1. NMS S EROTONIN S YNDROME D ELIRIUM T REMENS

3. DO I PLAY PSYCHIATRIST? NO, MEDICAL EMERGENCY!

4. CLINICAL SCENARIO A 21-year-old man with a history of schizophrenia and depression is brought in from home by paramedics for altered mental status. His mother reports that he started a new medication one month ago. He is hypertensive, tachycardic, febrile, and tachypneic with myoclonus and muscle rigidity. His mother is inconsolable and agitated at his decline in health over the last 3 days but is unable to provide any other medical history. Which medication likely precipitated this presentation? A. Aripiprazole B. Citalopram C. Diphenhydramine D. Ranitidine E. Alcohol cessation

5. KEY FEATURES Hot Sweaty Altered Time of onset PMHx / Rx

6. DIFFERENTIAL DIAGNOSIS Serotonin Syndrome –More likely to have hyperreflexia, myoclonus, ataxis, nausea and vomiting, diarrhea –Rigidity (LE >> UE) and hyperthermia, if present, is less severe than in NMS –Abrupt onset Malignant Hyperthermia –Distinguish by clinical setting (use of inhalational anesthetics or sux) –Hyperthermia, muscle rigidity, and dysautonomia is similar to NMS though more fulminant Neuroleptic Malignant Syndrome –Antipsychotics –Global lead-pipe muscle rigidity –Gradual onset (days – weeks) Anticholinergic Toxicity –Diaphoresis, rigidity, elevated CK are absent –Flushing, mydriasis, bladder distension are common Sympathomimetics –Hyperthermia yes, muscle rigidity is a big no-no Alcohol Withdrawal (the DTs) –History of recent alcohol cessation –Seizures yes, muscle rigidity no

7. NEUROLEPTIC MALIGNANT SYNDROME Rare adverse reaction to dopamine receptor antagonists, leading to autonomic dysfunction Can be fatal if not recognized early

8. TRIAD Change in Mental Status Fever Muscle Rigidity Autonomic Instability

9. SUDDEN CHANGE IN MENTAL STATUS Mental state changes usually precede other signs Ranging from: Confusion to stupor Agitation Delirium Catatonia Coma

10. FEVER Hyperpyrexia –>38 °C (87%) –>40 °C (40%)

11. MUSCLE RIGIDITY Abrupt onset of stiffening in large muscles –Especially head & neck –Can lead to difficulty swallowing Leads to excess body heat production, contributing to high temps Increased effects can cause hypoventilation and respiratory failure due to chest wall rigidity Other EPSEs: Akathisia Tremors Urinary incontinence

12. AUTONOMIC INSTABILITY Tachycardia Tachypnea Hypertension Diaphoresis

13. RISK FACTORS History of previous episode of NMS/EPSE Dehydration Withdrawal of benzodiazepines Organic brain disease High potency agents

14. PATHOPHYSIOLOGY Not fully understood, but… Dopaminergic blockade or depletion in CNS Similar to a drug induced malignant catatonia Genetics may play a yet unestablished role

15. COMMONLY ASSOCIATED DRUGS: Haloperidol -- >50% of all cases d/t commonly prescribed and potent Chlorpromazine LESS COMMONLY: Atypicals: quetiapine (Seroquel) risperidone (Risperdal) olanzapine (Zyprexa) Dopamine receptor antagonists: prochlorperazine (Stemetil) metoclopramide (Maxalon) promethazine (Phenergan)

16. ONSET At any time - can develop rapidly over several days Most cases appear when: Drug is started Dosage is increased Other drug initiated with synergistic effect

17. LABS Total CK –Typically >1000 –Correlates with degree of rigidity CBC –WBC >10K is typical Chemistry –May show hypocalcemia, hypomagnesemia, hyperkalemia, metabolic acidosis Urinalysis –Myoglobinuria (from rhabdo) LFT –Transaminitis CT/LP –CSF may have mildly elevated protein

18. MEDICAL MANAGEMENT Supportive Care Remove the offending agent Benzos for agitation Fluids Active cooling measure Intubation and paralysis for severe cases, chest wall rigidity or respiratory failure Medical Therapy (Controversial) Dantrolene (skeletal muscle relaxant) - Consider only in patients with severe rigidity –May cause hepatotoxicity in patients with liver disease Bromocriptine or Amantadine (dopamine agonist)

20. WHAT IS SEROTONIN SYNDROME Rare adverse reaction to serotonin agonists, leading to autonomic dysfunction. Can be fatal

21. TRIAD Change in Mental Status Fever Neuromuscular Abnormalities Autonomic Instability

22. FEVER Hyperpyrexia –>38 °C (87%) –>40 °C (40%) –Due to muscle contraction, not a change in thermal set point (like in NMS)

23. NEUROMUSCULAR ABNORMALITIES Abrupt onset of tremors, ataxia, and hyperreflexia –Lower Extr > Upper Extr Leads to excess body heat production, contributing to high temps Ocular clonus

