Clinical Dilemmas: the Differentiation between Lethal Catatonia and Neuroleptic Malignant Syndrome

1. Dr. Peter Chan, MD, FRCPC Geriatric and Consult-Liaison Psychiatrist and Head of ECT Program, Vancouver General Hospital. Clinical Associate Professor, Dept. of Psychiatry, University of British Columbia. Clinical Dilemmas: the Differentiation between Lethal Catatonia and Neuroleptic Malignant Syndrome

2. Learning Objectives • To review symptoms and signs of catatonia including lethal catatonia.  • To know the overlap between catatonia and neuroleptic malignant syndrome.  • To understand the role of ECT in both catatonia and neuroleptic malignant syndrome

3. Case Presentation-1: Ms. A • 68 y.o. Italian independent woman, some command of English, on Thioridazine (Mellaril) for 49 years, since last institutional admission. • History of Psychosis, postpartum. • No family psychiatric history • Brief hosp. In 1990’s at SVH after Thioridazine briefly D/C’d...hysterectomy • Widow in 2002, lives alone in house, Gr. 5 education, restaurant worker, supportive 2 sons,1 dtr., brother and sister

4. Case Presentation-2: Ms. A • June 2007 • Loxapine 25 mg bid after stop Mellaril in May 2007 • Labile, energetic, little sleep, racing thoughts • Smelling bad odours in home • Paranoid, carrying knife, throwing items in frustration • “Confused” , disorganized, suicidal • VGH Inpt Unit via emergency (June 10-July 18) • Dx: Bipolar Disorder • Olanzapine 15 mg qhs • Trazadone 100 mg qhs • Clonazepam 0.25 mg/d

5. Case Presentation-3: Ms. A • Short-term Assessment and Treatment (STAT) Geriatric In Unit (Aug 23, 2007) • Had been seen at STAT Dayprogram • Incontinent with urinary retention • Switched from Olanzapine to CPZ 250 mg/d by community psych. • Dependent on IADL’s • 3MS=72/100; FMMSE=24/29

6. Case Presentation-4: Ms. A • STAT In-Unit (Aug 23-Sept 14) • Mood labile, insomnia • Alternates between singing at night and weeping in daytime, playing opera • Some pressure of speech • Dx: Bipolar, mixed state • Epival 750 mg/d • Quetiapine 100 mg qhs

7. Case Presentation-5: Ms. A • Sept 15-28, 2007: Home • Hypomanic in Dayprogram • Increased home support • Compliant with Epival (level=498) , mixing up blister packed meds? • Son called emergency mental health services on Sept 25: threaten him with a knife “leave me alone”, crying continually, plays loud opera music in the phone, looking for a new partner, hostile and throwing things, isolate from family • Quetiapine up to 175 mg/d

8. Case Presentation-6: Ms. A • VGH Psych Emerg. and STAT (Sept 28-Nov 5) • Seroquel increased to 350 mg/d, multiple IM doses in Psych Emerg. Seclusion room. • Oct 3: • Mood labile • Demanded to see her husband, anniversary party • Sad...join husband, tearful, tangential, speak loud • Physically aggressive • Grandiose “I’m God. Don’t touch me...kill you” • Sleeping 2 hrs. • 3MS=49/100; FMMSE=18/30 • Clonazepam 2 mg/d, Seroquel, Epival (level = 571)

9. Case Presentation-7: Ms. A • Oct 31: • Feel dizzy, speech different, tremor, headache • CPK=37, WBC=8000, Valproic level=660 • Nov 2: • 3 hrs/nt sleep past 2 nts • Paranoid, hypervigilant • Fine resting tremor (no cogwheeling) • “Nothing inside”, Perseverate: “blood, blood, blood” • Resistance to food, labile mood

10. Case Presentation-8: Ms. A • Nov 2-5: • Meds: • Epival 875 mg/d, Seroquel 350 mg/d, Clonazepam 2 mg/d • “Can’t see”, “Can’t swallow”, more tremor, disorganized • Antipsychotic prn’s

