PISA SYNDROME: HOW DO I STAY UPRIGHT?

Case Presentation: Psychiatry Rotation

Rajwant Minhas

Outline• Learning Objectives• Patient Case: PC • Drug Related Problems• Goals of Therapy• Background: Pisa Syndrome & treatment• Clinical Question• Literature Evaluation• Recommendation• Monitoring Plan

Learning Objectives

• Gain understanding of Pisa Syndrome– Pathophysiology– Prevalence– Drug Causes

• Learn about strategies that can be used to manage Pisa Syndrome

Patient: PC• ID: 20 yo Korean Male, Wt: 67 kg Height: 1.76 m

• Allergies: Amoxicillin (rash, patient denies)

• C/C: Sedation, drooling, Pisa syndrome

• Diagnosis: Refractory Schizoaffective Disorder manifested by:– Paranoid and grandiose delusions– Sexual preoccupation– Disinhibition– Impaired insight & judgement

• Hx of extreme sensitivity to antipsychotics resulting in EPS, catatonic and Parkinsonian symptoms

History of psychiatric illness• Spring 2010: Disorganized thinking, grandiose, religious &

paranoid delusions, bizarre behaviour

• June 2010: RCH: Stabbed himself superficially in the chest with scissors as he felt “stronger than God.”

• Dec 2010: SMH, 2 admissions at MSA, Abbotsford

• May 13, 2011: Abbotsford ICU RCH

• May 26, 2011: RCH (5 month stay) RVH

• August 15, 2011: RVH (E4) D3 (Refractory Psychosis Unit)

Patient PC

• FH: Negative for any neuropsychiatric disorders– Hx of diabetes and hypertension

• Psychosocial History: Immigrated to Canada at 10 months of age– Excellent student until grade 11– Ambition to become a gay rapper, caged dancer

in bars

• No hx of substance abuse

Meds Prior to Admission

Lithium Citrate liquid 1050 mg HS

Paliperidone 6 mg HS

Loxapine 25 mg TID

Lorazepam 1 mg HS

Procyclidine 5 mg daily

Past Medical History• Catatonic: stopped eating and drinking

– July-Nov 2010: 12 ECT treatments, unclear response – March 2011: Carbamazepine substituted for Lithium

• poor results, increased agitation– Spring 2011- ECT course, mildly effective

• Sept 2010: Episodic unresponsiveness, mutism & intermittent incontinence

• EEG found to be normal, found more “withdrawn” than catatonic • At least 5 CT scans• July 19, 2010: CT scan within normal limits• August 2010: MRI & EEG normal• April 2011: Advanced global atrophy for age

• Drooling & dysarthria present prior to clozapine institution

Medications tried so far…Started Medication/ Maximum

doseResponse

Jul 2010 Fluoxetine 20 mg/day Disinhibited

June 2010 Olanzapine 20 mg/day Partial response, led to Catatonia

Nov 2010 Lithium 1050 mg/day Moderate mood stabilizing

Nov 2010 Benztropine 4 mg/day Marginal improvement on 2 mg BID

Nov 2010 Risperidone 4.5 mg/day Pisa syndrome & drooling

Dec 2010 Quetiapine 500 mg/day Tolerated well. Helped with insomnia but no strong antipsychotic effect. So switched to clozapine & loxapine

May 2011 Paliperidone 6 mg/day + loxapine 125 mg/day

Dysphagia & sialorrhea

May 2011 Clozapine 350 mg/day Sialorrhea & Pisa Syndrome

Some improvement in grandiosity, hyperthermia on 350 mg daily

Current Medications

Regular PRN Medications

Clozapine 350 mg qHS Lorazepam 1-2 mg PO/IM Q4H PRN

Tetrabenazine:12.5 mg po QAM started on Jan 19

Loxapine multi-route 10-25 mg PO/IM Q4H PRN

Ipratropium 0.03% 2 Puffs Q6H PRN

Benztropine 1-2 mg PO/IM Q6H PRN

Bowel regime

Al & Mg hydroxide 30 mL po Q4H PRN

Review of SystemsCNS Drowsy

HEENT Teeth malocclusion resulting in open mouth

Excessive drooling

Liver/Spleen/Endo Dec 20/2011

ALT=17 (<50), AST=23 (<36), GGT=51 (<49)

CK=62 (<165), Ammonia= 50 (11-35)

Ceruloplasmin = 23 (220-495)

Serum copper = 5.7 (10.1-18.4)

Fluid/Lytes/Heme Jan 24/2012

WBC=3.8 (4.2-10.8), Neutrophils = 2.10 Platelet = 115 (160-390)

Dec 20/2011

Clozapine = 1200 nmol/L

Norclozapine = 575 nmol/L

MSK/Skin/Extrem Leaning to the right

WBC Trend

Wilson’s Disease• Wilson disease first attacks the liver, the central nervous system, or both.

