Transcript An Update on 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.
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

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

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
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
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
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
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)
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
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
Loxapine
Seroquel
Nov 2
5
25
Nov 3
17.5
25
Nov 4
10
25
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
Case Presentation-10

What is your diagnosis?

What is the differential diagnosis?

What is your next step?
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)
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
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
Case Presentation-13

What is the next step?
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…
Catatonia: DSM-IV criteria





A.
B.
C.
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
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
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.
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.
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.
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%
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%?
Neuroleptic Malignant Syndrome:
DSM-IV criteria
Development of severe rigidity and elevated
temperature associated with the use of neuroleptic
medication
B. 2 of the following: diaphoresis, dysphagia, tremor,
incontinence, change LOC, mutism, tachycardia,
elevated or labile BP, elevated WBC or CPK (may
also observe myoclonus)
C. Not due to another substance, or neurological
disorder, or other general medical condition
D. Not better accounted for by a mental disorder
A.
NMS and Medications
Antipsychotic medications
 Withdrawal of L-Dopa or dopamine
agonists
 Prochlorperazine (Stemetil)
 Metoclopramide (Maxeran)
 Tetrabenanzine (Nitoman)

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
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
Item
Sachdev NMS Scale (2005): total=36
Subtotal
Score
Oral temperature
0 1
2
3
____
____
•Rigidity
0 1
2
3
•Dysphagia
0 1
•Resting tremor
0 1
•Systolic BP
0 1
____
Diastolic BP
0 1
____
•Tachycardia
0 1
____
•Diaphoresis
0 1
____
•Incontinence
0 1
____
•Tachypnea
0 1
____
____
Altered LOC
0 1
____
____
•Posturing
0 1
____
•Poverty of speech
0 1
____
•Mutism
0 1
•Choreiform
0 1
____
•Dystonia
0 1
____
•CK level (U/L)
0 1
2
•Leucocytosis
0 1
2
4
5
6
____
____
2
2
____
3
4
2
5
6
____
____
3
4
____
____
____
____
Sachdev NMS Rating Scale:
CK Levels (Psych Res. 2005)
CK level (U/L):
< 200
rate “0”
200–400
rate “1”
(0 if i.m. injection
in previous 24 h)
400–1000
rate “2”
(1 if i.m. injection
in previous 24 h)
1000–10,000
rate “3”
> 10,000
rate “4”
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)

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)
NMS: Catatonic and Non-Catatonic
Lee 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

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%
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 postneuroleptic in NMS
 Potentially effective treatments for NMS
(dopamine agonists, dantrolene) less proven in
catatonia

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)
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
Prevalence of Catatonia and Mania
From: Taylor MA, Am J. Psych 2003
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
From: Northoff 2000
Modulation in Catatonia
From: Northoff 2000
The Frontal Lobes and its Connections
From: Northoff 2000
Catatonia and PD: Differences
Catatonia
GABA
(lorazepam)
Parkinson
Gaba-ergic mediated neuronal
inhibition in medial orbitofrontal
cortex
- Modulation of functional and
behavioral inhibition
-
NMDA
- Down-regulation of
(Amantadine) glutamatergic-mediated
overexcitation in prefrontal and
orbitofrontal-parietal pathways
Dopamine
- Top-down modulation of striatal
D-2 receptors predisposing for
neuroleptic-induced catatonia
Down-regulation of glutamatergicmediated overexcitation in
subcortical pathways
-
-Compensation for striatal D-2
receptor deficit with "normalization"
of "bottom-up modulation
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 (neurolepticinduced catatonia)

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?
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)
NMS and ECT: Review of Lit.
Trollor and Sachdev, Aust.NZ J. of Psych 1999; 33:650-59




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
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
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
Catatonia Treatment Algorithm
Filip Van Den Eede et al. European Psychiatry 2005
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