Question 1 of 10

    Neuroleptic Malignant Syndrome (NMS)

    Haloperidol (Haldol)[1]

    Neuroleptic malignant syndrome is a drug-induced neurological disorder characterized by hyperthermia, rigidity, autonomic dysfunction and an altered mental status. It may cause rhabdomyolysis and renal failure or lead to aspiration pneumonia and is associated with mortality rates of up to 10%.

    Neuroleptic Malignant Syndrome emerges due to the following process: Poison.

    Presentation

    Major symptoms of NMS are hyperthermia, rigidity, autonomic dysfunction and an altered mental status, and NMS may be suspected if anamnestic data include therapy with neuroleptics, other psychotropic drugs, or if treatment with such compounds has recently been discontinued. Symptom onset is subacute; NMS develops in the course of several days or weeks [11] [6]. Manifestation is as follows:

    In general, the severity of single symptoms may vary in the course of the day and until resolution, e.g., patients may present with high fever, their body temperature may decrease and eventually rise again. Muscle tone may vary from mild hypotonia to manifest hypertonia, rigidity and opisthotonus.

    Entire body system
    Antipsychotic Agent
    • . neuroleptic [ noor″o-lep tik ] a term coined to refer to the effects on cognition and behavior of the original antipsychotic agents , which produced a state of apathy, lack of initiative, and limited range of emotion and in psychotic patients caused[medical-dictionary.thefreedictionary.com]
    • The condition is thought to occur more frequently with the use of high-potency conventional antipsychotics, but NMS is a potential adverse effect of any antipsychotic agent, including the newer atypical antipsychotics, Dr.[acep.org]
    • Definition (MSH) A potentially fatal syndrome associated primarily with the use of neuroleptic agents (see ANTIPSYCHOTIC AGENTS) which are in turn associated with dopaminergic receptor blockade (see RECEPTORS, DOPAMINE) in the BASAL GANGLIA and HYPOTHALAMUS[fpnotebook.com]
    • What is Neuroleptic Malignant Syndrome: This describes the combination of catatonic rigidity, stupor, unstable blood pressure, fever, profuse sweating, sweating and incontinence as a reaction to antipsychotic agents (phenothiazines) in therapeutic doses[drugs.com]
    • (Source: excerpt from NINDS Neuroleptic Malignant Syndrome Information Page: NINDS ) Definitions of Neuroleptic Malignant Syndrome: A potentially fatal syndrome associated primarily with the use of neuroleptic agents (see ANTIPSYCHOTIC AGENTS) which are[rightdiagnosis.com]
    Fever
    High Fever
    • Symptoms include high fever, sweating, unstable blood pressure, confusion, and stiffness.[fpnotebook.com]
    • Muscular rigidity Sweating High fever Instability of the autonomic nervous system Unstable blood pressure Changes in cognition Agitation Delirium Coma Neuroleptic Malignant Syndrome Treatment Options Immediate intensive care is usually required for those[schmidtlaw.com]
    • Symptoms of Neuroleptic Malignant Syndrome High fever Sweating Unstable blood pressure Stupor Muscular rigidity more symptoms...»[rightdiagnosis.com]
    • It features high fever, sweating, severe rigidity of muscles, wide swings of blood pressure, incontinence, confusion and coma.[medical-dictionary.thefreedictionary.com]
    • If a patient develops signs and symptoms indicative of NMS or serotonin syndrome, or presents with unexplained high fever without additional clinical manifestations, treatment with dopamine antagonists or serotonergic medicines should be discontinued[medsafe.govt.nz]
    Pallor
    • […] that may result in death, following the use of neuroleptic agents. neuroleptic malignant syndrome Etymology: Gk, neuron, nerve, lepsis, seizure; L, malignus, bad disposition; Gk, syn, together, dromos, course a condition characterized by hypertonicity, pallor[medical-dictionary.thefreedictionary.com]
    • 1-3 days Variable, 12 hours Identical Features Vital Signs Hypertension Tachycardia Tachypnoea Hyperthermia ( 40 C) Hypertension Tachycardia Tachypnoea Hyperthermia ( 40 C) Mucosa Hypersalivation Hypersalivation Overlapping Features Skin Diaphoresis Pallor[medsafe.govt.nz]
    • Autonomic instability may manifest as pallor, tachycardia, fluctuating blood pressure, excessive sweating/salivation, tremor and incontinence.[patient.info]
    • Autonomic instability Changes in the level of consciousness A summary of the clinical features of neuroleptic malignant syndrome includes the following: Muscular rigidity (typically, “lead pipe” rigidity) Hyperthermia (temperature 38 C) Diaphoresis Pallor[emedicine.medscape.com]
    • Autonomic dysfunction signs or symptoms included variation in systemic blood pressure, tachycardia, tachypnea, sialorrhea, diaphoresis, skin pallor, and urinary incontinence.[scielo.br]
    Rigor
    • It’s classic presentation is increased concentrations of end-tidal carbon dioxide, rigor mortis-like muscle rigidity, tachycardia, hyperthermia, and acidosis.[pharmacyjoe.com]
    • […] concurrent organic brain disease or sympathoadrenal hyperactivity. 21 Differential diagnosis Patients on neuroleptics who develop hyperthermia, muscle rigidity and autonomic dysfunction should have all psychotropic medications withdrawn immediately until rigorous[bja.oxfordjournals.org]
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  • neurologic
    Agitated Delirium
    • Muscular rigidity Sweating High fever Instability of the autonomic nervous system Unstable blood pressure Changes in cognition Agitation Delirium Coma Neuroleptic Malignant Syndrome Treatment Options Immediate intensive care is usually required for those[schmidtlaw.com]
    • […] metoclopramide , promethazine ) withdrawal of anti-Parkinson medication Develops over 1-3 days Majority of deaths occur from complications of muscle rigidity Mortality rates up to 5 to 20 percent [4] Clinical Features Tetrad of: [5] Altered mental status - Agitated[wikem.org]
