Neuroleptic malignant syndrome

Neuroleptic malignant syndrome
ICD-10	G21.0
ICD-9	333.92
DiseasesDB	8968

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Jesus Rosario Hernandez, M.D. [2]

Keywords and synonyms: NMS

Overview

The neuroleptic malignant syndrome is an uncommon adverse reaction to medications with dopamine receptor-antagonist properties or the rapid withdrawal of dopaminergic medications. The syndrome is characterized by severe rigidity, fever, tremor, autonomic dysfunction, altered mental status, and elevated serum creatinine phosphokinase. This is a life-threatening condition, with difficulties in diagnosis and treatment. This syndrome can further complicates psychiatric treatment.

Historical Perspective

The first reported case of NMS appeared in 1956, shortly after the introduction of the antipsychotic drug chlorpromazine (Thorazine). Additional case reports quickly followed, and in a 1960 study French clinicians gave the syndrome its current name when they reported on the adverse effects of the newly introduced neuroleptic haloperidol and characterized a ‘‘syndrome malin des neuroleptiques.’’2 Pooled data from 1966 to 1997 suggested the incidence of NMS ranges from 0.2% to 3.2% of psychiatric inpatients receiving neuroleptics; however, as physicians have become increasingly aware of the syndrome and with the advent of new neuroleptic medications, the incidence has decreased to around 0.01% to 0,02%.

Pathophysiology

The pathophysiologic mechanisms of NMS are complex and still under debate among physicians But the majority of physicians agree that sudden and significant reduction in central dopaminergic activity within the mesolimbic/cortical, the nigrostriatal, and hypothalamic pathways help explain the clinical features of the neuroleptic malignant syndrome. This theory is supported by the observation that the use of antipsychotic drugs that specifically block D 2 receptors primarily cause NMS and that the syndrome can also be induced by abrupt dopamine withdrawal.

Additionally, this theory is supported by the dopamine receptor imaging study of NMS patients in the acute phase which demonstrated a complete lack of D2 receptor binding. Another study demonstrated low levels of dopamine metabolite in the CSF of patients with NMS in the acute phase. However D2 receptor antagonism does not explain all the presenting signs and symptoms of NMS, nor does it explain its occurrence with antipsychotic medications with lower D2 activity and medications without known antidopaminergic activity. Abnormalities in the sympathetic system are supported by the frequent presence of autonomic symptoms in NMS as well as demonstrated changes in the urine and plasma catecholamine levels in patients with NMS. Some have hypothesized that NMS shares pathophysiological similarities with malignant hyperthermia and that a defect in calcium regulatory proteins within sympathetic neurons may be the essential factor that brings about the onset of NMS. Another system that also appears to play a role in the signs and symptoms of NMS is the peripheral skeletal muscle system. The release of calcium is increased from the sarcoplasmic reticulum of muscle cells with antipsychotic usage, possibly leading to increased muscle contractility and rigidity, breakdown of muscle, and hyperthermia. However, these theories are unable to explain why only a small fraction of patients develop NMS after exposure to neuroleptics. 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.

Causes

Potent typical neuroleptics such as fluphenazine, haloperidol, trifluoperazine, chlorpromazine, and prochlorperazine confer the greatest risk for the NMS. The atypical neuroleptics appear to have reduced the risk of developing NMS compared to typical neuroleptics. But a significant number of cases have been reported with most atypical neuroleptics including clozapine, risperidone, olanzapine, quetiapine, aripiprazole, olanzapine aripiprazole, and ziprasidone. Neuroleptic malignant syndrome has also been associated with nonneuroleptic agents with antidopaminergic activity such as diatrizoate, droperidol, tetrabenazine, and metoclopramide. The rapid switching from one type of dopamine receptor agonist to another in such patients has also been associated with NMS, and there may be some risk of NMS associated with the abrupt withdrawal of Parkinson medications that are not known to have direct dopaminergic activity such as amantadine and tolcapone.