11. Case Presentation-9: Ms. A • Nov 5: • Perseverate: “blood, blood, blood” • Thinks food is poisoned • Pacing, Didn’t sleep • CPK= 18,245 (normal < 230) • WBC= 12,400 (normal < 11,000) • T= 37.4 • BP = 170/90 (not labile) • PR = 120

12. Case Presentation-10 • What is your diagnosis? • What is the differential diagnosis? • What is your next step?

13. Case Presentation-11: Ms. A • Nov 5-7: • Nov 5: • Transfer to Acute Medicine Step Down: NMS? • Antipsychotics stopped • Nov 6: “lead pipe rigidity”, Dantrolene • Nov 7: Bromocryptine added, Desat 80% O2 • Transfer to ICU after code blue (aspiration LLL) • EEG: Mild slowing left side • Troponin 0.53 (normal < 0.10)

14. Case Presentation-12: Ms. A • Nov 8-12 (ICU): • Nov 8: Midazolam drip, no clonazepam, stop Epival. • Nov 9: • Repeat EEG • Mild diffuse encephalopathy, intermittent slowing ( 1-3 Hz delta) • CT head • Nil acute changes • Nov 12: • Rigidity, voluntary component, Rabbit-like jaw tremor

15. Case Presentation-13 • What is the next step?

16. Case Presentation-14: Ms. A • Nov 12: • BT ECT initiated in ICU (rocuronium used) • Hypotension, bolus helped • Nov 13-Dec 6 (ICU then Acute Medicine Unit) • BT ECT’s times 9, 50% energy dosing • Slow improvement in alertness, rigidity, speech • Tremor and “rabbit” jaw movements gone • Smiling, recognizing family • Feeding tube but eating some • Transferred to Provincial Institution from STAT on Dec 10 for further treatment…

17. Catatonia: DSM-IV criteria • Motor immobility as evidenced by catalepsy (including waxy flexibility) or stupor; • Excessive motor activity (purposeless, not influenced by external stimuli); • Extreme negativism (motiveless resistance to all instructions or maintenance of a rigid posture against attempts to be moved) or Mutism; • Peculiarities of voluntary movement as evidenced by posturing, stereotyped movements, prominent mannerisms, or prominent grimacing • Echolalia or Echopraxia. • At least 2 of the above features • Due to mental (eg: Schizophrenia or Mood Disorders) or medical disorder • Does not occur exclusively during the course of a Delirium *Gegenhalten, Mitgehen, Automatic Obedience, Ambitendency Fink Catatonia Scale (1996): www.ukppg.org.uk/catatonia.html

18. Catatonia: Phenomenology-1 • Posturing • Spontaneous maintenance of posture (s), including mundane (e.g. sitting or standing for long periods without reacting). • Limb posturing • “Psychic pillow” • Staring

19. Catatonia: Phenomenology-2 • Rigidity • Maintenance of a rigid position despite efforts to be moved, exclude if cog-wheeling or tremor present • Negativism • Apparently motiveless resistance to instructions or attempts to move/examine patients. Contrary behaviour, does exact opposite of instruction. • Waxy Flexability • During reposturing of patient, patient offers initial resistance before allowing himself to be repositioned, similar to that of a bending candle.

20. Catatonia: Phenomenology-3 • Gegenhalten • Continuous involuntary sustained muscle contraction When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. • Mitgehen • "Anglepoise lamp" arm raising in response to light pressure of finger, despite instructions to the contrary.

21. Catatonia: Phenomenology-4 • Ambitendency • Patient appears "motorically stuck" in indecisive, hesitant movement. • Automatic Obedience • Exaggerated cooperation with examiner's request or spontaneous continuation of movement requested.