    • The 4 characteristic symptoms usually develop over a few days and often in the following order: Altered mental status: Usually the earliest manifestation is a change in mental status, often an agitated delirium, and may progress to lethargy or unresponsiveness[merckmanuals.com]
    • The first symptoms of neuroleptic malignant syndrome are usually muscle cramps and tremors, fever, symptoms of autonomic nervous system instability such as unstable blood pressure, and sudden changes in mental status (agitation, delirium, or coma).[en.wikipedia.org]
    • delirium and the neuroleptic malignant syndrome - CV Wetli, D Mash, SB Karch - American Journal of Emergency , 1996 - exciteddelirium.org Beneficial effects of dantrolene in the treatment of neuroleptic malignant syndrome: a report of two cases. - M[symptoma.com]
    Altered Mental Status
    • Also, in neuroleptic malignant syndrome, unlike most infections, altered mental status and motor abnormalities tend to precede hyperthermia.[merckmanuals.com]
    • We describe a case of NMS in a patient who presented with acute onset of altered mental status complicated with aspiration pneumonia.[bjmp.org]
    • A 35-year-old man presents with fever, hypertension and altered mental status.[foamcast.org]
    • mental status - Agitated delirium progressing to stupor/coma Muscular Rigidity - Generalized, "lead pipe" rigidity Hyperthermia 38C (87%); 40C (40%) Autonomic Instability - Tachycardia, Hypertension, Diaphoresis Differential Diagnosis Serotonin Syndrome[wikem.org]
    • The patient presented with hyperthermia of over 38 C, severe muscle rigidity, autonomic dysfunction, and altered mental status.[dovepress.com]
    Catatonia
    • Rohan-Chabot, D Elkharrat, P Gajdos - Neurology, 1983 - ukpmc.ac.uk Case study Neuroleptic malignant syndrome induced by haloperidol following traumatic brain injury - R Wilkinson, JM Meythaler, S Guin-Renfroe - Brain Injury, 1999 - informahealthcare.com Catatonia[symptoma.com]
    • Risk factors include dehydration, agitation, and catatonia.[en.wikipedia.org]
    • The overlap between lethal catatonia and neuroleptic malignant syndrome has been the subject of debate, with evidence supporting the idea of some cases being related to catatonia ( Lee 2007 ; Wijemanne and Jankovic 2015 ).[medlink.com]
    • The many varieties of catatonia.[rarediseases.org]
    • (See "Catatonia in adults: Epidemiology, clinical features, assessment, and diagnosis", section on 'Malignant catatonia' .)[uptodate.com]
    Cogwheel Rigidity
    • Motor abnormalities: Patients may have generalized, severe muscle rigidity (sometimes with simultaneous tremor, leading to cogwheel rigidity), or, less often, dystonias, chorea, or other abnormalities.[merckmanuals.com]
    • […] readings 2. tachycardia (pulse 30 bpm above baseline) 3. diaphoresis (intense - may be episodic) 4. incontinence 5. tachypnoea ( 25 breaths/min) Extrapyramidal features are present if there are 2 or more of the following 1. bradykinesia 2. lead-pipe or cogwheel[curriculum.toxicology.wikispaces.net]
    Confusion
    • It features high fever, sweating, severe rigidity of muscles, wide swings of blood pressure, incontinence, confusion and coma.[medical-dictionary.thefreedictionary.com]
    • Furthermore, high temperature, confusion, and disorientation are not usually seen with psychosis.[healthyplace.com]
    • Learn the correct uses of these two commonly confused homophones.[dictionary.reference.com]
    • *(FATAL)-- MEDICAL EMERGENCY -severe muscle ridigity* (led pipe-ridigity) -temperature escalate of symptoms include (two or more of the following): -HTN, Tachycardia, fever, diaphoresis, incontinence, mutism, leukocytes, changes in LOC (ranging from confusion[quizlet.com]
    • Physical examination reveals a confused patient with muscle rigidity. [foamcast.org]
    Dysarthria
    • […] impaired heat dissipation abnormal reaction of predisposed skeletal muscle (like MH) CLINICAL FEATURES develops over 24-72 hrs hyperthermia rigidity rhabdomyolysis RESP – decreased chest wall compliance, tachypnoea, pulmonary infection NEURO – dyskinesia, dysarthria[lifeinthefastlane.com]
    • […] intense - may be episodic) 4. incontinence 5. tachypnoea ( 25 breaths/min) Extrapyramidal features are present if there are 2 or more of the following 1. bradykinesia 2. lead-pipe or cogwheel rigidity 3. resting tremor 4. sialorrhoea 5. dysphagia 6. dysarthria[curriculum.toxicology.wikispaces.net]
    • Patients can also have prominent sialorrhea, dysarthria, and dysphagia.[uptodate.com]
    • This increase in muscle tone may be accompanied by extrapyramidal symptoms including dyskinesia, dysarthria or Parkinsonism.[bja.oxfordjournals.org]
    Dysautonomia
    • Related disorders — NMS is one of a group of acute dysautonomias that share common features: rigidity, hyperpyrexia, and dysautonomia [ 4,6,40,42 ].[uptodate.com]
    • […] hyperreflexia, myoclonus, ataxis, nausea and vomiting, diarrhea Rigidity and hyperthermia, if present, is less severe than in NMS Malignant Hyperthermia Distinguish by clinical setting (use of inhalational anesthetics or sux) Hyperthermia, muscle rigidity, and dysautonomia[wikem.org]
    • Dentatorubral Atrophy Information Page Dermatomyositis Information Page Developmental Dyspraxia Information Page Devic's Syndrome Information Page Diabetic Neuropathy Information Page Diffuse Sclerosis Information Page Dravet Syndrome Information Page Dysautonomia[ninds.nih.gov]
    Dystonia
    • […] findings that are not better accounted for by a substance-induced, neurologic, or general medical condition, it can be difficult to distinguish the symptoms of NMS from some of the other, more common side effects of antipsychotic medications, such as dystonias[acep.org]
    • John’s wort, ginseng Extrapyramidal Symptoms Acute Dystonia – involuntary motor tics or muscle spasms classically including torticollis, tongue or lip protrusion, or oculogyric crisis Akathisia – a feeling of restlessness often accompanied by tapping,[foamcast.org]