24. AUTONOMIC INSTABILITY Tachycardia Tachypnea Hypertension Diaphoresis

25. RISK FACTORS History of previous episode of Serotonin Syndrome Withdrawal of benzodiazepines Medication Overlap

26. COMMONLY ASSOCIATED DRUGS (1) Antidepressants SSRIs, SNRIs, Buspirone TCAs Lithium Mirtazapine, Trazodone, Valproic acid MAOIs (should have washout period of 2+ wks prior to starting a SSRI) Drugs of Abuse Cocaine, Ecstasy (MDMA), Methamphetamine, LSD Antiemetics Metoclopramide, Ondansetron, Over the counter Medications Dextromethorphan Oral decongestants (Pseudoephedrine)

27. Herbal products St John’s Wort, Ginseng, Nutmeg, Yohimbe Analgesics Fentanyl Meperidine (Demerol) Methadone Tramadol Other Medications Triptans Ergot alkaloids Bromocriptine Linezolid Carbamazepine Cyclobenzaprine Methylene blue COMMONLY ASSOCIATED DRUGS (2)

28. ONSET Rapidly develops over hours Most cases appear when: Large overdose New drug is started Dosage is increased Other drug initiated with synergistic effect

29. LABS THAT ARE HELPFUL Elevations in CK, LFTs, and WBC, coupled with a low iron level, distinguishes NMS from serotonin syndrome among patients taking both neuroleptic and serotonin agonist medications simultaneously

30. MEDICAL MANAGEMENT Supportive Care Remove the offending agent Benzos for agitation Active cooling measure Intubation and paralysis for severe cases – to control hyperthermia Medical Therapy Cyproheptadine – Serotonin antagonist –has antihistamine and anticholinergic properties that may exacerbate other mixed toxicology picture Chlorpromazine – avoid if NMS still possible Precedex Discharge if stable after 6 hours unless: Hx of Serotonin Syndrome Prozac / Fluoxetine can have delayed onset

32. STAGES OF etOH WITHDRAWAL Tremulousness 6-12 hrs Tachycardia, agitation N/V, tremors Alcoholic Hallucinosis 12-24 hrs Visual hallucinations most common Resolves before onset of DTs No delirium Seizures 6-48 hrs Multiple seizures: 60% of patients Progression to DTs: 33% of patients Delirium tremens 48+ hrs Delirium & Agitation Autonomic hyperactivity

33. SAME SAME BUT DIFFERENT NMSSerotonin Syndrome OnsetGradual (days)Sudden Preceding featureAMS Agitation, Tremors Muscle RigidityLead-pipeSpastic w/ clonus Muscle Rig PatternHead & neck, whole body LE >> UE ReflexesReducedHyper

34. CLINICAL SCENARIO A 21-year-old man with a history of schizophrenia and depression is brought in from home by paramedics for altered mental status. His mother reports that he started a new medication one month ago. He is hypertensive, tachycardic, febrile, and tachypneic with myoclonus and muscle rigidity. His mother is inconsolable and agitated at his decline in health over the last 3 days but is unable to provide any other medical history. Which medication likely precipitated this presentation? A. Aripiprazole B. Citalopram C. Diphenhydramine D. Ranitidine E. Alcohol cessation

35. CLINICAL SCENARIO A 21-year-old man with a history of schizophrenia and depression is brought in from home by paramedics for altered mental status. His mother reports that he started a new medication one month ago. He is hypertensive, tachycardic, febrile, and tachypneic with myoclonus and muscle rigidity. His mother is inconsolable and agitated at his decline in health over the last 3 days but is unable to provide any other medical history. Which medication likely precipitated this presentation? A. Aripiprazole B. Citalopram C. Diphenhydramine D. Ranitidine E. Alcohol cessation

36. Correct Answer (A) Neuroleptic Malignant Syndrome (NMS) caused by the antipsychotic Aripiprazole must be distinguished from the clinically similar Serotonin Syndrome. Both are the result of an inappropriate physiologic response to psychiatric drugs and both classically present with hyperthermia, altered mental status, and skeletal rigidity. Tougher question stems will not offer the more obvious distinctions of lead-pipe rigidity (NMS) versus dilated pupils or hyperreflexia and clonus (Serotonin Syndrome). In this case, gradual onset over a several day period is a distinguishing feature of NMS caused by antipsychotics. Serotonin Syndrome from an SSRI like Citalopram (B) is more likely to occur with abrupt onset and most commonly due to overdose. Diphenhydramine (C) can also cause hyperthermia and rigidity but would typically present with more anticholinergic symptoms and a question stem that made overdose more likely. Ranitidine (D) is an H2 blocker and should not cause either NMS or serotonin syndrome. Overdose symptoms are vague but often include GI discomfort and GI distress, drowsiness, confusion, and flushing. Ethanol Withdrawal (E) would not result in rigidity but could cause altered mental status.

37. QUESTIONS?