Malignant neuroleptic syndrome - Clinicals, Diagnosis, and Management

Emergency Medicine

Clinicals - History

Fact Explanation
Fever Fever is one of the key symptoms found in neuroleptic malignant syndrome. Antipsychotic drug induced dopamine blockade is the main underlying pathophysiology of this condition. Dopamine is an important neurotransmitter in central thermoregulation, paticularly in mammals. Blockade of hypothalamic dopamine sites will result in hyperthermia due to impaired heat dissipation and also due to associated muscle rigidity which generates heat. Fever
Fever is one of the key symptoms found in neuroleptic malignant syndrome. Antipsychotic drug induced dopamine blockade is the main underlying pathophysiology of this condition. Dopamine is an important neurotransmitter in central thermoregulation, paticularly in mammals. Blockade of hypothalamic dopamine sites will result in hyperthermia due to impaired heat dissipation and also due to associated muscle rigidity which generates heat.
Severe muscle rigidity One of the major criteria to diagnose neuroleptic malignant syndrome. Central D2 receptor blockade in hypothalamus nigrostriatal pathways and spinal cord & peripherally, increase calcium release in muscles from sarcoplasmic reticulum by the action of anti-psychotics causing muscle rigidity. Severe muscle rigidity
One of the major criteria to diagnose neuroleptic malignant syndrome. Central D2 receptor blockade in hypothalamus nigrostriatal pathways and spinal cord & peripherally, increase calcium release in muscles from sarcoplasmic reticulum by the action of anti-psychotics causing muscle rigidity.
Mental status changes Dopamine neurotransmission blockade at mesocortex, basal ganglia, spinal cord within central nervous system has been the reason for mental status alterations and autonomic disturbancies in neuroleptic malignant syndrome. Patients and their family members will complain change in patient's mental status. It can ranges from agitation to stupor or coma. Mental status changes
Dopamine neurotransmission blockade at mesocortex, basal ganglia, spinal cord within central nervous system has been the reason for mental status alterations and autonomic disturbancies in neuroleptic malignant syndrome. Patients and their family members will complain change in patient's mental status. It can ranges from agitation to stupor or coma.
Autonomic dysfunction: Excessive sweating, urinary incontinence Diaphoresis, which is also called excessive sweating and urinary incontinence are found in most patients with neuroleptic malignant syndrome due to associated autonomic dysfunction.
In addition to dopamine blockage, sympathetic nervous system activation or dysfunction also known to involve in the pathogenesis of neuroleptic malignant syndrome.
Autonomic dysfunction: Excessive sweating, urinary incontinence
Diaphoresis, which is also called excessive sweating and urinary incontinence are found in most patients with neuroleptic malignant syndrome due to associated autonomic dysfunction.
In addition to dopamine blockage, sympathetic nervous system activation or dysfunction also known to involve in the pathogenesis of neuroleptic malignant syndrome.
History of recent use of antipsychotic drugs, other dopaminergic agent or recent discontinuation of a dopamine agonist Neuroleptic malignant syndrome is typically found in patients with a history of recent use of antipsychotics and other medications that affect/block dopaminergic neurotransmission causing sudden reduction in dopamine activity.
Nearly all dopamine antagonists have been associated with NMS, although high-potency conventional antipsychotics are associated with a greater risk compared with low-potency agents and atypical antipsychotics. Majority develop neuroleptic malignant syndrome within first week of treatment and it is unlikely to develop it beyond 1 month after starting treatment.
History of recent use of antipsychotic drugs, other dopaminergic agent or recent discontinuation of a dopamine agonist
Neuroleptic malignant syndrome is typically found in patients with a history of recent use of antipsychotics and other medications that affect/block dopaminergic neurotransmission causing sudden reduction in dopamine activity.
Nearly all dopamine antagonists have been associated with NMS, although high-potency conventional antipsychotics are associated with a greater risk compared with low-potency agents and atypical antipsychotics. Majority develop neuroleptic malignant syndrome within first week of treatment and it is unlikely to develop it beyond 1 month after starting treatment.
Difficulty in breathing Patients may present with shortness of breath due to decreased chest wall compliance with the chest wall muscle rigidity. Difficulty in breathing
Patients may present with shortness of breath due to decreased chest wall compliance with the chest wall muscle rigidity.
Abnormal behaviour Patients may develop involuntary abnormal movements including tremors, dystonic or choreiform movements as a result of severe muscle rigidity and muscle contractures. Abnormal behaviour
Patients may develop involuntary abnormal movements including tremors, dystonic or choreiform movements as a result of severe muscle rigidity and muscle contractures.
Difficulty in swallowig Because of muscle rigidity patients may develop dysphagia. Difficulty in swallowig
Because of muscle rigidity patients may develop dysphagia.
History of risk factors - Patients with catatonia, advanced cancer, physical stressors such as dehydration, malnutrition, exhaustion Patients with these risk factors are at risk of progressing to neuroleptic malignant syndrome after receiving antipsychotics. History of risk factors - Patients with catatonia, advanced cancer, physical stressors such as dehydration, malnutrition, exhaustion
Patients with these risk factors are at risk of progressing to neuroleptic malignant syndrome after receiving antipsychotics.
Age and gender of the patient Commonly found in men than in females, with a men to women ratio of 2:1. Ages of patients vary from 3 to 80 years, 40 years
of age being the peak age.
Age and gender of the patient
Commonly found in men than in females, with a men to women ratio of 2:1. Ages of patients vary from 3 to 80 years, 40 years
of age being the peak age.