    • Synonyms Drug-Induced Movement Disorder Neuroleptic-Induced Acute Dystonia Hyperthermia Disorder Subdivisions None General Discussion Neuroleptic malignant syndrome is a rare but potentially life-threatening reaction to the use of almost any of a group[webmd.com]
    • Motor abnormalities: Patients may have generalized, severe muscle rigidity (sometimes with simultaneous tremor, leading to cogwheel rigidity), or, less often, dystonias, chorea, or other abnormalities.[merckmanuals.com]
    • It can occur along with a cluster of other extrapyramidal symptoms and has been associated with dystonia and parkinsonism.[healthyplace.com]
    Extrapyramidal Symptoms
    • symptoms, rhabdomyolysis Laboratory findings include elevated creatinine kinase, leukocytosis and deranged liver function tests.[pharmaceutical-journal.com]
    • It can occur along with a cluster of other extrapyramidal symptoms and has been associated with dystonia and parkinsonism.[healthyplace.com]
    • John’s wort, ginseng Extrapyramidal Symptoms Acute Dystonia – involuntary motor tics or muscle spasms classically including torticollis, tongue or lip protrusion, or oculogyric crisis Akathisia – a feeling of restlessness often accompanied by tapping,[foamcast.org]
    • The evidence behind this isn’t grade A, but the pathophysiology of the theory makes sense, and multiple studies have found elevated levels of catecholamines in both the serum and the CSF. 38,41-43 NMS manifests classically as extrapyramidal symptoms,[emdocs.net]
    • Resolution of the delirium may take several days longer than the resolution of the autonomic and extrapyramidal symptoms.[curriculum.toxicology.wikispaces.net]
    Resting Tremor
    • After 10 days the patient became somnolent with a high body temperature (40.3 C), diaphoresis, tachycardia, rigid skeletal muscles of a 'lead pipe' character, cogwheel phenomena and resting tremor (video footage is available in Additional data file 1[ccforum.com]
    • (pulse 30 bpm above baseline) 3. diaphoresis (intense - may be episodic) 4. incontinence 5. tachypnoea ( 25 breaths/min) Extrapyramidal features are present if there are 2 or more of the following 1. bradykinesia 2. lead-pipe or cogwheel rigidity 3. resting[curriculum.toxicology.wikispaces.net]
    Stupor
    • CPK****)--- late finding -dysphagia -stupor/catatonia -labile pulse and BP temperature greater than 99.5 (usually between 101 and 103) with no apparent cause 1.HOLD ANY ANTIPSYCHOTIC MEDICATION AND NOTIFY PHYSICIAN 2.[quizlet.com]
    • […] is characterised by four groups of symptoms: Hyperthermia — body temperature over 38.5C Autonomic instability — eg, tachycardia, fluctuating blood pressure, diaphoresis, incontinence Altered consciousness — eg, drowsiness, stupor, confusion, delirium,[pharmaceutical-journal.com]
    • Features Vital Signs Hypertension Tachycardia Tachypnoea Hyperthermia ( 40 C) Hypertension Tachycardia Tachypnoea Hyperthermia ( 40 C) Mucosa Hypersalivation Hypersalivation Overlapping Features Skin Diaphoresis Pallor Diaphoresis Mental Status Variable, stupor[medsafe.govt.nz]
    • […] withdrawal of anti-Parkinson medication Develops over 1-3 days Majority of deaths occur from complications of muscle rigidity Mortality rates up to 5 to 20 percent [4] Clinical Features Tetrad of: [5] Altered mental status - Agitated delirium progressing to stupor[wikem.org]
    • What is Neuroleptic Malignant Syndrome: This describes the combination of catatonic rigidity, stupor, unstable blood pressure, fever, profuse sweating, sweating and incontinence as a reaction to antipsychotic agents (phenothiazines) in therapeutic doses[drugs.com]
    Tremor
    • Other extrapyramidal movement disorders such as tremor and cogwheel phenomena are also frequently present.[ccforum.com]
    • Symptoms – Classical clinical triad of AMS Autonomic instability (Hyperthermia, Tachycardia, diaphoresis)  Neuromuscular Abnormalities: Myoclonus, ocular clonus, rigidity, hyperreflexia, tremor.[foamcast.org]
    • Primidon esansiyel tremor tedavisinde de kullan lan bir antiepileptik ila t r.[scopemed.org]
    • Tremor PLUS hyperreflexia 5.[pharmacyjoe.com]
    • . • T 38.2o C • Alert • GCS 14/15 • Confused • Symmetrical limb rigidity • Tremor R L hand • Diaphoretic • P 125/min SR • BP 155/92 • Lungs clear • Abdo soft, non-tender, absent bowel sounds • No meningism/ focal neurology • Normal pupils • No clonus[slideshare.net]
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  • Skin
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  • gastrointestinal
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  • musculoskeletal
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  • cardiovascular
    Tachycardia
    • Signs/Symptoms : tachycardia, hypercarbia, muscle rigidity, hyperthermia Treatment – Dantrolene.[foamcast.org]
    • Tachypnoea Hyperthermia ( 40 C) Hypertension Tachycardia Tachypnoea Hyperthermia ( 40 C) Mucosa Hypersalivation Hypersalivation Overlapping Features Skin Diaphoresis Pallor Diaphoresis Mental Status Variable, stupor, coma, alert Variable, agitation,[medsafe.govt.nz]
    • Characterized by hyperthermia, tachycardia, sweating, muscle rigidity and mild rhabdomyolysis.[aic.cuhk.edu.hk]
    • Life threatening Condition***(FATAL)-- MEDICAL EMERGENCY -severe muscle ridigity* (led pipe-ridigity) -temperature escalate of symptoms include (two or more of the following): -HTN, Tachycardia, fever, diaphoresis, incontinence, mutism, leukocytes, changes[quizlet.com]
    • F or 38.0 C on at least 2 occasions; creatine kinase elevation, at least 4 times the upper limit of normal; blood pressure elevation, 25% above baseline; blood pressure fluctuation, 20 mm Hg (diastolic) or 25 mm Hg (systolic) change within 24 hours; tachycardia[psychiatrist.com]
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  • Workup