• Most patients develop signs and symptoms that accompany chronic liver disease – swelling of the liver or spleen– jaundice, or yellowing of the skin and whites of the eyes– Fluid buildup in the legs or abdomen– A tendency to bruise easily– Fatigue

• A build up of copper in the CNS result in neurologic symptoms, including– problems with speech, swallowing, or physical coordination– tremors or uncontrolled movements– muscle stiffness– behavioural changes

• Other symptoms:– anemia– low platelet or white blood cell count– slower blood clotting,high levels of amino acids, protein, uric acid, and carbohydrates in

urine– premature osteoporosis and arthritis

Pisa Syndrome or Pleurothotonus

• Reported with use of: antipsychotics, antidepressants, lithium, benzodiazepines, antiemetics, cholinesterase inhibitors

• Occurs mostly after dose changes in antipsychotic therapy

Clinical Characteristics

Pisa Syndrome: Pathophysiology• Organic changes in the brain

• Dopaminergic-cholingeric imbalances induced by antipsychotic drugs

• Norepinephrine, Serotonin and dopamine interaction in patients on TCAs and SSRIs

• Does not always reappear when rechallenged with antipsychotic

– May be far more neurochemical changes involved

• Uncertain if it is a subtype of acute or chronic dystonia– May develop not only as a subtype of acute dystonia, but also as atypical

subtype of tardive dystonia

• Clinical evidence suggests that from a pharmacological viewpoint drug-induced Pisa syndrome is similar to tardive dystonia – Develops insidiously during prolonged treatment and benefits little from

anticholinergic therapy

Pisa Syndrome: Prevalence• Documented in young and elderly patients

• Predominantly in female and elderly patients

• Young males more susceptible to both acute and tardive dystonia

• In contrast: – Pisa syndrome more prevalent in young and elderly females with

organic brain changes.

• Also appeared in patients on anticholinergics

Pisa Syndrome: Treatment

• Therapy not established

• Generally disappears after discontinuing antipsychotics or decreasing dose

• Effects of anticholinergics not systematically studied

Neurology Consult Dec 2011• Dysarthria and drooling

• Denied dysphagia, rigidity, epsiodes of freezing

• Felt a bit “slowed down” and body felt heavy

• Tardive dystonia possibility as first observed during tx with risperidone – Although usually associated with retrocollis (absent here)

• Absence of benefit from benztropine 4 mg/day – Does not preclude diagnosis of TD

Neurology Consult Suggestions

1. Trihexiphenidyl 1 mg tid, titrate to 2 mg tid over several weeks

2. Tetrabenazine but quite prone to induce drug-induced parkinsonism, might worsen symptoms

3. Restart quetiapine, titrate dose up above 500 mg/day

4. If clozapine should be continued add aripiprazole:One case report: Clozapine-induced Pisa syndrome improved with the combination

Drug Related Problems• PC is experiencing Pisa syndrome secondary to clozapine and/or

wilson’s disease and would benefit from reassessment of his schizoaffective therapy.

• PC is at risk of acquiring infections secondary to low WBC count due to clozapine and or wilson’s disease and would benefit from reassessment of his schizoaffective therapy.

PC is experiencing continued drooling secondary to receiving clozapine and would benefit from reassessment of his schizoaffective therapy.

• PC is experiencing sedation secondary to receiving clozapine and would benefit from reassessment of his schizoaffective therapy.

Goals of Therapy

• Control symptoms of schizoaffective disorder

• Treat Wilson’s disease

• Relieve symptoms of Pisa Syndrome

• Minimize side effects from medications: drooling, sedation

Clinical Question

• P: In a 20 year old Asian male

• I: is tetrabenazine better than

• C: trihexiphenidyl

• O: to treat symptoms of Pisa syndrome?

Tetrabenazine & Pisa Syndrome

• No studies found

• Approved by FDA for treatment of hyperkinetic movement disorders: Huntington's chorea, hemiballismus, senile chorea, Tourette syndrome, and tardive dyskinesia

• Depletes monoamine neurotransmitters (dopamine, serotonin, norepinephrine) in presynaptic vesicles.– Inhibits presynaptic dopamine release – Blocks CNS dopamine receptors.

Effectiveness of anticholinergics and neuroleptic dose reduction on neuroleptic-induced pleurothotonus (Suzuki et al.)

