1. Treatments in Parkinson’s disease

2. Treatment in PD Complex because of Progressive nature of disease
Motor and non-motor features
Early and late side effects associated with the treatments

3. Available Interventions

4. 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

5. 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.”

6. Motor symptoms Symptoms that are being targeted by medications Tremor
Rigidity
Bradykinesia
Gait/postural instability

7. 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

8. Overview of topics Levodopa Entocapone Dopamine agonists
MAOB inhibitors
Amantadine
Anticholinergics
Deep brain stimulation
Treatment of non-motor symptoms

9. 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

10. 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.

11. MAO INHIBITORS

12. 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

13. Substrates of MAOs

14. MAO Inhibitors (MAOI)
Serendipitously discovered group of drugs with anti-depressant effect
Despite effectiveness, second-line drug
“Cheese reaction”
Extensive side effect profile

15. 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
The cheese reaction is the consequence of inhibition of MAO-A, an enzyme predominantly present in the gut, portal system, and peripheral and central adrenergic neurons, by at least 80%

16. 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
Note: almost no MAO activity in neurons of the SN

17. 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

18. 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)
Neuroprotection was initially thought to be the case, because in comparison to placebo, patients on selegiline had improved UPDRS scores and slower disease progression. However, this was later determined that these were likely be due to symptomatic relief and not neuroproteciton
The trials were done in patients who were early onset PD and were compared to placebo. Neuroprotection was suspected because there was a delay to initiation of L-dopa.

19. 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)
Be careful with cold remedies that contain pseudoephedrine or phenylephrine

20. 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)

21. Rasagiline (Azilect) Doses Side effects Start at 0.5mg daily
Increase to 1mg daily (maximum dose)
Side effects
Same as selegiline
More potent than selegiline and irreversible action

22. other

23. 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

24. 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
ounteracting the imbalance between striatal dopamine and acetylcholine activities caused by the degeneration of dopaminergic nigrostriatal neurons in Parkinson´s disease

25. 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

26. Anticholinergics – Side effects
Main ones (start low, go slow):
Trihexyphenidyl (Artane)
Start 0.5-1mg bid, increase to 2mg tid
Benztropine (Cogentin)
Start mg bid, increase to 2 bid
Side effects
Confusion, hallucinations, blurry vision, increased intraocular pressure, dry mouth, urinary retention, constipation

27. Amantadine Used in PD for over 40 years
Antiparkinsonian MoA not fully known
Partial NMDA receptor antagonist
Partial dopamine agonist

28. 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

29. Amantadine - Use Role in motor complications ctn’d Dose Side effects
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

30. Non-motor symptoms

31. 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

32. 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”

33. 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

35. Non-motor symptoms Neuropsychiatric symptoms Sleep disorders
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

36. Management Depression Anxiety Psychosis Orthostatic hypotension
Dementia
Sexual dysfunction
Sleep dysfunction

37. 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
amitriptyline,
nortriptyline, citalopram, fluoxetine, sertraline, pergolide, pramipexole, and nefazodone

38. 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

39. 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
Side effects are worsening of motor function, weight gain, insulin resistance and diabetes

40. 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.
Donepezil – non-competitive ACHesterase inhibitor
One study – measured at 20 weeks, MMSE, improved by 2 points

41. 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
Symptoms variable – can be disabling
Lightheadedness, syncope, fatigue, cognitive slowing, neck tightness, headache, unsteadiness

42. 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
Domperidone – peripheral DA antagonist therefore blocks peripheral effects of DA

43. 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

44. 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

45. 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

46. Management – Sleep Dysfunction
Range of sleep dysfunction
REM sleep behavior disorder (RBD)
Excessive daytime somnolence (EDS)
Insomnia
Restless legs syndrome and periodic limb movement

47. 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 to 1mg po qhs
Melatonin

48. Question

49. 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

50. 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

51. 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)

52. 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

54. Summary MAOB Inhibitors Anticholinergics Amantadine
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

55. Summary Depression Psychosis Dementia Orthostatic hypotension
Consider amitryptilline
Psychosis
Clozapine > quetiapine
Dementia
Rivastigmine and donepezil
Orthostatic hypotension
Non-pharm; fludro, midodrine, domperidone

56. Summary RBD EDS RLS Clonazepam Warn patients! Remove offending agent
Pramipexole and ropinirole

57. Cases

58. 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?

59. 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

60. 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

61. 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?

62. 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

63. 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

64. 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?

65. 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

66. Thank you

69. 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

70. 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

71. Figure 1. The mechanism of potentiation of cardiovascular effects of tyramine, the cheese reaction, and NE release and metabolism after MAO-A inhibition.
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

72. Mechanism of action of MAOI (no pdf)
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: Movement Disorders 2005;20(5):523

73. Goetz CG, Koller WC, Poewe W, et al
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:

74. 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) ...
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) and nonselective (TV3326) inhibitors. D1 and D2″ = dopamine receptors; DAT = dopamine transporter; AR = amine reuptake; SV = synaptic vesicle; DDC = dopa decarboxylase; COMT = catechol-o-methyl transferase; 3OMD = O-methyl dopa.
Youdim M B , Riederer P F Neurology 2004;63:S32-S35
©2004 by Lippincott Williams & Wilkins

75. 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