Ooo6Neuroleptic malignant syndrome (NMS) is a lethal medical emergency associated with the use of neuroleptic agents and antiemetics that is characterized by a typical clinical syndrome of hyperthermia, rigidity, mental status alteration, and dysautonomia.
Neuroleptic drugs, block part or all the CNS dopamine and have become a principal form of treatment for psychosis and in particular schizophrenia.
Neuroleptic drugs are used for delirium, anxiety disorders, Tourette syndrome, and neurogastrointestinal dysfunction.
Associated with dopamine receptor blocking agents – antipsychotic agents, and may be misdiagnosed as serotonin syndrome.
Neuroleptic antipsychotic agents Block dopamine D2 receptors that bind extracellular dopamine and this blockade is implicated in the disorder.
It is also hypothesized that the autonomic symptoms in neuroleptic syndrome is due to hyperactivity of the sympathoadrenal system, which leads to increase concentrations of intracellular calcium ions in muscles and contributes to the increased muscle tone.
The blockade of dopamine receptors in the hypothalamus causes impaired heat dissipation, and blockade of dopamine receptors in the caudate nucleus, and ventral striatum causing muscular rigidity: excess heat production association with decreased heat dissipation results in hyperthermia a main sign of the syndrome.
NMS develops in an estimated .02 -3% of patients exposed to an implicated drug, depending on the population, the type of agent, and the duration of its use.
Risk factors for NMS include dehydration, the use of multiple antipsychotic drugs, high and escalating drug doses, previous episode of the syndrome, and intramuscular route of injection.
There may be an increased propensity for the syndrome impatience with auto immune and encephalitis.
Symptoms typically evolve over 1 to 3 days and include hyperthermia, rigidity, mental status changes, and autonomic dysregulation.
Autonomic dysregulation: tachycardia, 88% of cases, high blood pressure,up to 77% of cases, dysrhythmias, and tachypnea are seen.
Autonomic instability, which can manifest with tachycardia, nausea, vomiting, and diaphoresis.
Hyperthermia
-Mental status change with confusion, hallucinations, coma.
Muscle rigidity
Laboratory abnormalities: elevated creatine kinase, reduced iron plasma levels, electrolyte abnormalities.
It occurs within 10 days after the start of therapy in up to 90% of cases.
A rare but life-threatening neurologic disorder most often caused by an adverse reaction to neuroleptic or anti-psychotic drugs.
High potency, first generation antipsychotic agents, such as haloperidol, fluphenazine, , and pimozide are most often implicated in cases of neuroleptic malignant syndrome.
Genetic polymorphisms of drug metabolizing enzymes, drug transporters, drug targeting molecules can affect drug responses and can tincrease the risk of neuroleptic malignant syndrome.
Second generation drugs are associated with a low incidence of this disorder.
Additional agents associated with NMS are clozapine, metoclopramide, droperidol, prochlorperazine, and dopamine depleting agents such as tetrabenazine.
NMS symptoms usually develop during the first 10 to 14 days of neuroleptic drugtherapy initiation.
It is not a dose-dependent phenomenon, but high doses is a risk factor.
Risk factors include: high-potency antipsychotics, rapid dose increase of antipsychotics, and using long-acting injectable neuroleptics such as fluphenazine enanthate and haloperidol decanoate.
Additional risk factors include dehydration, malnutrition, organic brain disease, and lithium usage.
Causative medications include: antipsychotics and antiemetics, mainly high-potency first-generation antipsychotic agents such as fluphenazine and haloperidol.
Can occur with use of low-potency antipsychotics such as chlorpromazine and second-generation antipsychotic drugs such as clozapine and olanzapine, as well as antiemetic drugs such as prochlorperazine, metoclopramide, and promethazine.
It may occur with the withdrawal of l-dopa or dopamine agonist therapy.
Drug dose reductions and a switch from one agent to another in patients treated for Parkinsonism can cause NMS.
Antipsychotic medications lead to increased calcium release from the sarcoplasmic reticulum, resulting in increased contractility, which can worsen the rigidity and hyperthermia and increase the chance of rhabdomyolysis.
Associated with fever, blood pressure variation, muscle rigidity and increased creatine kinase.
Characterized by the following symptoms: tremor, rigidity, hyperthermia, tachycardia, mental status changes.
Diagnostic criteria include: exposure to a dopamine blocking drug, severe muscular rigidity, fever, and at least two of the following features; diaphoresis, dysphagia, tremor, incontinence, altered level of consciousness, mutism, tachycardia, elevated or labile blood pressure, leukocytosis, or an elevated serum creatine kinase level.