Neuroleptic and Nonneuroleptic Medications Associated With Neuroleptic Malignant Syndrome

Typical Neuroleptics	Atypical Neuroleptics	Nonneuroleptics with antidopaminergic activity	Dopaminergics (withdrawal)	Others
a. Haloperidol b. Fluphenazine c. Chlorpromazine d. Prochlorperazine e. Trifluoperazine f. Thioridazine g. Thiothixene h. Loxapine i. Perphenazine J. Bromperido k. Clopenthixol l. Promazine	a. Clozapine b. Risperidone c. Olanzapine d. Quetiapine e. Ziprasidone f. Aripiprazole	(1) Metoclopromide 2) Tetrabenazine (3) Reserpine 4) Droperidol (5) Promethazine (6) Amoxapine (7) Diatrizoate	(1) Levodopa 2) Dopamine agonists (3) Amantadine 4) Tolcapone	(1) Lithium 2) Phenelzine (3) Dosulepin 4) Desipramine (5) Trimipramine

Differential Diagnosis

• Infection (sepsis, SIRS)
• Serotonin syndrome
• Delirium tremens
• Heat Stroke
• Malignant hyperthermia

NMS and Serotonin Syndrome

The clinical features of NMS and serotonergic syndrome are very similar. This can make differentiating them very difficult.

Features, classically present in NMS, that are useful for differentiating the two syndromes are:

• Fever
• Muscle rigidity
• Laboratory values (WBC and CK)

One the basis of stiffness and fever it can be differentiated from:

• Tetanus
• Stiff man syndrome
• Meningitis
• Tardive dyskinesia
• Parkinsonism

Differential Diagnosis of Fever and Stiffness

Disease	Diagnosis			Treatment
	Symptoms	Signs	Laboratory Findings
Tetanus	Tonic contraction of muscles between the spasmodic episodes Trismus or lockjaw Neck stiffness Swallowing difficulty Stiffening of the calf and pectoral muscle groups	Opisthotonos Leg extension with arm flexion Risus sardonicus respiratory distress	Not significant	Diazepam Magnesium  Human TIG
Neuroleptic Malignant Syndrome	History of intake of offending drugs e.g neuroleptics like: Fluphenazine Haloperidol Olanzapine Risperidone Autonomic instability Rigidity Disorientation Fever	Dysphagia Pallor Dyspnea Shuffling gait Agitation	Myoglobinemia Elevated LDH Elevated creatine kinase Hyperkalemia Elevated AST and ALT Hyperphosphatemia Elevated alkaline phosphatase Hyperuricemia	Supportive therapy Stop the offending agent Medical Therapy Dantrolene Amantadine Bromocriptine
Viral Meningitis	Fever Irritability Lack of appetite Lethargy Disoriented High grade fever Severe headache Stiff neck Sensitivity to bright light Nausea Vomiting	Headache Photophobia Phonophopia Pharyngitis in case of enterovirus infeciton Orchitis (In mumps) Vesicular or macular skin rash Petichiae Nuchal rigidity Signs of meningeal irritation: Kernig's sign Brudzinski's sign Altered mental status Hypotonia	CSF / plasma glucose ratio (>0.6) Lactate (mmols/l) (<2.1) Lymphocytes > granulocytes	Supportive Analgesics for pain. Acetaminophen for fever. Anti-viral therapy: Acyclovir Pleconaril
Stiff man syndrome	Marked rigidity Spasms Intermittent Painful Absent during sleep	Diaphoresis Arterial hypertension Tachypnea Cyanosis Apnea, tachypnea Respiratory arrest Dilatation of the pupils Tachycardia	CSF has Elevated IgG Oligoclonal bands Positive anti-GAD antibodies Elevated creatine kinase Normal CBC & ESR	Benzodiazepines Baclofen Vigabatrin  Valproic Acid, Neurontin Injected botulinum toxin  Prednisone, plasmapheresis, IVIG ( some success)
Drug induced (Tardive dyskinesia)	History of intake of the offending drug for at least one month Neuroleptics (antipsychotics) Metoclopramide Eye deviation Head and neck jerky movements No tonic contraction of the muscles between the spasms	Dyskinesia of the tongue and lips Dyskinesia of the limbs Dyskinesia of the neck	It is a clinical diagnosis depending on Dyskinetic movements Hx of > 1 month of antipsychotic use Labs may be done to rule out other differentials	Stop the offending agent Benztropine Benzodiazepines Injection of botulinum toxin Valbenzine Tetrabenazine
Strychnine poisoning	Hx of up to date tetanus immunizations History of intentional or accidental intake Strychnos nux vomica seeds Rodenticide	Hypervigilance Anxiety Mydriasis Hypereflexia Clonus Facial and neck stiffness	Blood assay Tissue assay Urine assay	Initial stabilization High dose Benzodiazepines Intubation and airway securing
Hypocalcaemia	Muscle twitching and cramping Circumoral and extremity paresthesia or tingling Altered mental status Irritability Depression Psychosis Seizure	Tetany (carpopedal spasm) Latent tetany Trousseau sign of latent tetany  Chvostek's sign  Hyperactive tendon reflexes	Decreased blood calcium levels	Two ampules of intravenous calcium gluconate 10% is given slowly in a period of 10 minutes, or If hypocalcemia is severe, calcium chloride is given instead Maintenance doses of both calcium and vitamin-D
Parkinson's disease	Stiffness Inability to write Jerky movements at rest Constipation Sleeping difficulty Walking difficulty	Tremor Rigidity Bradykinesia Postural instability Shuffling gait	Clinical diagnosis Improvement with dopaminergic therapy confirms diagnosis	Symptomatic therapy Dopamine agonists Levodopa Amantadine MAO inhibitors COMT inhibitors Anticholinergics

