PowerPoint Presentation...Title PowerPoint Presentation Author Sharon Baudry Created Date 5/17/2016...

International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA

Tel: +1 414-276-2145 | www.movementdisorders.org | [email protected]

Medical management of

advanced PD Raja Mehanna MD



What is advanced PD?

• Levodopa is the most effective symptomatic treatment for PD

• All PD patients eventually require levodopa.

• Chronic levodopa treatment -> motor complications – ELLDOPA: 9 months on levodopa 200 mg tid: 16%

developed dyskinesia and 20% had motor fluctuations

– Higher risk with younger age at onset and high dose of levodopa

• Motor complications (MF and /or LID) = advanced PD

Olanow et al.,2001; Agid et al., 2002; Miyasaki et al., 2002; Rascol et al., 2002; Korczyn et al., 2002



OFF



ON



Why does it happen?

• Motor effects of levodopa

– Presynaptic mechanisms (synthesis and

storage of dopamine in remaining nigral

neurons)

– Postsynaptic mechanisms (activation of

postsynaptic dopamine receptors on striatal

neurons)

Fabbrini et al., 1988



L Dopa central pharmacodynamic

Early PD Late PD

Mouradian et al., 1988



THERAPEUTIC

WINDOW

0 5 10 15

Change in therapeutic window with PD progression

Years from symptom

onset

ON

OFF

ON

OFF

BRADYKINESIA

DYSKINESIA

THERAPEUTIC WINDOW



Dyskinesia Threshold “on”

“off”

Levodopa 2 4 6 hours

Early Parkinson’s disease



“on”

Dyskinesia Threshold

“off”


Moderate Parkinson’s disease



“on”

Dyskinesia Threshold

off”


Late Parkinson’s disease



OFF



ON w LID



How can we manage it?

• Medical management.

• Deep Brain Stimulation

• Infusion therapies.



Medical management

• MF

– Manipulate C/L

– Dopamine agonists

– MAO-I

– COMT-I

• LID

– Fractionating

– Amantadine

– Namenda?Clozapine? Levetiracetam?



Manipulate C/L

• Dropped dose or delayed latency: Take far

form high protein meals (1 hour b/a)

• Unpredictable effects of dose : Switch CR

to IR

• Delayed latency: Dissolvable C/L

(Madopar, parcopa) or diluting IR in

ascorbic acid drink

Nutt JG et al., 1984; Leenders et al., 1986; Stocchi et al., 1996;Stocchi et al., 2008



COMT-I

• Entacapone , Tolcapone

• Addition to C/L

• Increases ON time by 1.3 to 1.8 hours/day

and increases UPDRS.

• Increases risk of LID if used in early PD

Rinne et al., 1998; The Parkinson Study Group 1997; Deane et al., 2004, Stocchi et al., 2010



MAOB-I

• Rasagiline

• PRESTO – n= 472, RCT, add on Rasagiline 0.5 mg vs 1 mg vs

placebo, f/u 26 weeks.

– Decreased OFF time by 1.85h (1mg), 1.41h (0.5mg) and 0.91h (P)

• LARGO – n= 687, RCT, add on Rasagiline 1 mg (R) vs

Entacapone (E) vs placebo (P) , 18 weeks f/u.

– Decreased OFF time by 1.2h with R or E , 0.4 h with P

– Increased ON w/o troublesome LID: 0.85h with R or E, 0.03 with P



MAOB-I

• Selegiline

– Usually in early PD as dopamin paring

– Showed to decreased OFF time when added

to C/L

• Selegiline ODT

– Bypasses first-pass hepatic metabolism

– Add on to C/L decreases OFF time by 1.6

hours v/s placebo

Golbe et al., 1988.



Dopamine agonists

• Pergolide, cabergoline: valvular fibrotic disease/ pulmonary fibrosis.

• Pramipexole, ropinirole, rotigotine.

• Added to C/L, decrease OFF time by 1.1 to 1.5 hours/day

• More so with ER tablets and patch

• Useful for nighttime symptoms

• Can decrease LID indirectly by decreasing C/L dose by up to 30%

• SE: EDS, ICD, leg edema, cognitive impairment, hallucinations

Olanow et al., 1994; Lieberman et al., 1998; Pinter et al., 1999; Clarke et al.,2001



Apomorphine

• SubQ only

• Very short latency and half-life

• Dropped dose, unexpected OFF

• First dose always in clinic wih EKG and

BP monitoring

• Individualized dose 2-5mg

Frankel et al., 1990; Hughes et al.,1993; Attanasio A, et al., 1990.