22. Lethal Catatonia (Kahlbaum 1874)Mann et al., Amer. J. Psych. 1986; 143:11, p. 1374-81 • Classic description (Pre-neuroleptic era): • Intense motor excitement followed by hyperthermia and exhaustion or stupor • Often prodromal phase of insomnia, anorexia, labile mood • May demontrate catatonic signs, and be delirious-like (disorganized thinking, psychosis, destructive) • May have rigidity, or flaccidity, in terminal stages • Presence of acrocyanosis in some • Fatal in 75-100%

23. Lethal Catatonia • Post-neuroleptic era: • Stupor may be predominant presentation • Antipsychotics, benzo’s, etc. can decrease excitement • Up to 10% inpatient psych. admission? • Fatal in 60%?

24. Neuroleptic Malignant Syndrome: DSM-IV criteria • Development of severe rigidity and elevated temperature associated with the use of neuroleptic medication • 2 of the following: diaphoresis, dysphagia, tremor, incontinence, change LOC, mutism, tachycardia, elevated or labile BP, elevated WBC or CPK (may also observe myoclonus) • Not due to another substance, or neurological disorder, or other general medical condition • Not better accounted for by a mental disorder

25. NMS and Medications • Antipsychotic medications • Withdrawal of L-Dopa or dopamine agonists • Prochlorperazine (Stemetil) • Metoclopramide (Maxeran) • Tetrabenanzine (Nitoman)

26. NMS risk factors • Exhaustion and Dehydration • Agitation, Stress, Psychosis • Higher potency, rapid titration, multiple I.M.’s • Environmental heat a factor? • Previous history (trait vulnerability?) • 17% hx. of NMS • 30% will develop NMS again upon re-challenge

27. NMS: Pathogenic Mechanisms Figure 1. Simplified Pathophysiology of Neuroleptic Malignant Syndrome (NMS), and Elements of Sympathoadrenal Dysregulation From: Strawn J. Neuroleptic Malignant Syndrome (review). Am J Psychiatry 164:870-876, June 2007

29. Sachdev NMS Rating Scale: CK Levels (Psych Res. 2005)

30. NMS Course • 0.2% of patients • 16% develop within 24 hrs of exposure • 66% develop within 1 week of exposure • Virtually all by 1 month of exposure • 63% recover within 1 week of elimination • Virtually all recover by 1 month of elimination • Should wait 2 weeks at least after recovery before re-challenge with antipsychotics • 10-20% mortality rate • Few have persistent catatonic and/or parkinsonian state (Caroff, S. J. Clin. Psychopharm. 2000)

31. NMS Treatment: Information • Neuroleptic Malignant Syndrome Information Service (NMSIS): • 24 hr. Hotline for professionals: 1-888-667-8367 • www.nmsis.org • Information: 1-888-776-6747 • Non-profit clinical and research group—Drs. Caroff, Mann, Campbell (U. Penn)

32. NMS: Catatonic and Non-CatatonicLee JW, Aust NZ J. of Psych. 2000; 34(5): 877-8 • Antecedent Catatonia may predispose to catatonic NMS • Non-catatonic NMS more likely preceded by severe EPS and delirium

33. NMS and Catatonia: Similarities • Appearance of catatonic symptoms in NMS • Appearance of rigidity and hyperthermia in (lethal) catatonia • Treatment with Lorazepam in NMS (Francis A. CNS Spectrum 2000) and Catatonia can improve • ECT effective in both • N=292 Lethal Catatonia patients from 1960 (Mann S. Am J Psychiatry 1986; 143:1374-1381) • Unable to distinguish from NMS in 22%

34. NMS and Catatonia: Differences • Extreme (lead pipe) rigidity uncommon in catatonia • Stereotypic signs of catatonia unusual in NMS • Excitement then hyperthermia pre-neuroleptic in lethal catatonia; rigidity then hyperthermia post-neuroleptic in NMS • Potentially effective treatments for NMS (dopamine agonists, dantrolene) less proven in catatonia