Clinicals - Examination

Fact Explanation
Elevated temperature Patients usually have increased body temperature which is one of the major criteria to diagnose neuroleptic malignant syndrome. Dopamine is an important neurotransmitter in central thermoregulation, paticularly in mammals. Blockade of hypothalamic dopamine sites will result in hyperthermia due to impaired heat dissipation and also due to associated muscle rigidity which generates heat. Elevated temperature
Patients usually have increased body temperature which is one of the major criteria to diagnose neuroleptic malignant syndrome. Dopamine is an important neurotransmitter in central thermoregulation, paticularly in mammals. Blockade of hypothalamic dopamine sites will result in hyperthermia due to impaired heat dissipation and also due to associated muscle rigidity which generates heat.
Severe muscle rigidity Cog wheel rigidity of muscles can be elicitied in patients with neuroleptic malignant syndrome. Neuroleptic drugs induce abnormal calcium availability in muscle cells of susceptible individuals and trigger muscle rigidity. Sometimes it is found out that neuroleptics could be directly toxic to normal skeletal muscle. Severe muscle rigidity
Cog wheel rigidity of muscles can be elicitied in patients with neuroleptic malignant syndrome. Neuroleptic drugs induce abnormal calcium availability in muscle cells of susceptible individuals and trigger muscle rigidity. Sometimes it is found out that neuroleptics could be directly toxic to normal skeletal muscle.
Tachycardia Because of the associated autonomic dysfunction heart rate will be increased. Tachycardia
Because of the associated autonomic dysfunction heart rate will be increased.
Abnormal blood pressure Blood pressure readings may vary due to autonomic dysfunction. Abnormal blood pressure
Blood pressure readings may vary due to autonomic dysfunction.
Tachypnea Patients' respiratory rate will be increased. Muscle rigidity occurs in neuroleptic malignant syndrome is a generalized ‘lead pipe’ variety which decreases chest‐wall compliance with resulting tachypnoeic hypoventilation. Tachypnea
Patients' respiratory rate will be increased. Muscle rigidity occurs in neuroleptic malignant syndrome is a generalized ‘lead pipe’ variety which decreases chest‐wall compliance with resulting tachypnoeic hypoventilation.
Extra pyramidal signs (tremor, cogwheeling, dystonia or choreiform movements) Due to blockade in the dopamine neurotransmission and associated muscle rigidity may be give rise to extrapyramidal signs such as dyskinesia, dysarthria or Parkinsonism. Extra pyramidal signs (tremor, cogwheeling, dystonia or choreiform movements)
Due to blockade in the dopamine neurotransmission and associated muscle rigidity may be give rise to extrapyramidal signs such as dyskinesia, dysarthria or Parkinsonism.