    Anamnestic data and clinical presentation may prompt a strong suspicion of NMS, and laboratory analyses of blood and urine samples are usually carried out to confirm this tentative diagnosis. The following findings are characteristic of NMS:

    While the patient remains hospitalized, those parameters should be re-evaluated periodically.

    Laboratory

    Serum
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  • Treatment

    Withdrawal of the causative drug and supportive therapy to remedy and relieve neurological deficits are the mainstays of treatment; due to the possibility of life-threatening complications, NMS patients need to be hospitalized.

    • Discontinuation of the causative treatment is of utmost importance. Even if the patient depends on psychotropic drugs, it is recommend to interrupt the corresponding therapy for at least two weeks. If an episode of NMS has been induced by the cessation of dopaminergic therapy, it should be reinitiated. Patients who suffer from neuroleptic-induced NMS may also benefit from amantadine or bromocriptine [12].
    • Hydration is critical and may require fluid therapy. In mild cases, patients will be able to drink sufficiently. Patients who present with dysphagia may receive fluids and nutrients by means of a nasogastric tube. In severe cases, fluids have to be administered intravenously. Aggressive fluid therapy is necessary to avoid renal failure in case of rhabdomyolysis and aims at reducing serum concentrations of myoglobin. Sodium bicarbonate may be required in case of metabolic acidosis.
    • With regards to hyperthermia, physical cooling seems to be more effective than antipyretic drugs. Sedation and intubation may be necessary in case of body temperatures >41°C [11].
    • In order to induce muscle relaxation, benzodiazepines or dantrolene may be employed. The latter are also effective against psychomotor agitation and may be employed to achieve sedation, as mentioned above. However, benzodiazepines may exacerbate dyspnea and delirium. Still, they are often preferred over dantrolene as first-line therapeutics.
    • Electroconvulsive therapy has occasionally been reported to be effective in NMS.

