1. Morbidity and Mortality report MICU Bliss 11I Veena Panduranga Juliana Alvarez-Argote

2. Neuroleptic malignant syndrome

3. Learning Objectives Describe a case of neuroleptic malignant syndrome Review the pathophysiology, diagnosis, and management of neuroleptic malignant syndrome

4. Overview Life-threatening, idiosyncratic reaction to medications affecting central dopaminergic neurotransmission. Early recognition is critical to prevent morbidity and death First reported case in 1956 with chlorpromazine Berman. Neurohospitalist. 2011 January

5. Overview Dopamine depletion Dopamine receptor blockers:  Virtually all antipsychotics, including atypical antipsychotics Cessation of dopaminergic medications:  levodopa, amantadine, tolcapone Incidence: 0.02% to 2% of pts on neuroleptics Adnet et al. Br J Anaest. 2000

6. Medications associated with NMS Berman. Neurohospitalist. 2011 January

7. Pathophysiology Strawn et al. Am J Psychiatry 164:6, June 2007

8. Clinical presentation Within 2 weeks after exposure Most cases hours to days after exposure Muscular rigidity followed by hyperthermia in several hours, along with wide range of altered mental status  Drowsiness, agitation, confusion, delirium, coma Autonomic dysfunction: labile BP, tachypnea, tachycardia, sialorrhea, diaphoresis, flushing, skin pallor, incontinence Berman. Neurohospitalist. 2011 January

9. Lab findings High CK (rhabdomyolysis) Leukocytosis Iron deficiency (96%) Renal failure (from rhabdomyolysis) Metabolic acidosis EEG: non generalized slowing Berman. Neurohospitalist. 2011 January

10. Diagnosis: DSM IV criteria:  Muscular rigidity (96%)  T>100,4  Use of neuroleptic medication  Two or more of:  Diaphoresis  Dysphagia  Tremor  Incontinence (54%)  AMS  Mutism (96%)  Tachycardia  Labile BP (40%)  Leukocytosis  Elevated CK (91%)  Symptoms not explained by another substance or medical condition Perry and Wilborn. Ann Clin Psychiatry. 2012

11. Diagnosis DSM IV criteria:  Severe muscular rigidity and high temperature, associated with use of neuroleptic medication  Two or more of: diaphoresis, dysphagia, tremor, incontinence, AMS, mutism, tachycardia, labile BP, leukocytosis, elevated CK  Symptoms not explained by another substance or medical condition

12. Differential diagnosis Heat stroke:  flaccid extremities, abrupt onset, hypotension, dry skin CNS infection:  Prodrome symptoms, meningismus, CSF labs Serotoninergic sd.  Absence of high CK, leukocytosis, presence of GI symptoms (n/v/d) Lethal catatonia:  Psychosis for weeks prior to presentation Malignant hyperthermia:  History of depolarizing muscle relaxants or inhaled anesthetics Cocaine intoxication Alcohol w/d Strawn et al. Am J Psychiatry. 2007

13. Management Neurologic emergency  Many will need ICU level of care Stop neuroleptic Restart dopaminergic meds in withdrawal (levodopa) Aggressive hydration (if high CK, AKI) Control temperature Bicarb for AKI Cardio respiratory support Adnet et al. Br J Anaest. 2000 Reulbach et al. Critical Care 2007

14. Management Bromocriptine: dopaminergic  PO or NGT  2.5mg BID or TID  increase up to 45mg/d  Monitor liver function Benzodiazepines:  Reasonable first line  1-2mg IV/IM q 4-6h  Mild/moderate cases or primarily catatonic symptoms Strawn et al. Am J Psychiatry. 2007 Reulbach et al. Critical Care. 2007

15. Management Amantadine: anticholinergic  100mg PO/NGT q 8h  Moderate cases Dantrolene: muscle relaxant, inhibits calcium release from sarcoplasmic reticulum  Severe cases (T >104, HR >120)  2.5mg/Kg + 1mg/Kg q 6h IV  Increase up to 10mg/Kg/d  Stop once symptoms resolving (resp failure/hepatotoxicity) ECT:  Cases with no response to medications/supportive care Strawn et al. Am J Psychiatry. 2007 Reulbach et al. Critical Care. 2007

16. Complications Renal failure DIC Rhabdomyolysis MI Asp. PNA Seizures, arrhythmias (lyte abnormalities) Reulbach et al. Critical Care 2007

17. When to restart neuroleptics Wait 2 weeks for PO antipsychotics Wait 5 weeks for depot forms Change neuroleptic med Switch from typical to atypical Start at low doses, titrate slowly Neuroleptic Malignant Syndrome Information Service. 2011. http://www.nmsis.org

18. Prognosis Mortality ~40% before 1984  Mortality greatly reduced (~10%) when recognized and treated early Recurrence of NMS in 30-50% cases after restarting neuroleptics Complete recovery in first 2 days to 2 weeks Mortality 2/2 arrhythmia, DIC, renal or CV complications Bottoni. Hospital physician. 2002

19. Take home points… NMS is a rare but severe reaction to dopamine blocking agents or withdrawal to dopaminergic agents Early recognition is critical in preventing significant morbidity and mortality Main manifestations are muscular rigidity, hyperthermia and history of medication intake or abrupt cessation Main management consists of stopping offending agent/restarting dopaminergic, aggressive hydration and temperature control Medications for NMS treatment include benzos, dantrolene, Many will require ICU level 2/2 cardiorespiratory decompensation

20. Thank you!