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Treatments in Parkinson’s disease Treatment in PD • Complex because of – Progressive nature of disease – Motor and non-motor features – Early and late side effects associated with the treatments Available Interventions Goals of treatment in PD • Prevention of disease progression • Symptomatic treatment of motor symptoms • Management of motor complications – Wearing off/motor fluctuations – Dyskinesias • Symptomatic treatment of non-motor symptoms Prevention of disease progression • “Neuroprotection is an unmet need in Parkinson’s disease and no drug can be recommended yet for this purpose in practice.” Motor symptoms • Symptoms that are being targeted by medications – Tremor – Rigidity – Bradykinesia – Gait/postural instability Motor complications • What are motor fluctuations/off time? • Periods of alteration of symptom control • On/off time – initially predictable, later unpredictable • What are dyskinesias? • Drug-induced involuntary movements that include chorea and dystonia • Risk factors for development • Younger age at onset of PD, severity, higher L-dopa dose and longer disease duration Overview of topics • • • • • • • • Levodopa Entocapone Dopamine agonists MAOB inhibitors Amantadine Anticholinergics Deep brain stimulation Treatment of non-motor symptoms Question • The mechanism of the antiparkinsonian effect of rasagiline and selegiline is inhibition of: – A. aromatic amino acid decarboxylase – B. catechol-O-methyltransferase – C. monoamine oxidase type A – D. monoamine oxidase type B – E. tyrosine hydroxylase Question • True or false? • There is good evidence to support the use of MAOB inhibitors as adjuncts to DA-agonists. • MAOB inhibitors effectively reduce dyskinesias in patients with PD. MAO INHIBITORS Monoamine Oxidase (MAO) • Group of enzymes involved in monoamine metabolism – Dopamine, serotonin, norepinephrine • Two enzyme subtypes – Type A and type B • In brain Both A+B • In GI tract mostly A Substrates of MAOs MAO Inhibitors (MAOI) • Serendipitously discovered group of drugs with anti-depressant effect • Despite effectiveness, second-line drug – “Cheese reaction” – Extensive side effect profile What is the Cheese Reaction? • Hypertensive crisis in patients on MAOIs who ingest tyramine • Tyramine is a monoamine present in aged cheeses, red wine, sausages • Usu. metabolised by MAO-A • Gut, portal circulation, peripheral neurons • With MAOI (non-selective or selective for A) – Tyramine stimulates peripheral adrenergic neurons – Hypertensive crisis Why use MAOIs in PD? • MAO is present in brain, including the BG – Type B (80%) >> A • If use selective MAO-B inhibitor: – Will inhibit dopamine metabolism in the BG (80% type B) – Avoid cheese reaction (dependent on MAO-A) – Avoid extensive side effect profile • Selective MAO-B inhibitors – Selegiline and rasagiline Selegiline - Use • What is the role of selegiline in the treatment of PD for relief of motor symptoms? • AAN Practice Parameters (2002): – Can be used initially as monotherapy for mild symptomatic relief • Movement Disorder Society (2002) – Effective as monotherapy – Insufficient data to recommend use as as adjunct in patients already on DA-ergic agents Selegiline - Use • What about its role in motor complications? – Insufficient data for fluctuations – Non-efficacious in preventing dyskinesias • What about its role in neuroprotection? – Insufficient evidence to suggest that it has a neuroprotective effect (despite initial studies) • Doses – Start at 5mg daily – Increase to 5mg bid (maximum dose) Selegiline – Side effects • Mortality – One study showed excess mortality in selegiline group – Meta-analysis did not confirm this • Headache, nausea, insomnia • Confusion in the elderly • Can enhance side effects of L-dopa – (But no evidence to use together) Rasagiline (Azilect) • What is the role for rasagiline in mgmnt of motor symptoms? • Movement Disorder Society (2005) – Effective as monotherapy – Insufficient data to recommend use as adjunct in patients already on DA-ergic agents – Insufficient data regarding role in motor complications (MDS) Rasagiline (Azilect) • Doses – Start at 0.5mg daily – Increase to 1mg daily (maximum dose) • Side effects – Same as selegiline OTHER Question • In which group of PD patients would you consider using anticholinergics? – A. Younger patients with predominant rigidity – B. Younger patients with predominant tremor – C. Elderly patients with predominant motor fluctuations – D. Elderly patients with predominant non-motor symptoms Anticholinergics • Mechanism of Action in PD – Not clearly known – Degeneration of DA-ergic nigrostriatal neurons imbalance between striatal dopamine and Ach – Anticholinergics help counteract the imbalance Anticholinergics - Use • What is the role for anticholinergics in the management of PD? • 1993 AAN Practice parameters – Can be considered as initial therapy esp. if tremor predominant • MDS (2002) – Likely efficacious as monotherapy in early PD and as adjunct in patients on L-dopa – Insufficient data re: efficacy for prevention/treatment of motor fluctuations • Typically: young patients with predominant tremor Anticholinergics – Side effects • Main ones (start low, go slow): – Trihexyphenidyl (Artane) • Start 0.5-1mg bid, increase to 2mg tid – Benztropine (Cogentin) • Start 0.5-1 mg bid, increase to 2 bid • Side effects – Confusion, hallucinations, blurry vision, increased intraocular pressure, dry mouth, urinary retention, constipation Amantadine • Used in PD for over 40 years • Antiparkinsonian MoA not fully known – Partial NMDA receptor antagonist – Partial dopamine agonist Amantadine - Use • What is the role for amantadine in the treatment of motor symptoms? – Safe and modestly effective (AAN) – “Likely efficacious” as monotherapy in early PD (MDS) • What about its role in motor complications? – “Possibly efficacious” at reducing dyskinesias – May be considered for pts with motor fluctuations – Efficacious in pts on L-Dopa with motor complications Amantadine - Use • Role in motor complications ctn’d – Effect on dyskinesias likely better than more frequent dosing of L-Dopa – Unknown efficacy in comparison to DA-agonist (pramipexole, ropinirole) • Dose – 100 mg po daily to qid • Side effects – Livedo reticularis, leg edema, – Same side effect profile as dopamine agonists – Generally well-tolerated NON-MOTOR SYMPTOMS • A 78-year-old woman with a 15-year history of PD has developed visual hallucinations. Her medications include carbidopa/levodopa, ropinirole, and rasagiline. Her hallucinations have not diminished significantly with trials of reductions of each of her medications. Which of the following medications is most appropriate for this patient? – – – – – A. chlorpromazine B. haloperidol C. quetiapine D. thioridazine E. thiothixene Non-motor symptoms • “Non-motor symptoms dominate the clinical picture of advanced Parkinson’s disease and contribute to severe disability, impaired quality of life, and shortened life expectancy” Pathophysiology • Non-dopaminergic-cell dysfunction thought to play a major part in the development of the non-motor symptoms • However, neuroanatomy and neurochemistry of non-motor symptoms are unknown Non-motor symptoms • Neuropsychiatric symptoms – Depression, apathy, anxiety, hallucinations, dementia, impulsive behavior (usu drug-induced) • Sleep disorders – Restless legs and period limb movements, REM-sleep behavior disorder, excessive daytime somnolence • Autonomic symptoms – Bladder (urgency, nocturia, frequency), sweating, orthostatic hypotension, sexual dysfunction • GI symptoms (overlap with dysautonomia) – Dribbling saliva, constipation, dysphagia, ageusia, • Sensory symptoms – Olfactory disturbance, pain, paresthesias Management • • • • • • • Depression Anxiety Psychosis Orthostatic hypotension Dementia Sexual dysfunction Sleep dysfunction Management - Depression • Can affect from 10-45% of patients • Likely has a biological contribution – May be a result of impaired 5HT transmission • What is best pharmacological treatment? (AAN 2006) – The highest level of evidence is for amitriptyline – Although it may be considered, it is not necessarily the first choice for treatment of depression associated with PD. – Insufficient evidence to make recommendations regarding other treatments for depression • SSRIs and SNRIs are used but little published data in PD Management – Anxiety and Apathy • Anxiety disorder common – Often coexists with depression – Panic attacks, phobias, GAD, related to motor fluctuations • AAN practice parameters regarding treatment – Insufficient evidence to make any recommendations Management - Psychosis • What is the best treatment for patients with PD and psychosis? – Clozapine should be considered • Remember: associated with agranulocytosis that may be fatal. The absolute neutrophil count must be monitored. – Quetiapine may be considered – Olanzapine should not be routinely considered • No proven efficacy and may worsen motor function • Note that not FDA approved because of increased risk of death in pts with dementia Management - Dementia • What are the most accurate screening tools in PD? – MMSE and CAMCog (Cambridge cognitive assessment) – MMSE as sensitive but not as specific • What is the most effective treatment for dementia in PD? – Rivastigmine probably effective in improving cognitive function. Modest effect and may exacerbate tremor – Donepezil is probably effective in improving cognitive function. Modest effect. Management – Orthostatic Hypotension • Defined as a 20mmHg drop in systolic BP or a 10mmHg drop in diastolic BP • Challenge in PD – DA-ergic agents often worsen OH – Reducing dose usually insufficient to treat • What treatments are effective? (AAN 2006) – Insufficient data to recommend to any particular treatment Management – Orthostatic Hypotension • Compression stockings • Increasing water intake • Fludrocortisone • Dose: 0.1 – 0.3mg daily + high Na intake • Supine hypertension, peripheral edema • Midodrine • Peripheral alpha1 receptor agonist • Dose: 2.5 to 5mg tid • Others: domperidone, pyridostigmine, indomethacin Management – Sexual Dysfunction • Common in both men and women • Multifactorial – Motor dysfunction, medication side effects, mood disorders, and dysautonomia – Dysautonomia erectile dysfunction • One study looked at sildenafil in ED – 12 patients with PD, BP > 90/50 – Sildenafil at 50mg significantly improved ED Management – Sexual Dysfunction • AAN Practice Parameter – Sildenafil possibly efficacious • Need to ensure that other treatable causes of ED/sexual dysfctn have also been addressed • Note: hypersexuality can be seen in PD associated with DA-ergic agents • A 48-year-old man with a 1-year history of PD comes to the office with his wife. She states that for the past 5 years he’s had episodes of kicking and punching during sleep. This has resulted in injuries to both. He is currently taking no medications. • What is the diagnosis? • Which of the following is most likely to benefit this patient’s nocturnal symptoms? – – – – – A. amantadine B. clonazepam C. pramipexole D. ropinirole E. selegiline Management – Sleep Dysfunction • Range of sleep dysfunction – REM sleep behavior disorder (RBD) – Excessive daytime somnolence (EDS) – Insomnia – Restless legs syndrome and periodic limb movement Management – RBD • A type of parasomnia characterized by patients acting out dramatic or violent dreams during the REM sleep stage. • What treatments are effective in PD? – Insufficient data • What treatments are available for RBD? – Clonazepam - 0.25 to 1mg po qhs – Melatonin Question Management - EDS • May be 2ary to disease process or medication side effect • Dopaminergic agents can cause mild to severe somnolence – Falling asleep at wheel of car – Agonists > L-dopa – FDA warnings for pramipexole and ropinirole – Patients should be advised to d/c DA agonists if marked increase in sleepiness Management - EDS • What treatments are available? – Modafinil improves SUBJECTIVE feeling of sleepiness but doesn’t change OBJECTIVE measurements of somnolence – Dose: 200mg daily in am Management - Insomnia • Etiology is multifactorial – Mood disturbances, persistent tremor, nighttime PD symptoms, nocturia, and reversal of sleep patterns • Practice parameter: Insufficient data • Available treatments – – – – – Bedtime L-dopa – may improve nocturnal PD sx Melatonin – Improves perception Sedating antidepressants (trazodone) Mild sedatives – zopiclone, zolpidem Over-the-counter sleeping aids – beware of side effects (anticholinergic effect) Management - RLS • Occurs in up to 20% of patients • No evidence on how to treat of RLS in PD • May use ropinirole and pramipexole – FDA approved treatment in primary RLS Summary • MAOB Inhibitors – Monotherapy, early PD – Not for motor complications or neuroprotection • Anticholinergics – Young patients with predominant tremor – Not for motor complications • Amantadine – Monotherapy for motor symptoms – Adjunct if L-dopa induced motor complications Summary • Depression – Consider amitryptilline • Psychosis – Clozapine > quetiapine • Dementia – Rivastigmine and donepezil • Orthostatic