    Treatment should be continued until few days past full recovery in order to avoid an immediate relapse.

    Prognosis

    An individual patient's prognosis highly depends on their condition upon the initiation of treatment. In general, resolution can be expected within one or two weeks if adequate care is provided [11]. Recovery times are prolonged in case depot medication triggered NMS. Rhabdomyolysis, myoglobinuria and subsequent renal failure, aspiration pneumonia, disseminated intravascular coagulation and thromboembolic events, as well as multiple organ dysfunction syndrome are severe, potentially life-threatening complications; they are also the most common causes of death in NMS patients. To date, the overall mortality associated with NMS is approximately 10% [2]. The average outcome for patients who present with any of the aforementioned complications is considerably worse, though. Recurrence is likely if the causative drug is administered again while alternative psychotropic compounds are usually well tolerated. Ideally, such treatment is discontinued entirely.

    Complications

    Acidosis
    • […] liberal fluid resuscitation cool cardiovascular support (may require cautious beta-blockade) paralyse - rigidity will respond to NDNMBS Electrolytes and Acid-base hypermetabolic syndrome may require bicarbonate therapy if there is documented severe acidosis[lifeinthefastlane.com]
    • Heat stroke Delirium tremens Hypothalamic stroke Pheochromocytoma Thyroid storm Evaluation Workup Total CK Typically 1000 Correlates with degree of rigidity CBC WBC 10K is typical Chemistry May show hypocalcemia, hypomagnesemia, hyperkalemia, metabolic acidosis[wikem.org]
    • The patient may suffer hypertensive crisis and metabolic acidosis.[en.wikipedia.org]
    • It’s classic presentation is increased concentrations of end-tidal carbon dioxide, rigor mortis-like muscle rigidity, tachycardia, hyperthermia, and acidosis.[pharmacyjoe.com]
    Drug-induced Movement Disorder
    • Drug-induced movement disorders in children.[rarediseases.org]
    • Synonyms Drug-Induced Movement Disorder Neuroleptic-Induced Acute Dystonia Hyperthermia Disorder Subdivisions None General Discussion Neuroleptic malignant syndrome is a rare but potentially life-threatening reaction to the use of almost any of a group[webmd.com]
    Electrolyte Imbalance
    • imbalance Acute renal failure ( rhabdomyolysis ) Dysrhythmias ACS Respiratory failure Chest wall rigidity, aspiration pneumonia , PE DIC Seizure ( hyperthermia , electrolyte derangements ) Hepatic failure Sepsis See Also References Su YP, Chang CK, Hayes[wikem.org]
    • imbalance and myoglobinemia with the possibility of myoglobinuric acute renal failure.[signavitae.com]
    • These include: Dehydration Electrolyte imbalance Acute renal failure associated with rhabdomyolysis Cardiac arrhythmias including torsades de pointes and cardiac arrest Myocardial infarction Cardiomyopathy Respiratory failure from chest wall rigidity,[uptodate.com]
    Heat Stroke
    • Differential diagnoses include serotonin syndrome, malignant hyperthermia, heat stroke, infection, toxicity from other drugs (eg, monoamine-oxidase inhibitors, lithium), use of drugs of abuse (eg, amphetamines, cocaine) and alcohol or sedative withdrawal[pharmaceutical-journal.com]
    • The patient did not respond to the usual heat stroke treatment.[scielo.isciii.es]
    • Responds rapidly and completely to centrally acting anticholinergics phenothiazine-related heat stroke.[aic.cuhk.edu.hk]
    • Neuroleptic‐induced heat stroke Classic heat stroke is a life‐threatening condition in which heat gain from metabolism and the environment exceeds heat loss by evaporation and convection.[bja.oxfordjournals.org]
    • […] mental status and fever Infectious Sepsis Meningitis Encephalitis Cerebral malaria Other Neuroleptic malignant syndrome Serotonin syndrome Malignant hyperthermia Sympathomimetic toxicity ( cocaine , amphetamine , ketamine ) Anticholinergic toxicity Heat[wikem.org]
    Hypernatremia
    • Other associated lab abnormalities were also noticed including leukocytosis at 17,400 wbc/mcl (4,500–10,000 white blood cells per microliter), hypernatremia at 149 mEq/L (135–145 milliequivalents per liter), mild hypocalcemia with a corrected serum calcium[hindawi.com]
    • American Academy of Child , 1992 - Elsevier Abrupt withdrawal from intrathecal baclofen: recognition and management of a potentially life-threatening syndrome - RJ Coffey, TS Edgar, GE Francisco, V Graziani - Archives of physical , 2002 - Elsevier Acute hypernatremia[symptoma.com]
    • Electrolyte abnormalities - hypocalcemia, hypomagnesemia, hypo and hypernatremia, hyperkalemia, and metabolic acidosis are frequently observed.[uptodate.com]
    • Acute hypernatremia and neuroleptic malignant syndrome in Parkinson disease.[bja.oxfordjournals.org]
    Hyperpyrexia
    • Clinical features of NMS are muscle rigidity, hyperpyrexia, autonomic instability, mental status changes, and high level of creatine phosphokinase.[scopemed.org]
    • Symptoms commonly include hyperpyrexia, muscle rigidity, autonomic dysfunction and altered mental status.[benthamscience.com]
    • […] do not necessarily have such effects. neuroleptic malignant syndrome a rare but dramatic condition that occurs in severely ill patients being treated with high-potency antipsychotics (neuroleptics); symptoms include diaphoresis, muscle rigidity, and hyperpyrexia[medical-dictionary.thefreedictionary.com]
    • Symptoms do not include rigidity or sweating (in fact hyperpyrexia is due to impairment of sweating) idiopathic lethal catatonia.[aic.cuhk.edu.hk]
    Hypertension
