Clinical%20Dilemmas:%20%20the%20Differentiation%20between%20Lethal%20Catatonia%20and%20Neuroleptic%20Malignant%20Syndrome

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Clinical Dilemmas the Differentiation between
Lethal Catatonia and Neuroleptic Malignant
Syndrome

• 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.

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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 1990s at SVH after Thioridazine
  briefly D/Cd...hysterectomy
• Widow in 2002, lives alone in house, Gr. 5
  education, restaurant worker, supportive 2 sons,1
  dtr., brother and sister

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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

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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 IADLs
• 3MS72/100 FMMSE24/29

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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

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Case Presentation-5 Ms. A

• Sept 15-28, 2007 Home
• Hypomanic in Dayprogram
• Increased home support
• Compliant with Epival (level498) , 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

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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 Im God. Dont touch me...kill you
• Sleeping 2 hrs.
• 3MS49/100 FMMSE18/30
• Clonazepam 2 mg/d, Seroquel, Epival (level 571)

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Case Presentation-7 Ms. A

• Oct 31
• Feel dizzy, speech different, tremor, headache
• CPK37, WBC8000, Valproic level660
• 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

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Case Presentation-8 Ms. A

• Nov 2-5
• Meds
• Epival 875 mg/d, Seroquel 350 mg/d, Clonazepam 2
  mg/d
• Cant see, Cant swallow, more tremor,
  disorganized
• Antipsychotic prns

Loxapine Seroquel
Nov 2 5 25
Nov 3 17.5 25
Nov 4 10 25
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Case Presentation-9 Ms. A

• Nov 5
• Perseverate blood, blood, blood
• Thinks food is poisoned
• Pacing, Didnt sleep
• CPK 18,245 (normal lt 230)
• WBC 12,400 (normal lt 11,000)
• T 37.4
• BP 170/90 (not labile)
• PR 120

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Case Presentation-10

• What is your diagnosis?
• What is the differential diagnosis?
• What is your next step?

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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 lt 0.10)

Temperature CPK WBC
Nov 5 37.4 18,245 12,900
Nov 6 36-38.2 12,210 13,900
Nov 7 37. 2 3354 15,800
Nov 8 38.3 666 8100-14,600
Nov 9 37.3 471 8800
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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

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Case Presentation-13

• What is the next step?

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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 ECTs 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

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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/cata
  tonia.html

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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

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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.

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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.

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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.

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Lethal Catatonia (Kahlbaum 1874)Mann et al.,
Amer. J. Psych. 1986 14311, 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

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Lethal Catatonia

• Post-neuroleptic era
• Stupor may be predominant presentation
• Antipsychotics, benzos, etc. can decrease
  excitement
• Up to 10 inpatient psych. admission?
• Fatal in 60?

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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

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NMS and Medications

• Antipsychotic medications
• Withdrawal of L-Dopa or dopamine agonists
• Prochlorperazine (Stemetil)
• Metoclopramide (Maxeran)
• Tetrabenanzine (Nitoman)

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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

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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 164870-876, June 2007

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Item Sachdev NMS Scale (2005) total36 Sachdev NMS Scale (2005) total36 Sachdev NMS Scale (2005) total36 Sachdev NMS Scale (2005) total36 Sachdev NMS Scale (2005) total36 Sachdev NMS Scale (2005) total36 Sachdev NMS Scale (2005) total36 Subtotal Score
Oral temperature 0 1 2 3 4 5 6 ____ ____
Rigidity 0 1 2 3 ____
Dysphagia 0 1 ____
Resting tremor 0 1 2 ____ ____
Systolic BP 0 1 ____
Diastolic BP 0 1 ____
Tachycardia 0 1 ____
Diaphoresis 0 1 ____
Incontinence 0 1 ____
Tachypnea 0 1 ____ ____
Altered LOC 0 1 2 3 4 5 6 ____ ____
Posturing 0 1 ____
Poverty of speech 0 1 ____
Mutism 0 1 2 ____
Choreiform 0 1 ____ ____
Dystonia 0 1 ____
CK level (U/L) 0 1 2 3 4 ____
Leucocytosis 0 1 2 ____ ____
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Sachdev NMS Rating Scale CK Levels (Psych Res.
2005)
CK level (U/L) lt 200 rate 0
200400 rate 1 (0 if i.m. injection in previous 24 h)
4001000 rate 2 (1 if i.m. injection in previous 24 h)
100010,000 rate 3
gt 10,000 rate 4
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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)

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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 groupDrs.
  Caroff, Mann, Campbell (U. Penn)

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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

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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
• N292 Lethal Catatonia patients from 1960 (Mann
  S. Am J Psychiatry 1986 1431374-1381)
• Unable to distinguish from NMS in 22

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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

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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)

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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

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Prevalence of Catatonia and Mania
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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/bbs00002
  244-00/bbs.northoff.htm
• 54 page paper
• Top Down Modulation subcortical and cortical
  circuits reciprocally connect
• More GABA-mediated, rather than D2 mediated

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Modulation in Catatonia
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The Frontal Lobes and its Connections
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Catatonia and PD Differences
Catatonia Parkinson
GABA (lorazepam) - Gaba-ergic mediated neuronal inhibition in medial orbitofrontal cortex - Modulation of functional and behavioral inhibition
NMDA (Amantadine) - Down-regulation of glutamatergic-mediated overexcitation in prefrontal and orbitofrontal-parietal pathways - Down-regulation of glutamatergic-mediated overexcitation in subcortical pathways
Dopamine - Top-down modulation of striatal D-2 receptors predisposing for neuroleptic-induced catatonia -Compensation for striatal D-2 receptor deficit with "normalization" of "bottom-up modulation
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Catatonia Treatment Review of Lit.Hawkins et
al., Int. J. Psych. Med. 1995 25(4) 345-69

• N178, 1985-1994 published cases
• Benzos effective in 70 (Lorazepam)
• ECT effective in 85
• Antipsychotics effective in 7.5, or may even
  worsen symptoms (neuroleptic-induced catatonia)

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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?

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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)

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NMS and ECT Review of Lit.Trollor and Sachdev,
Aust.NZ J. of Psych 1999 33650-59

• 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 hyperthermiaonly one case of
  hyperkalemia following ECT for NMS

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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

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