Investigations - Diagnosis

Fact Explanation
Serum creatine kinase Will be elevated. Associated rhabdomyolysis secondary to sever muscle contracture causes elevation of the serum creatinine kinase level. Serum creatine kinase
Will be elevated. Associated rhabdomyolysis secondary to sever muscle contracture causes elevation of the serum creatinine kinase level.
Lactate dehydrogenase, aldolase and transaminases Associated rhabdomyolysis, will cause increase in serum aldolase, transaminases, and lactic acid dehydrogenase concentrations with the risk of subsequent myoglobinuric renal failure. Lactate dehydrogenase, aldolase and transaminases
Associated rhabdomyolysis, will cause increase in serum aldolase, transaminases, and lactic acid dehydrogenase concentrations with the risk of subsequent myoglobinuric renal failure.
Full blood count Will reveal leukocytosis (>12.0 × 109/L). Full blood count
Will reveal leukocytosis (>12.0 × 109/L).
Lumbar puncture - CSF analysis Essential if suspecting central nervous system infection. But results of CSF analysis are normal in more than 95% of cases. Lumbar puncture - CSF analysis
Essential if suspecting central nervous system infection. But results of CSF analysis are normal in more than 95% of cases.
Neuroimaging and electroencephalography Need to exclude some important differential diagnosis. Findings of neuroimaging studies in neuroleptic malignant syndrome are generally within normal limits, and electroencephalography may demonstrate generalized slowing consistent with metabolic encephalopathy. Neuroimaging and electroencephalography
Need to exclude some important differential diagnosis. Findings of neuroimaging studies in neuroleptic malignant syndrome are generally within normal limits, and electroencephalography may demonstrate generalized slowing consistent with metabolic encephalopathy.
Arterial blood gas analysis Patients may also have metabolic acidosis and hypoxia. Arterial blood gas analysis
Patients may also have metabolic acidosis and hypoxia.
Serum electrolytes Need serial monitoring to detect abnormalities of serum electrolytes. Serum electrolytes
Need serial monitoring to detect abnormalities of serum electrolytes.

Management - Supportive

Fact Explanation
Immediate management: Basic life support In any type of clinical emergency, especially in neuroleptic malignant syndrome airway, breathing, circulation should be assessed and intervened to save patient's life, as these patients can present with difficulty in breathing, altered blood pressure values, tachycardia, dehydration... etc which need immediate attention. Immediate management: Basic life support
In any type of clinical emergency, especially in neuroleptic malignant syndrome airway, breathing, circulation should be assessed and intervened to save patient's life, as these patients can present with difficulty in breathing, altered blood pressure values, tachycardia, dehydration... etc which need immediate attention.

