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.[1,5]
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.[1,2,4,5]
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.[1,5,6]
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. [1,5,6]
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.[1,2,3]
Difficulty in breathing Patients may present with shortness of breath due to decreased chest wall compliance with the chest wall muscle rigidity.[2,5]
Abnormal behaviour Patients may develop involuntary abnormal movements including tremors, dystonic or choreiform movements as a result of severe muscle rigidity and muscle contractures. [2,5]
Difficulty in swallowig Because of muscle rigidity patients may develop dysphagia.[2]
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.[1,4]
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.[6]
References
  1. STRAWN JEFFREY. Neuroleptic Malignant Syndrome. Am J Psychiatry [online] 2007 June [viewed 05 June 2014] Available from: doi:10.1176/appi.ajp.164.6.870
  2. DALLAS P. SEITZ. Diagnostic uncertainty in a case of neuroleptic malignant syndrome. CJEM[online] 2005;7(4):266-272. [viewed 05 June 2014] Available from: http://cjem-online.ca/v7/n4/p266
  3. AMBULKAR RESHMAP, PATIL VIJAYAP, MOIYADI ALIASGARV. Neuroleptic malignant syndrome: A diagnostic challenge. J Anaesthesiol Clin Pharmacol [online] 2012 December [viewed 15 June 2014] Available from: doi:10.4103/0970-9185.101946
  4. NOZAKI I, FURUKAWA Y, KATO-MOTOZAKI Y, IKEDA T, TAGAMI A, TAKAHASHI K, ISHIDA C, KOMAI K. Neuroleptic Malignant Syndrome Induced by Combination Therapy with Tetrabenazine and Tiapride in a Japanese Patient with Huntington's Disease at the Terminal Stage of Recurrent Breast Cancer. Intern Med [online] 2014, 53(11):1201-4 [viewed 15 June 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/24881749
  5. ADNET P.. Neuroleptic malignant syndrome. [online] 2000 July, 85(1):129-135 [viewed 16 June 2014] Available from: doi:10.1093/bja/85.1.129
  6. CRISTIAN MIHAILESCU. Neuroleptic malignant syndrome - current approach to diagnosis and management. Review articles. [online] [viewed 16 June 2014] Available from: http://www.romjpsychiat.ro/uploads/revista/3-2010/3.pdf

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.[1,3]
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. [1,3]
Tachycardia Because of the associated autonomic dysfunction heart rate will be increased.[2]
Abnormal blood pressure Blood pressure readings may vary due to autonomic dysfunction.[2]
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.[2,3]
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.[2,3]
References
  1. STRAWN JEFFREY. Neuroleptic Malignant Syndrome. Am J Psychiatry [online] 2007 June [viewed 05 June 2014] Available from: doi:10.1176/appi.ajp.164.6.870
  2. DALLAS P. SEITZ. Diagnostic uncertainty in a case of neuroleptic malignant syndrome. CJEM[online] 2005;7(4):266-272. [viewed 05 June 2014] Available from: http://cjem-online.ca/v7/n4/p266
  3. ADNET P.. Neuroleptic malignant syndrome. [online] 2000 July, 85(1):129-135 [viewed 16 June 2014] Available from: doi:10.1093/bja/85.1.129