    • Table 1: Characteristics of NMS and serotonin syndrome 2 Neuroleptic malignant syndrome Serotonin syndrome Precipitated By Dopamine Antagonists Serotonergic Agents Onset Variable, 1-3 days Variable, 12 hours Identical Features Vital Signs Hypertension[medsafe.govt.nz]
    • On day 4 of admission, the patient was persistently febrile up to 40.5 C, hypertensive at 160/90 mmHg, and tachycardic at 110 beats per minute.[hindawi.com]
    • […] to 5 to 20 percent [4] Clinical Features Tetrad of: [5] Altered mental status - Agitated delirium progressing to stupor/coma Muscular Rigidity - Generalized, "lead pipe" rigidity Hyperthermia 38C (87%); 40C (40%) Autonomic Instability - Tachycardia, Hypertension[wikem.org]
    • A 35-year-old man presents with fever, hypertension and altered mental status.[foamcast.org]
    • Criteria A • Fever • Muscular rigidity Criteria B • Altered sensorium • Mutism • Tachycardia • Hypertension/ Labile BP • Diaphoresis • Tremor • Dysphagia • Leucocytosis • Lab evidence of Muscle injuryBoth major criteria and 2 minor criteria AND not due[slideshare.net]
    Hypotension
    • Tumors Information Page Polymyositis Information Page Pompe Disease Information Page Porencephaly Information Page Post-Polio Syndrome Information Page Postherpetic Neuralgia Information Page Postinfectious Encephalomyelitis Information Page Postural Hypotension[ninds.nih.gov]
    • On examination, the patient was drowsy, afebrile (Temp 36.8 o C/98.3 o F), hypotensive (BP 85/64 mmHg), tachycardic (HR 105 bpm), and tachypnic (24/min).[bjmp.org]
    • Up to 14% of patients with SS present with hypotension 19 and when the vital organs aren’t perfused, patient outcomes suffer significantly.[emdocs.net]
    • Hypotension is the most limiting side‐effect.[bja.oxfordjournals.org]
    Leukocytosis
    • […] and deranged liver function tests Muscle rigidity — eg, trismus (jaw contraction), extrapyramidal symptoms, rhabdomyolysis Laboratory findings include elevated creatinine kinase, leukocytosis and deranged liver function tests.[pharmaceutical-journal.com]
    • A correlation between a decrease in urine concentration of fluphenazine breakdown products and a decrease insymptoms has been reported Investigations rise in CPK /- myoglobinaemia leukocytosis /- left shift common elevated transaminases, LDH and alk.[aic.cuhk.edu.hk]
    • The initial laboratory results showed: CPK 6308 IU/L, CPK MB 70 IU/L sodium 113 mEq/L , potassium 3.7 mEq/L, mildly elevated transaminases, leukocytosis 10,700/mm3 , Hgb 12.8 g/dL, with other routinely used tests in a reference range.[signavitae.com]
    • Serum CPK level elevation and a leukocytosis may also be present.[fpnotebook.com]
    Malignant Catatonia
    • Malignant catatonia is also less likely, as such patients typically demonstrate positive motor phenomena such as dystonic posturing, waxy flexibility and stereotyped repetitive movements.[prognosisapp.com]
    • Malignant catatonia — Most problematic in the differential diagnosis of NMS, malignant catatonia shares clinical features of hyperthermia and rigidity with NMS.[uptodate.com]
    • There is also thought to be considerable overlap between malignant catatonia and NMS in their pathophysiology, the former being idiopathic and the latter being the drug-induced form of the same syndrome.[en.wikipedia.org]
    Malignant Hyperthermia
    • Neuroleptic malignant syndrome and malignant hyperthermia.[bja.oxfordjournals.org]
    • Malignant hyperthermia Malignant hyperthermia occurs rarely after exposure to halogenated volatile anesthetics and depolarizing muscle relaxants (succinylcholine).[pharmacyjoe.com]
    • Clinically, neuroleptic malignant syndrome resembles malignant hyperthermia.[merckmanuals.com]
    • A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in malignant hyperthermia, the neuroleptic malignant syndrome and an update - A Ward, MO Chaffman, EM Sorkin - Drugs, 1986 - ukpmc.ac.uk A successful electroconvulsive[symptoma.com]
    • To assist clinicians and advance consensus and understanding of NMS, the Neuroleptic Malignant Syndrome Information Service (NMSIS) was founded in 1997 by the Malignant Hyperthermia Association of the United States ( MHAUS ) in collaboration with a group[mhaus.org]
    Metabolic Acidosis
    • acidosis Urinalysis Myoglobinuria (from rhabdo) LFT Transaminitis CT/ LP CSF may have mildly elevated protein Serotonin syndrome vs Neuroleptic malignant syndrome History of a new serotonergic drug or a dose increase of a serotonergic drug are helpful[wikem.org]
    • The patient may suffer hypertensive crisis and metabolic acidosis.[en.wikipedia.org]
    • acidosis See Workup for more detail.[emedicine.medscape.com]
    • Transaminases, alkaline phosphatase (ALP), and lactic acid dehydrogenase (LDH) levels may also be elevated, while electrolyte abnormalities and metabolic acidosis may be seen.[prognosisapp.com]
    Rhabdomyolysis
    • Termination of dantrolene therapy may not be necessary during rhabdomyolysis and elevated aminotransferase levels. 1.[dx.doi.org]
    • - 2 theories neuroleptic-induced alteration of central neuroregulatory mechanisms - impaired heat dissipation abnormal reaction of predisposed skeletal muscle (like MH) CLINICAL FEATURES develops over 24-72 hrs hyperthermia rigidity rhabdomyolysis RESP[lifeinthefastlane.com]
    • Characterized by hyperthermia, tachycardia, sweating, muscle rigidity and mild rhabdomyolysis.[aic.cuhk.edu.hk]
    • Abstract Neuroleptic malignant syndrome (NMS) can be defined as an idiosyncratic and potentially fatal reaction to neuroleptic agents that consists of fever, mental status changes, muscle rigidity, autonomic dysfunction, respiratory distress and rhabdomyolysis[jdc.jefferson.edu]
    • Laboratory results revealed creatine kinase to be 15.1 μkat/l and myoglobin to be 8,654 μg/l, indicating rhabdomyolysis.[ccforum.com]
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  • Etiology