• Most previous reports failed to show results with anticholinergics – Benztropine in 5 cases – Trihexyphenidyl in 1 case– Amantadine slightly beneficial in 2 cases; failed in 2 other cases– 2 cases among 20 patients (10%)

• Suzuki et al study: – N = 21, 13 diagnosed with schizophrenia

– 20 patients: >2 of the following antipsychotic drugs:• Phenothiazines (chlorpromazine, levomepromazine etc.)• butyrophenones (haloperidol) & zotepine

– 1 patient: TCAs combination

– Trihexiphenidyl 6 mg/day to prevent EPS

Suzuki et al• Pleurothotonus treatment:

Trihexiphenidyl 4 mg tid – Or

Biperiden HCl IM 5mg/dose

• Pleurothotonus disappeared within 3 weeks after dose increase in 9 patients • 40% response

Higher dose & ethnic homogeneity

• No definitive toxic side effects (delirium, confusion, urinary retention)

• Recurred in 2 cases within 1-year of follow-up– Improved after dose reduction

• Use high-dose anticholinergics if dose reduction may worsen psychotic symptoms

Suzuki et al.• Remaining cases improved by a reduction or withdrawal

– Efficacy consistent with previous reports.

• Although not always appearing insidiously, pleurothotonus may be neurochemically similar to tardive dystonia.

• Striking difference between drug-induced pleurothotonus and tardive dystonia:– Benefit from withdrawal or reduction of antipsychotics vs. tardive

dystonia– Thus, clinical evidence suggests that distinct pathophysiologic

mechanisms may underlie drug-induced acute and tardive dystonia. 

• Garcia and Diez-Martin: Clozapine effective in treating Pisa syndrome induced by antipsychotics– Rarely develops in patients on clozapine, worthwhile to use clozapine to

treat

Quetiapine• Hepatic impairment (30%): lower clearance

– May result in higher concentrations. Dosage adjustment

– IR tablet: Oral: Initial: 25 mg/day, increase dose by 25-50 mg/day to effective dose

– Extended release tablet Oral: Initial: 50 mg/day; increase dose by 50 mg/day to effective dose, based on clinical response and tolerability to patient.

• Hematologic side effects: Neutropenia (≤2%), leukopenia (≥1%), hemorrhage (1%)

• Hepatic: Transaminases increased (1% to 6%), GGT increased (1%)•

Overall SummaryOption Pros Cons

Trihexiphenidyl Some evidence might be effective

Anticholinergic side effects: sedation, constipation

Tetrabenazine No evidence found. Contraindicated in hepatic impairment

EPS (15% to 33%), sedation (31%), fatigue (22%), insomnia (22%), akathisia (19%), depression (19%), anxiety (15%) Parkinsonism (3% to 10%)

Clozapine Effective for his psychosis (grandiosity)

Pisa syndrome, sedation, risk of agranulocytosis. Contraindicated in active hepatic disease associated with nausea, anorexia, or jaundice; progressive hepatic disease or hepatic failure

Quetiapine Tolerated well in the past Side effects: neutropenia(2%),

Adjustment in hepatic impairment

Recommendations• Initiate treatment of Wilson’s disease

• Continue trial of tetrabenazine– Titrate to max 25 mg TID– Usual maximum tolerated dosage: 25 mg 3 times/day; maximum

recommended dose: 200 mg/day–  If no improvement at the maximum tolerated dose after 7 days,

improvement is unlikely; consider discontinuation

• If no improvement with tetrabenazine:– Consider decreasing clozapine dose to 300 mg

• If no improvement in CBC consider discontinuing clozapine– Consider switching to quetiapine and titrate up to >500 mg/day

• Consider monitoring CBC every week vs. biweekly

MonitoringParameter When Who

Efficacy:

Improvement in Pisa syndrome

Delusions/Hallucinations

Ongoing

Ongoing

Doctor, RN, Pharmacist

Doctor, RN, Pharmacist

Safety:

CBC

Sedation

Depression

Every week

Ongoing

Ongoing

Doctor, Pharmacist

Doctor, Patient, RN, Pharmacist

Doctor, Patient, RN, Pharmacist

References• Toshihito Suzuki, Hisashi Matsuzaka. Drug-Induced Pisa Syndrome

(Pleurothotonus) Epidemiology and Management. CNS Drugs 2002; 16 (3): 165-174.

• The Pisa Syndrome [cited 2012 Jan 19]. Available from: http://mirecc.stanford.edu/pdf/Pisa%20Syndrome.pdf

• Toshihito Suzuki et al. Effectiveness of anticholinergics and neuroleptic dose reduction on neuroleptic-induced pleurothotonus (the Pisa syndrome). J Clin Psychopharmacol. 1999 Jun;19(3):277-80.

• Yassa R, Nastase C, Cvejic J et al. The Pisa syndrome (or pleu- rothotonus): prevalence in a psychogeriatric population. Biol. Psychiatry 1991; 29: 942–5.

• National Institute of Diabetes and Digestive and Kidney Diseases. Wilson’s disease. Available from: http://digestive.niddk.nih.gov/ddiseases/pubs/wilson/WilsonDisease.pdf