Epidemiology and Demographics

The incidence of neuroleptic malignant syndrome is 0.02 % to 3% among patients taking antipsychotic medications. This wide range in the incidence probably reflects differences among population samples and differences in the surveillance methods used.

The majority of the patients is of adult populations but this rare disorder has been documented in all age groups from 0.9 to 78 years.Age is not a risk factor. In most studies, men outnumber women twofold.

Risk Factors

Following are the major risk factors for the development of NMS.

• Initiation or dose escalation of neuroleptioc medication
• Use of high dose, high potency intramuscular neuroleptics
• Concurrent use of multiple neuroleptics
• physical exhaustion
• Heat stroke
• Dehydration
• hyponatremia
• thyrotoxicosis
• psychoactive substances
• presence of a structural or functional brain disorder such as encephalitis, tumor, delirium, or dementia

Screening

There is insufficient evidence to recommend routine screening for NMS.

Natural History, Complication and Prognosis

As with most illnesses, the prognosis is best when identified early and treated aggressively. In these cases NMS is usually not fatal, although there is currently no agreement on the exact mortality rate for the disorder. Studies have given the disorder a mortality rate as low as 5% and as high as 76%, although most studies agree that the correct percentage is in the lower spectrum, perhaps between 10% - 15%. Re-introduction to the drug that originally caused NMS to develop may also trigger a recurrence, although in most cases it does not.

Poor prognostic factors include:

• Administration of dopamine antagonists
• Administration of new atypical antipsychotics