LID

Peak dose LID vs DID



Peak dose LID

• Fractionation of C/L

– Give smaller doses at smaller interval: try to

avoid peak effect

• Decrease C/L and start/increase DA

Facca and Sanchez-Ramos , 1996; Cristina et al., 2003; Storch et al., 2005.



Amantadine

• Amantadine

– Decreases LID scores by 45-60% w/o

worsening OFF Sustained effect

– SE: hallucination and cognitive issues

• Some concern that this effect does not last

Verhagen et al.,1998; Luginger et al., 2000.



Amantadine

• AMANDYSK trial , 2014

– Multicenter RCT placebo-controlled, parallel-group, wash-out study , n=57 PD with LID, on amantadine ≥200 mg/d for ≥6 months, 3 months f/u.

– Mean duration of therapy: 2.7 y (placebo), 4.3y (treatment), p=0.16

– In discontinuing group: • LID worsened in duration and severity.

• Drop out 2/2 LID

• Apathy and fatigue worsened.

– No difference in UPDRS III between the groups.

Ory-Magne et al., 2014



Antipsychotics

• Clozapine

– Atypical antipsychotic

– In 1 RTC, decreased LID by 1.5 hour/day

– SE: sedation, agranulocytosis

• Other antipsychotics: not proven and likely

to worsen motor symptoms of PD

Durif et al., 2004



Levetiracetam

• Zesiewicz et al., 2005

– Open-label, n= 9 PD with LID, increased ON

w/o LID from 43% to 61% of the day

– Decreased ON with troublesome LID from

23% to 11%

– 50% drop out (somnolence)



Leviteracetam

• Wong et al., 2011 – RCT, cross over, n=16, 6 weeks x 2 + 4 week

wash out. Titration of Leviteracetam 500mg weekly up to 200 mg/day.

– Hourly videotaped dyskinesia assessments and UPDRS on 1 day at the end of each treatment period.

– Direct observation: LID slightly less on placebo (P = .26).

– Patient diary: LID less on placebo (P = .10).

– Parkinsonism a little worse on levetiracetam (P = .05).



Memantine

• Wictorin and Widner, 2016

– RCT , n=15, 3 weeks, memantine 20 mg v/s

placebo

– No change in LID ratings, but

• 7/15 reduced LID score by 32%

• 5/15 no change

• 3/15 worsened by 33%

• 35% reduction of LID in self administered diaries

(25%-> 16%)

• No side effects



DA vs MAOB-I vs COMT

• Stowe et al., 2010, Cochrane Database review.

– Metanalysis: 44 trials, n=8436.

– Compared to placebo, adjuvant therapy

significantly

• Reduced off-time ,

• Reduced levodopa dose

• Improved UPDRS scores

– However, dyskinesia and SE increased:,

constipation, dizziness, dry mouth , hallucinations,

hypotension, insomnia , nausea , somnolence and

vomiting .



DA vs MAOB-I vs COMT

• Indirect comparisons of the three drug classes : – Impact on OFF time :DA: -1.54 hours/day;

COMTI: -0.83 hours/day; MAOBI: -0.93 hours/day;

– Decrease in L-dopa dose : DA: -116 mg/day; COMTI: -52 mg/day; MAOBI: -29 mg/day;

– Change in total UPDRS scores : DA: -10.01 point COMTI: -1.46 ; MAOBI: -2.20 points;

– LID : DA :OR 2.70;COMTI :OR 2.50: than with MAOBI :OR 0.94.

– Other side effects: DA : OR 1.52 ;COMTI :OR 2.0; MAOBI :OR 1.32



Non Motor Symptoms in PD

• Depression – Paroxetine and venlafaxine

• Dementia – Donepezil and rivastigmine

• Hallucinations – Quetiapine, clozapine and pimavanserine

• Constipation – Lubiprostone and polyethylene glycol

• Urinary urgency

• Orthostatic hypotension – droxidopa

• REM Sleep Behavior disorder

• EDS

• Dysphagia – ST

• Dysarthria – ST

• Falls/gait disorders – PT



References

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