PISA SYNDROME: HOW DO I STAY UPRIGHT?

1. PISA SYNDROME: HOW DO I STAY UPRIGHT? Case Presentation: Psychiatry Rotation Rajwant Minhas

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

3. Learning Objectives Gain understanding of Pisa Syndrome Pathophysiology Prevalence Drug Causes Learn about strategies that can be used to manage Pisa Syndrome

4. 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

5. 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)

6. 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

7. Meds Prior to Admission

8. 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effective Sept 2010: Episodic unresponsiveness, mutism & intermittent incontinence EEG found to be normal, found more “withdrawn” than catatonic At least 5 CT scans July 19, 2010: CT scan within normal limits August 2010: MRI & EEG normal April 2011: Advanced global atrophy for age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

9. Medications tried so far…

10. Current Medications

11. Review of Systems

12. WBC Trend

13. 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

14. Pisa Syndrome or Pleurothotonus Reported with use of: antipsychotics, antidepressants, lithium, benzodiazepines, antiemetics, cholinesterase inhibitors Occurs mostly after dose changes in antipsychotic therapy

15. Clinical Characteristics

16. 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

17. 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

18. Pisa Syndrome: Treatment Therapy not established Generally disappears after discontinuing antipsychotics or decreasing dose Effects of anticholinergics not systematically studied

19. 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

20. Neurology Consult Suggestions Trihexiphenidyl 1 mg tid, titrate to 2 mg tid over several weeks Tetrabenazine but quite prone to induce drug-induced parkinsonism, might worsen symptoms Restart quetiapine, titrate dose up above 500 mg/day If clozapine should be continued add aripiprazole: One case report: Clozapine-induced Pisa syndrome improved with the combination

21. 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.

22. Goals of Therapy Control symptoms of schizoaffective disorder Treat Wilson’s disease Relieve symptoms of Pisa Syndrome Minimize side effects from medications: drooling, sedation

23. Clinical Question P: In a 20 year old Asian male I: is tetrabenazine better than C: trihexiphenidyl O: to treat symptoms of Pisa syndrome?

24. 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.

25. 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

26. 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

27. 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

28. 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%)

29. Overall Summary

30. 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

31. Monitoring

32. 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