Diagnosis

Diagnosis Criteria

DSM-V Diagnostic Criteria for Neuroleptic Malignant Syndrome

“

Patients have generally been exposed to a dopamine antagonist within 72 hours prior to symptom development. Hyperthermia (>100.4°F or >38.0°C on at least two occasions, measured orally), associated with profuse diaphoresis, is a distinguishing feature of neuroleptic malignant syndrome, setting it apart from other neurological side effects of anti psychotic medications. Extreme elevations in temperature, reflecting a breakdown in central thermoregulation, are more likely to support the diagnosis of neuroleptic malignant syndrome. Generalized rigidity, described as "lead pipe" in its most severe form and usually unresponsive to antiparkinsonian agents, is a cardinal feature of the disorder and may be associated with other neurological symptoms (e.g., tremor, sialorrhea, akinesia, dystonia, trismus, myoclonus, dysarthria, dysphagia, rhabdomyolysis). Creatine kinase elevation of at least four times the upper limit of normal is commonly seen. Changes in mental status, characterized by delirium or altered consciousness ranging from stupor to coma, are often an early sign. Affected individuals may appear alert but dazed and unresponsive, consistent with catatonic stupor. Autonomic activation and instability manifested by tachycardia (rate >25% above baseline), diaphoresis, blood pressure elevation (systolic or diastolic >25% above baseline) or fluctuation (>20 mmHg diastolic change or >25 mmHg systolic change within 24 hours), urinary incontinence, and pallor—may be seen at any time but provide an early clue to the diagnosis. Tachypnea (rate >50% above baseline) is common, and respiratory distress—resulting from metabolic acidosis, hyper metabolism, chest wall restriction, aspiration pneumonia, or pulmonary emboli can occur and lead to sudden respiratory arrest. A workup, including laboratory investigation, to exclude other infectious, toxic, metabolic, and neuropsychiatric etiologies or complications is essential. Although several laboratory abnormalities are associated with neuroleptic malignant syndrome, no single abnormality is specific to the diagnosis. Individuals with neuroleptic malignant syndrome may have leukocytosis, metabolic acidosis, hypoxia, decreased serum iron concentrations, and elevations serum muscle enzymes and catecholamines. Findings from cerebrospinal fluid analysis and neuroimaging studies are generally normal, whereas electroencephalography shows generalized slowing. Autopsy findings in fatal cases have been nonspecific and variable, depending on complications.

”

Symptoms

The first symptom to develop is usually muscular rigidity, followed by high fever and changes in cognitive functions. Other symptoms can vary, but may be unstable blood pressure, confusion, coma, delirium, muscle tremors, etc. Once symptoms do appear, they rapidly progress and can reach peak intensity in as little as three days. These symptoms can last anywhere from eight hours to forty days.

Laboratory Studies

A raised creatine phosphokinase (CPK) plasma concentration will be reported due to increased muscular activity. The patient may be hypertensive and suffering from a metabolic acidosis.

EEG Studies

A non-generalised slowing on an EEG is reported in around 50% of cases.

Unfortunately, symptoms of NMS are sometimes misinterpreted by doctors as symptoms of mental illness, delaying treatment.

Mnemonic

A mnemonic used to remember the features of NMS is: FEVER.

• F - Fever
• E - Encephalopathy
• V - Vitals unstable
• E - Elevated enzymes (elevated CPK)
• R - Rigidity of muscles

Treatment

Medical Therapy

The management of patients with NMS should be based upon a hierarchy of clinical severity and diagnostic certainty [4,30]. When manifestations are severe, intensive care unit monitoring and treatment are required.

Stop causative agent

The single most important step in the treatment of NMS is removal os causative agents. If possible, other potential contributing psychotropic agents should also be stopped. When the precipitant is the discontinuation of dopaminergic therapy, it should be reinstituted.

Supportive care

Complications of the NMS are often fatal and following supportive treatment is required in the intensive care unit.

• Discontinue any precipitating antipsychotic medication
• Maintain cardiorespiratory stability. Mechanical ventilation and cardio consultation may be required.
• Maintain euvolumic state through administration of intravenous fluids,
• If CK is elevated then urine alkalinization with high volume fluid should be done to prevent renal failure from rhabomyolysis
• Cooling blankets should be used to lower fever, more aggressive measures such as ice water gastric lavage may be required.
• Lower blood pressure if markedly elevated. clonidine may be used.
• Prescribe heparin or LMWH to prevent deep venous thrombosis
• If needed, use benzodiazepines (eg, lorazepam 0.5 to 1 mg) to control agitation

Pharmacotherapy

Recommendations for the treatment of NMS are based on clinical experience and case reports and randomized control trials were never done. Dantrolene, amantadine, and bromocriptine are commonly used medications. These agents are used in more severe cases and the dose is escalated if the patient gets worse. A reasonable approach is to start with benzodiazepines (lorazepam or diazepam) along with dantrolene in moderate or severe cases, followed by the addition of bromocriptine or amantadine.