Management - Specific

Fact Explanation
Discontinue antipsychotics Once neuroleptic malignant syndrome is diagnosed and oral antipsychotic drugs should be discontinued, as it is self-limited in most cases. The mean recovery time after drug discontinuation is in the range of 7–10 days, with 63% of patients recovering within 1 week and nearly all within 30 days. Discontinue antipsychotics
Once neuroleptic malignant syndrome is diagnosed and oral antipsychotic drugs should be discontinued, as it is self-limited in most cases. The mean recovery time after drug discontinuation is in the range of 7–10 days, with 63% of patients recovering within 1 week and nearly all within 30 days.
Supportive therapy - fluid management, correction of electrolyte abnormalities, hyperthermia management Dehydration should be corrected aggressively. Should monitor for electrolyte abnormalities and should be corrected as soon as possible. Alkalinized fluids or even bicarbonate loading may benefit in preventing renal failure. In extreme hyperthermia, physical cooling measures should be carried out, as the peak and duration of temperature elevation are predictive of morbidity and mortality. Supportive therapy - fluid management, correction of electrolyte abnormalities, hyperthermia management
Dehydration should be corrected aggressively. Should monitor for electrolyte abnormalities and should be corrected as soon as possible. Alkalinized fluids or even bicarbonate loading may benefit in preventing renal failure. In extreme hyperthermia, physical cooling measures should be carried out, as the peak and duration of temperature elevation are predictive of morbidity and mortality.
Monitor and manage complications Careful monitoring for complications, including cardiorespiratory failure, renal failure, aspiration pneumonia, and coagulopathies, and may involve support of cardiac, respiratory, and renal function. Monitor and manage complications
Careful monitoring for complications, including cardiorespiratory failure, renal failure, aspiration pneumonia, and coagulopathies, and may involve support of cardiac, respiratory, and renal function.
Benzodiazepines Parenteral lorazepam, starting with 1–2 mg is a reasonable first-line therapy in patients with acute neuroleptic malignant syndrome, particularly in those with milder and primarily catatonic symptoms. Benzodiazepines
Parenteral lorazepam, starting with 1–2 mg is a reasonable first-line therapy in patients with acute neuroleptic malignant syndrome, particularly in those with milder and primarily catatonic symptoms.
Dopaminergic agents - bromocriptine and amantadine May reverse parkinsonism in neuroleptic malignant syndrome and reduce time to recovery.
Note: Bromocriptine can worsen psychosis and hypotension and may precipitate vomiting and thus should be used carefully in patients at risk of aspiration. Premature discontinuation of bromocriptine has resulted in rebound symptoms in some cases.
Dopaminergic agents - bromocriptine and amantadine
May reverse parkinsonism in neuroleptic malignant syndrome and reduce time to recovery.
Note: Bromocriptine can worsen psychosis and hypotension and may precipitate vomiting and thus should be used carefully in patients at risk of aspiration. Premature discontinuation of bromocriptine has resulted in rebound symptoms in some cases.
Dantrolene Dantrolene, the muscle relaxant may be useful only in cases with extreme temperature elevations, rigidity, and true hypermetabolism. Dantrolene
Dantrolene, the muscle relaxant may be useful only in cases with extreme temperature elevations, rigidity, and true hypermetabolism.
Electro Convulsive Therapy (ECT) Effective if symptoms are refractory to supportive care and pharmacotherapy or if idiopathic malignant catatonia due to an underlying psychotic disorder cannot be excluded, or if the patient has persistent residual catatonia and parkinsonism after resolution of the acute metabolic symptoms of neuroleptic malignant syndrome.
Treatment includes 6-10 times with bilateral electrode placement.
Electro Convulsive Therapy (ECT)
Effective if symptoms are refractory to supportive care and pharmacotherapy or if idiopathic malignant catatonia due to an underlying psychotic disorder cannot be excluded, or if the patient has persistent residual catatonia and parkinsonism after resolution of the acute metabolic symptoms of neuroleptic malignant syndrome.
Treatment includes 6-10 times with bilateral electrode placement.
Restarting antipsychotic following episode of neuroleptic malignant syndrome Chance of developing neuroleptic malignant syndrome again is high as 30%. Precautions should be taken to maintain patient's safety.
Indications should be clearly documented. Should consider alternative medications. Should wait at least 2 weeks before starting antipsychotic treatment again. Low doses of low-potency conventional antipsychotics or atypical antipsychotics can be used. Patients should be carefully monitored.
Restarting antipsychotic following episode of neuroleptic malignant syndrome
Chance of developing neuroleptic malignant syndrome again is high as 30%. Precautions should be taken to maintain patient's safety.
Indications should be clearly documented. Should consider alternative medications. Should wait at least 2 weeks before starting antipsychotic treatment again. Low doses of low-potency conventional antipsychotics or atypical antipsychotics can be used. Patients should be carefully monitored.

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