35. Similar Conditions: DDx • Malignant Hyperthermia • Anticholinergic Delirium • Heatstroke • Manic Delirium • Serotonin Syndrome • Abusable alcohol or drug withdrawal (eg: delirium tremens) and intoxication (eg: Ecstasy) • Status epilepticus and other CNS conditions • Systemic Conditions: infection, hyperthyroidism, pheochromocytoma, adrenal cortical abnormalities, other causes of rhabdomyolysis (eg: collapse)

36. Catatonia • In the modern era, the most likely psychiatric cause for catatonia is Bipolar Disorder, esp. Mania • More likely when severe mania • Kahlbaum, Bleuler, Kraepelin all noted mood disturbance preceding catatonia From: Taylor MA, Am J Psych 2003

37. Prevalence of Catatonia and Mania From: Taylor MA, Am J. Psych 2003

38. Pathogenic Mechanisms: Catatonia • Neurochemical substrates: • D2 antagonists can worsen catatonia • GABA-B, 5-HT1A agonists promote catatonia • GABA-A, 5-HT2A, NMDA agonists reduce catatonia • G. Northoff (2000): • www.bbsonline.org/documents/a/00/00/22/44/bbs00002244-00/bbs.northoff.htm • 54 page paper • “Top Down Modulation”: subcortical and cortical circuits reciprocally connect • More GABA-mediated, rather than D2 mediated

39. From: Northoff 2000

40. Modulation in Catatonia From: Northoff 2000

41. The Frontal Lobes and its Connections From: Northoff 2000

42. Catatonia and PD: Differences

43. Catatonia Treatment: Review of Lit.Hawkins et al., Int. J. Psych. Med. 1995; 25(4): 345-69 • N=178, 1985-1994 published cases • Benzo’s effective in 70% (Lorazepam) • ECT effective in 85% • Antipsychotics effective in 7.5%, or may even worsen symptoms (neuroleptic-induced catatonia)

44. Catatonia: Treatment • Rule out medical condition • Lorazepam 1-12mg/day, up to 72hrs. Trial • Specific GABA-A agonist • Dantrolene to be considered if rigidity • ECT is treatment of choice • May consider mECT if recurrent • Others: • Atypical Antipsychotic? (not for lethal catatonia) • Amantadine? • Memantine?

45. NMS Treatment: Biological • Discontinue Antipsychotic Drug • Supportive Medical Treatments • Mild to Moderate NMS: • Bromocryptine 2.5-5 mg q8h (up to 30mg/d) • Amantadine 100mg q8h (to 200-400mg/d) • May use Benzo (eg: Lorazepam 1-8 mg/d) • Moderate to Severe NMS: • Dantrolene IV 1-2.5mg/kg (1mg/kg q6h) • ECT (bilateral, may even be daily)

46. NMS and ECT: Review of Lit.Trollor and Sachdev, Aust.NZ J. of Psych 1999; 33:650-59 • 45 published cases from 1966, and 9 new cases • Catatonia manifested in 76% of cases • 63% complete and 28% partial recovery with ECT • Onset of ECT response average 4 treatments, generally by 6 treatments • 4 cases of cardiovascular complications • Supports the use of succinylcholine unless familial malignant hyperthermia—only one case of hyperkalemia following ECT for NMS

47. NMS and ECT: Potential Use • Trollor and Sachdev: • Severe NMS • Differental between NMS and catatonia uncertain • Psychotic depression is the underlying disorder • Catatonia predominates in NMS

48. Catatonia Treatment AlgorithmFilip Van Den Eede et al. European Psychiatry 2005

49. Conclusions • It can be difficult to differentiate NMS and catatonia in practice, and definitive treatments are similar • Use of antipsychotics with less dopamine blockade is probably less likely to produce NMS and less likely to be severe, according to the dopaminergic hypothesis • Both NMS and catatonia can be safely and effectively treated with ECT, providing precautions are considered