    NMS is a drug-induced disorder that has first been described by the French psychiatrist Jean Delay and his colleagues who associated it with haloperidol [1]. By now, a myriad of psychotropic drugs has been related to this symptom complex, some others even state that NMS has been associated with "every single antipsychotic compound" used so far [2]. Most cases are ascribed to the administration of dopamine D2 receptor antagonists and it is generally assumed that antidopaminergic effects account for the majority of symptoms shown by NMS patients. Other drugs related to NMS mediate only minor alterations of dopaminergic pathways or none at all. In detail, the following compounds may trigger NMS:

    • First-generation antipsychotics, e.g., flupentixol, fluphenazine, haloperidol, trifluoperazine, zuclopenthixol
    • Second-generation antipsychotics, e.g., aripiprazole, clozapine, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone
    • Antidepressants like amoxapine and phenelzine
    • Antiemetics, e.g., metoclopramide, prochlorperazine, and promethazine
    • Lithium

    Patients who are administered highly potent drugs at high doses, or who are subjected to sudden changes of medication, e.g., treatment with more potent compounds, dose increase, or withdrawal of dopamine agonists, are at high risks of developing NMS. This also applies to individuals who receive parenteral treatment or who receive more than one drug.

    Available data don't allow for the deduction of dose-response relationships and additional factors, presumably genetic, developmental and environmental influences, are likely to predispose and contribute to NMS. A few studies have been published on the genotype of NMS patients [3], but large-scale analyses have not yet been carried out. With regards to environmental factors, high temperatures, dehydration and physical restraint have been proposed to contribute to the onset of NMS [2]. Infectious diseases, ileus, stroke and trauma have also been listed as precipitating events [4].

    Epidemiology

    NMS is a rather uncommon side effect of antipsychotic and related treatment, with an estimated 0.2 to 30 per 1,000 patients receiving such therapy developing this disorder [5]. However, the respective drugs are prescribed to large numbers of people and thus, NMS is regularly seen by neurologists and emergency physicians. Incidence rates have been decreasing though, and this trend may reflect changed prescription habits due to an increased awareness, or improved pharmacovigilance. With regards to the class of drugs most commonly associated with NMS, a literature review yields contradictory results. To date, it cannot be concluded that NMS incidence diminished owing to the preferential prescription of second-generation antipsychotics.

    A predilection for males has been reported, but race seems unlikely to influence the individual risk of NMS. The mean age of onset is 50 years [6].