Patients typically present with dysautonomia, tachycardia, and rapidly fluctuating hypertensive or hypotensive blood pressure, temperature elevations to 40°C or higher, delirium that in its severe form is catatonic, and increased the muscle tone.
Patients have muscular rigidity, but is essentially an extrapyramidal lead pipe sign perceived as uniform resistance to movement through a range of passive motion of a limb.
Intense rigidity may result into rhabdomyolysis, elevated serum, creatine kinase levels, and renal failure.
Altered mental status occurs as delirium with confusion and possible profound encephalopathy and coma.
Muscular rigidity is mostly generalized and can be accompanied with dystonia and dyskinesias.
Fevers with temperatures above 38C are typical.
Temperatures greater than 40C are not uncommon, seen in up to 40% of cases.
Occurs as a result of changes in dopamine signaling: proposed mechanism by which antipsychotics and antiemetics cause NMS is that of dopamine D2 receptor antagonism.
The median interval between drug exposure, and the appearance of symptoms is about four days, and the median duration of illness is about nine days.
Most patients experience this process from a single drug.
Parkinson’s disease may have a neuroleptic type syndrome associated with it as a result of exposure to antipsychotic agents.
A reduced dopamine signaling may result from sudden withdrawal of dopaminergic agents, or when the drug dosage is abruptly reduced in people taking dopaminergic drugs such as levodopa for Parkinson disease.
Suspected central D2 receptor blockade in the nigrostriatal pathways, hypothalamus, and spinal cord leads to increased tremor and muscle rigidity through the extrapyramidal pathways.
D2 receptor blockade in the hypothalamus results in an increased temperature set point and impairment of heat-dissipating mechanisms.
Genetic studies reveal the presence of a specific allele of the dopamine D2 receptor gene that is overrepresented in persons with NMS.
The sympathetic nervous system hyperactivity and dysregulation, leads to autonomic dysfunction manifesting as labile blood pressure, tachycardia, and tachypnea due to D2 receptor blockade.
D2 receptor blockade might cause NMS by removing tonic inhibition from the sympathetic nervous system.
Dopamine receptor blockade has a slow onset and typically evolves over several days after administration of a neuroleptic drug and responds to dopamine agonists such as bromocriptine.
It carries high morbidity and mortality.
Incidence rates for NMS range from 0.07% to 2.2% among those taking neuroleptic medications.
Recent estimates of mortality from 10% to 20%.
It is more common in men than in women, possibly because of greater use of neuroleptics among men rather than a greater susceptibility.
Distinguishing NMS from other states of rigidity and hyperthermia may be difficult and similar conditions include malignant hyperthermia from anesthetic agents, heat stroke, withdrawal syndrome, acute intoxication with recreational drugs, such as amphetamines, cocaine, MDMA, and phencyclidine, abrupt discontinuation of muscle relaxants, acute serotonin syndrome, use of metoclopramide, extreme catatonia, and fever of unknown origin.
Management includes withdrawal of the offending agent, when possible, and approaches to the syndrome include managing blood pressure instability, hyperthermia, and rhabdomyolysis from severe rigidity and the potential for respiratory compromise.
Patients may require intubation and mechanical ventilation and aspiration of gastric contents.
Patients with agitation and delirium may require sedative, hypnotic, and anxiolytic agents.
Severe cases may manifest with hypocalcemia, hypomagnesemia, hyponatremia, hypernatremia, hyperkalemia and metabolic acidosis, all of which require management.
Significant fluids may be required to maintain euvolemia and manage rhabdomyolysis.
Rigidity is monitored and managed with the lorazepam and or dantrolene.
Dantrolene mitigates hyperthermia with effects on central thermal regulatory areas and reduces rigidity.
NMS is classified in three stages. The severe stage includes marked rigidity, catatonia or confusion, temperature 40°C to higher in a heart rate of 120 bpm or higher.
Recovery times range from 7 to 11 days, and may be predicted from the half-life of the implicated neuroleptic drug.
In rare cases the syndrome persists for months with residual catatonia and motor findings.
Mortality with modern therapy ranges from 4.7% at 30 days to 9.9% at 90 days and up to 15.1% at one year, indicating late complications may be fatal.
Prolonged illness requiring ventilator care is associated pneumonia and sepsis.
Rhabdomyolysis and acute kidney injury occur in up to 30% of inpatient cases.
Acute respiratory failure, sepsis, coexisting congestive heart failure, are independent potential modifying risk factors for poor outcome.
The resumption of treatment with antipsychotic drugs, may result in a recurrence of the NMS, even up to two years after the first exposure.