Differential Diagnoses

Fact Explanation
Heat stroke Since neuroleptic malignant syndrome is a diagnosis of exclusion, differential diagnoses are very important. Heatstroke can present with hyperthermia, confusion, tachycardia, and tachypnea, and its differentiation from neuroleptic malignant syndrome may be difficult in a psychiatric patient receiving antipsychotic medication. However, in heatstroke patients, in addition to a history of exertion or exposure to high ambient temperatures, the skin is dry and muscle flaccidity is commonly observed. [1]
Malignant hyperthermia Patients undergoing general anesthesia may develop malignant hyperthermia. In contrast to neuroleptic malignant syndrome, these patients usually develop symptoms intraoperatively, have a primary pharmacogenetic skeletal muscle disorder (which consequently is not relieved by neuromuscular blocking agents), and may have a family history of malignant hyperthermia during surgery. [1]
Infective causes - Meningitis, viral encephalitis, brain abscess, sepsis Prodromal viral illnesses, headaches, meningeal signs, seizures, localizing neurological signs, cerebro spinal fluid studies, and neuroimaging may suggest an infectious etiology.[1]
Agitated delirium Very important to exclude and always should keep in mind.[1,2]
Anatomic lesions affecting midbrain and brainstem structures, as well as rare cases of nonconvulsive status epilepticus Neuroimaging and electroencephalography will aid diagnosis.[1]
Advanced stages of psychotic disorders associated with excited or stuporous catatonia (delirious mania and malignant catatonia) Advanced stages of psychotic disorders associated with excited or stuporous catatonia (delirious mania and malignant catatonia) can present with hyperthermia. Some features may occur only in neuroleptic malignant syndrome such as parkinsonian symptoms, extreme hyperthermia and stupor.[1,2]
Drug induced - Dopamine antagonists, serotonin syndrome Several classes of drugs may cause symptoms resembling those of neuroleptic malignant syndrome (NMS). Dopamine antagonists other than antipsychotic drugs (e.g., metoclopramide, amoxapine, and prochlorperazine) have reportedly caused NMS. Withdrawal of dopaminergic agents (e.g., amantadine and l-dopa) or of the GABA-ergic drug baclofen can precipitate an NMS-like reaction. Serotonergic drugs, including selective serotonin reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors (including linezolid), and triptans used to treat migraine headaches, can cause serotonin syndrome, which most often presents as an agitated delirium but resembles NMS in severe cases. [1]
Substance abuse - cocaine and amphetamine (especially Ecstasy), Hallucinogen intoxication (phencyclidine) and withdrawal from alcohol and sedative-hypnotics These may also cause fever, autonomic changes, and other symptoms that can be confused with neuroleptic malignant syndrome. [1]
Parkinson's disease Abnormal body, limb movements may be found making diagnostic diffculties. But usually there is no history of recent use of antipsychotics. Note: both conditions can co-exist in patients with Parkinson's disease and those who are taking antipsychotics. [2]
Endocrine causes - Thyrotoxicosis, pheochromocytoma Can present with similar symptoms like in neuroleptic malignant syndrome, but there won't be history of antipsychotic drug use.[1]
References
  1. STRAWN JEFFREY. Neuroleptic Malignant Syndrome. Am J Psychiatry [online] 2007 June [viewed 05 June 2014] Available from: doi:10.1176/appi.ajp.164.6.870
  2. DALLAS P. SEITZ. Diagnostic uncertainty in a case of neuroleptic malignant syndrome. CJEM[online] 2005;7(4):266-272. [viewed 05 June 2014] Available from: http://cjem-online.ca/v7/n4/p266

Investigations - for Diagnosis

Fact Explanation
Serum creatine kinase Will be elevated. Associated rhabdomyolysis secondary to sever muscle contracture causes elevation of the serum creatinine kinase level.[1,3]
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.[1]
Full blood count Will reveal leukocytosis (>12.0 × 109/L).[2]
Lumbar puncture - CSF analysis Essential if suspecting central nervous system infection. But results of CSF analysis are normal in more than 95% of cases.[1]
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. [1]
Arterial blood gas analysis Patients may also have metabolic acidosis and hypoxia.[1]
Serum electrolytes Need serial monitoring to detect abnormalities of serum electrolytes.[1]
References
  1. STRAWN JEFFREY. Neuroleptic Malignant Syndrome. Am J Psychiatry [online] 2007 June [viewed 05 June 2014] Available from: doi:10.1176/appi.ajp.164.6.870
  2. DALLAS P. SEITZ. Diagnostic uncertainty in a case of neuroleptic malignant syndrome. CJEM[online] 2005;7(4):266-272. [viewed 05 June 2014] Available from: http://cjem-online.ca/v7/n4/p266
  3. ADNET P.. Neuroleptic malignant syndrome. [online] 2000 July, 85(1):129-135 [viewed 16 June 2014] Available from: doi:10.1093/bja/85.1.129

Management - General Measures

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. [1]
References
  1. THIM T, KRARUP NH, GROVE EL, ROHDE CV, LøFGREN B. Initial assessment and treatment with the Airway, Breathing, Circulation, Disability, Exposure (ABCDE) approach. Int J Gen Med [online] 2012:117-21 [viewed 16 June 2014] Available from: doi:10.2147/IJGM.S28478

Management - Specific Treatments

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. [1]
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. [1]
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.[1]
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.[1]
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.[1]
Dantrolene Dantrolene, the muscle relaxant may be useful only in cases with extreme temperature elevations, rigidity, and true hypermetabolism. [1]
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.[1]
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.[1]
References
  1. STRAWN JEFFREY. Neuroleptic Malignant Syndrome. Am J Psychiatry [online] 2007 June [viewed 05 June 2014] Available from: doi:10.1176/appi.ajp.164.6.870