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 2007Labile, energetic, little sleep, racing thoughtsSmelling bad odours in homeParanoid, carrying knife, throwing items in frustration“Confused” , disorganized, suicidalVGH 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 DayprogramIncontinent with urinary retentionSwitched from Olanzapine to CPZ 250 mg/d

by community psych.Dependent on IADL’s3MS=72/100; FMMSE=24/29

Case Presentation-4: Ms. A STAT In-Unit (Aug 23-Sept 14)

Mood labile, insomniaAlternates between singing at night and

weeping in daytime, playing operaSome 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 DayprogramIncreased home supportCompliant 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, headacheCPK=37, WBC=8000, Valproic level=660

Nov 2:3 hrs/nt sleep past 2 ntsParanoid, hypervigilantFine 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 poisonedPacing, 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”, DantroleneNov 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 EEGMild diffuse encephalopathy, intermittent slowing ( 1-3 Hz delta)

○ CT headNil 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 dosingSlow improvement in alertness, rigidity, speechTremor and “rabbit” jaw movements goneSmiling, recognizing familyFeeding tube but eating someTransferred to Provincial Institution from STAT on Dec 10

for further treatment…

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.A. At least 2 of the above features B. Due to mental (eg: Schizophrenia or Mood Disorders) or medical disorderC. 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

NegativismApparently motiveless resistance to instructions or

attempts to move/examine patients. Contrary behaviour, does exact opposite of instruction.

Waxy FlexabilityDuring 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 stuporOften prodromal phase of insomnia, anorexia, labile

moodMay demontrate catatonic signs, and be delirious-like

(disorganized thinking, psychosis, destructive)May have rigidity, or flaccidity, in terminal stagesPresence of acrocyanosis in someFatal in 75-100%

Lethal Catatonia

Post-neuroleptic era:Stupor may be predominant presentationAntipsychotics, benzo’s, etc. can decrease

excitementUp to 10% inpatient psych. admission?Fatal in 60%?

Neuroleptic Malignant Syndrome: DSM-IV criteria

A. 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

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 NMS30% 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 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 ____ ____

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”

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

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: 1-888-667-8367www.nmsis.orgInformation: 1-888-776-6747Non-profit clinical and research group—Drs. Caroff,

Mann, Campbell (U. Penn)

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

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 post-neuroleptic 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 catatoniaGABA-B, 5-HT1A agonists promote catatoniaGABA-A, 5-HT2A, NMDA agonists reduce catatonia

G. Northoff (2000):www.bbsonline.org/documents/a/00/00/22/44/

bbs00002244-00/bbs.northoff.htm54 page paper“Top Down Modulation”: subcortical and cortical circuits

reciprocally connectMore 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

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

Catatonia Parkinson

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)

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

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 NMSDifferental between NMS and catatonia uncertainPsychotic depression is the underlying disorderCatatonia predominates in NMS

Catatonia Treatment AlgorithmFilip 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