    Sex distribution
    Age distribution

    Pathophysiology

    The pathophysiological mechanisms underlying NMS are only partially understood. Administration of high doses of dopamine D2 receptor antagonists ensues a sudden inhibition of dopaminergic signaling in distinct brain regions, namely in the hypothalamus (associated with hyperthermia), the nigrostriatal bundle (related to rigidity and tremor), and the mesolimbic and mesocortical pathways (accounting for the altered mental state) [7], and it is generally agreed on that NMS is the result of these events. This hypothesis is further supported by the fact that NMS may be triggered by withdrawal of dopamine agonists, which are generally prescribed to patients suffering from Parkinson's disease [8]. However, NMS has been described in patients on psychotropic drugs that are not known to interfere with dopaminergic pathways. In this context, involvement of the sympathetic nervous system in NMS pathogenesis has been studied. In fact, autonomic dysfunction as well as hyperthermia and rigidity may be related to such effects [9], and NMS patients often show enhanced levels of urine and plasma catecholamines. Moreover, it has been speculated that serotonergic signaling cascades may be compromised in NMS patients. Lithium, for instance, may trigger NMS and does modulate noradrenergic and serotonergic signaling. Despite the fact that serotonin syndrome is considered a different entity, there are etiological, pathophysiological and clinical similarities between this disorder and NMS [10].

    Prevention

    To date, the etiology of NMS is only partially understood. Consequently, the risk of NMS should be considered in any patient treated with psychotropic drugs, particularly if neuroleptics are administered. Thus, prescription of such drugs should be considered carefully. Patients with a history of NMS are at risk of recurrence, and because discontinuation of therapy is often not an option, alternative treatment regimens should be applied in such cases. Furthermore, patients should be advised of this uncommon side effect and should be encouraged to inform their physician upon first perception of symptoms.

    Summary

    Neuroleptic malignant syndrome (NMS) is a severe neurological disorder; it is also an uncommon side effect of treatment with antipsychotic drugs, antidepressants, antiemetics and lithium. Symptom onset is generally ascribed to high doses of the corresponding pharmaceuticals, to sudden dose increase or even withdrawal of medication mediating contrary effects. To date, it is not possible to predict the development of NMS in an individual patient, though, and additional, as-of-yet unknown factors are likely to play a pathogenetic role.

    The clinical hallmarks of NMS are hyperthermia, rigidity, autonomic dysfunction and an altered mental status. A thorough analysis of the patient's medical history, recent changes in medication, as well as laboratory analyses of blood and urine samples are the mainstays of NMS diagnosis. An early initiation of therapy is crucial for survival, since NMS patients may suffer rhabdomyolysis and renal failure, aspiration pneumonia and coagulation disorders in advanced stages of the disease. If such complications are developed, the patient's prognosis worsens significantly.

    Treatment consists in withdrawal of the causative agent and measures to relieve symptoms. In this context, fluid therapy, muscle relaxants and dopaminergic agents are most frequently applied. Most patients recover within two weeks after symptom onset. Continuation of neuroleptic therapy has to be re-evaluated thereafter since patients with a history of NMS are more likely to suffer additional episodes of this disease. In many cases, change to an alternative treatment regimen is sufficient to prevent new bouts of NMS.

    Patient Information

    Neuroleptic malignant syndrome (NMS) is a drug-induced neurological disorder characterized by high fever, rigidity, autonomic dysfunction and an altered mental status. It is most frequently related to medication prescribed to patients suffering from schizophrenia, bipolar disorder and other forms of psychosis, but antidepressants and antiemetics have also been reported to induce NMS. Commonly, the onset of symptoms is associated with a recent change in medication or increased doses. The majority of the aforementioned compounds inhibits dopaminergic signaling pathways in the brain, i.e., they reduce the availability of the neurotransmitter dopamine for brain functions. Of note, patients who are diagnosed with Parkinson's disease suffer from dopamine deficiency, and they are generally treated with drugs that stimulate dopaminergic signaling. Therefore, sudden discontinuation of antiparkinson treatment may result in NMS, too.

    Symptom onset is subacute and complaints develop gradually in the course of several days. Besides the abovementioned cardinal symptoms of NMS, affected individuals may also develop tremor and gait disturbances, difficulties in breathing, speaking and swallowing, palpitations, fluctuations in blood pressure, incontinence, hallucinations, disorientation, psychomotor agitation and delirium. In severe cases, breakdown of muscle proteins with subsequently increasing serum concentrations of myoglobin may impair kidney function. This process does indeed account for a considerable share of NMS-associated mortality. Since renal failure does generally not occur in early stages of the disease, the initiation of treatment in a timely manner is crucial for a favorable prognosis.

    Treatment with the psychotherapeutic drug that induced the episode of NMS has to be discontinued, but may be restarted at a later point in time. Then, a change to an alternative treatment regimen should be considered. Most patients recover within about two weeks if adequate symptomatic therapy is provided.

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    References

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    7. Berman BD. Neuroleptic malignant syndrome: a review for neurohospitalists. Neurohospitalist. 2011; 1(1):41-47.
    8. Fiore S, Persichino L, Anticoli S, De Pandis MF. A neuroleptic malignant-like syndrome (NMLS) in a patient with Parkinson's disease resolved with rotigotine: a case report. Acta Biomed. 2014; 85(3):281-284.
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    Media References

    1. Haloperidol (Haldol), CC BY-SA 3.0

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