration of NMS being approximately 7-10 days after the
withdrawal of oral neuroleptics and up to 22 days for
depot neuroleptics (1). There have been cases reported
where amnesia, permanent parkinsonism, ataxia or even
dementia remain after NMS (29, 30).
Mortality, historically as high as 22-30%, is now
estimated at 5-11,6% (1) possibly due to an increased
awareness, earlier diagnosis and treatment. The occurence
of acute renal failure increase the mortality rate to 50%
(1). Events leading to death are usually respiratory,
cardiovascular or acute renal failure, arrhythmias or
diffuse intravascular coagulation.
CONCLUSION
NMS is an infrequent but severe condition that
may lead to life-threatening complications. Its nonspecific and heterogeneous presentation explains why it
remains a diagnostic and therapeutic challenge. The
increased awareness can play a major role in the strategy
where an earlier diagnosis and treatment might improve
the poor prognosis in NMS.
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