hypotension – Non-pharm; fludro, midodrine, domperidone Summary • RBD – Clonazepam • EDS – Warn patients! – Remove offending agent • RLS – Pramipexole and ropinirole CASES Case 1 • 44 y.o. woman. New left hand tremor and shoulder stiffness. Not yet interfering with work. • On exam – left sided rigidity, bradykinesia and tremor • Assuming that your best diagnosis is IPD: – Should you start the patient on treatment? – What treatment would you start? What are the benefits/disadvantages of the different options? Case 1 • Should you start the patient on treatment? – No evidence that starting treatment early is harmful or worsens long-term outcome – Therefore, generally decision to start treatment should take into account degree of symptoms/disability versus adverse effects of medication Case 1 • What treatment would you start? What are the benefits/disadvantages of the different options? – Levodopa –less sleepiness and psych Ses, but higher rate of dyskinesias – Dopamine agonists – longer duration of action, less dyskinesias, but greater sleepiness and psychiatric SEs – MAOB inhibitors – Anticholinergics – Amantadine Case 2 • 65 y.o. man, PD x 5 yrs • On Sinemet 100/25 qid and selegiline 5 bid • For 1 yr: am off time before meds kick in and pm dyskinesias • How can you decrease morning off time? • How can you decrease dyskinesias? Case 2 • How can you decrease morning off time? – Adding a COMT inhibitor however, can increase dyskinesias – Adding pramipexole or ropinirole may increase dyskinesias – Adding amantadine (less evidence for motor fluctuations) • How can you decrease dyskinesias? – Adding DA- agonist and reducing L-Dopa dose slowly – Adding Amantadine Case 3 • 73 y.o. woman, PD x 10 years • On Sinemet and pramipexole – Mild dyskinesias and motor fluctuation • Recent forgetfulness and apparent visual hallucinations. • On exam, MMSE 27/30 and mild choreatic dyskinesias Case 3 • What single intervention is most likely to reduce hallucinations? • If that fails to control hallucinations, what is the next step? • Would you treat her mild cognitive impairment? Case 3 • What single intervention is most likely to reduce hallucinations? – Remove the pramipexole – This may lead to increased motor fluctuations and dyskinesias and require Sinemet dose adjustment • If that fails to control hallucinations, what is the next step? – Atypical antipsychotics: clozapine, quetiapine Thank you Review Question • A 51 y.o. woman developed PD and was started on treatment. Soon after, she began to spend money on frivolous items and went to the casino where she lost her life savings. • What is the diagnosis? • It is a side effect of which class of medication? – – – – MAOB inhibitors Dopamine agonists Anticholinergics COMT inhibitors Review Question • Which of the following agents can be used as monotherapy in PD (choose as many as apply) – Pramipexole – Ropinirole – Rasagiline and selegiline – Benztropine and trihexyphenidyl – Amantadine Figure 1. The mechanism of potentiation of cardiovascular effects of tyramine, the cheese reaction, and NE release and metabolism after MAO-A inhibition. Youdim M B , Riederer P F Neurology 2004;63:S32-S35 ©2004 by Lippincott Williams & Wilkins • Mechanism of action of MAOI (no pdf) – http://www.neurology.org/content/63/7_suppl_2/S32 .full • Treatment interventions in PD: and evidence based assessment. Rascol et al. Lancet 2002;359:1589. • Evidence-based medical review update: Pharmacological and surgical treatments of PD: 2001-2004. Movement Disorders 2005;20(5):523 • Goetz CG, Koller WC, Poewe W, et al. Management of Parkinson’s disease: an evidence-based review. Mov Disord 2002;17(Suppl. 4)S1–S166. • Update on the medical management of parkinson disease. Continuum 2010;16:96-109 • Chaudhuri et al. Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol 2006;5:235-45. Figure 2. The pathway of dopamine (DA) synthesis from levodopa (l-dopa) and its metabolism by intraneuronal MAO-A and by MAO-A and B extraneuronally by glia and astrocytes and the inhibition of MAO by various selective (moclobemide, selegiline, rasagiline) ... Youdim M B , Riederer P F Neurology 2004;63:S32-S35 ©2004 by Lippincott Williams & Wilkins • Which of the following sleep disorders is most common in patients with Parkinson disease? • A. central sleep apnea • B. delayed sleep phase syndrome • C. narcolepsy • D. REM sleep behavior disorder