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Boala Parkinson

Prof. Dr. Bogdan O. Popescu


Disciplina de Neurologie Spitalul
Clinic Colentina
U.M.F. Carol Davila Bucuresti
1817
Modularea micrii de ctre
ganglionii bazali
Substana neagr i boala Parkinson

PD CTR

The pathological changes in certain neurological diseases provide insights about the function of the
basal ganglia. (A) Left: The midbrain from a patient with Parkinson's disease. The substantia nigra
(pigmented area) is largely absent in the region above the cerebral peduncles (arrows). Right: The
mesencephalon from a normal subject, showing intact substantia nigra (arrows). (B) The size of the
caudate and putamen (the striatum) (arrows) is dramatically reduced in patients with Huntington's
disease. (From Bradley et al., 1991.)
SN n boala Parkinson
Conceptul de neurodegenerare. Mecanisme
patogenice comune ale bolilor
neurodegenerative
Neurodegenerare = un proces de pierdere
neuronal continu, pe o perioad lung de
timp, care afecteaz anumite ppuplaii neuronale
specifice n SNC, cu o evoluie clinic progresiv

Apoptoz neuronal (vs. necroz)


Alterarea homeostaziei calciului intracelular
(neuroexcitotoxicitate)
Acumularea de proteine anormale
intracitoplasmatic (proteinopatie)
Stresul oxidativ
Patogeneza bolii Parkinson
Corpii Lewy

www.saigata-nh.go.jp/saigata/rinken/neuropat/
Scenariul Heiko Braak despre
stadializarea BP si posibila etiologie a
BP
Definitia Bolii Parkinson

Boala Parkinson (BP) este o afectiune


neurodegenerativa progresiva, marcata, din
punct de vedere motor, de semne precum
tremorul de repaus, rigiditatea, bradikinezia si
instabilitatea posturala.
Apare din cauza mortii celulare progresive a
unor celule din regiuni bine determinate ale
SNC, inclusiv substanta neagra din mezencefal
(dar nu numai!).
Boala Parkinson generaliti
De obicei debuteaz la sfritul decadei a asea sau
nceputul decadei a aptea
Boala Parkinson duce la un declin progresiv al controlului
micrilor voluntare, afectnd iniierea micrii, viteza
micrii i precizia acesteia
Simptome parkinsoniene se pot ntlni n pn la 15%
dintre cei cu vrst ntre 65-74 i aproape la 30% din cei
peste 75 de ani
BP afecteaz peste 1,000,000 de persoane in UE att
brbai ct i femei, cu aprox. 50.000 de cazuri noi pe an
Imensa majoritate a cazurilor de BP sunt sporadice
~5% PD mutaii genetice motenite (mai rar
spontane)
Etiologia BP (I)
Necunoscut, ca n toate bolile
neurodegenerative (susceptibilitate genetic +
factori de mediu)
Semnele i simptomele motorii sunt determinate
de pierderea neuronilor dopaminergici din SN
din mezencefal, unul din centrele cerebrale de
control al micrii voluntare
Semnele non-motorii degenerarea altor arii din
trunchiul cerebral sau cortex
Marca neuropatologic a bolii Parkinson corpii
Lewy (depozite anormale de alfa-sinuclein)
Etiologia BP (II)
Boala Parkinson parkinsonism
Moartea celular care duce la parkinsonism poate fi
provocat de o serie de alte condiii patologice:
Infecie
Trauma
Toxice
Medicaie anti-dopaminergic - haloperidol (Haldol),
clorpromazine (tioridazin)
Cnd nu se poate identifica o asemenea cauz pentru
pierderea neuronilor nigrali se diagnosticheaz un
parkinsonism primar, neurodegenerativ (BP sau
parkinsonism atipic)
Parkinsonism atipic sau Parkinson plus paralizia
supranuclear progresiv, atrofia multisistemic,
degenerescena cortico-bazal
Boala Parkinson i parkinsonismul
Parkinsonism +alte semne
Parkinsonism pur Pseudoparkinsonism
clinice
Paralizia supranuclear
Boala Parkinson Tremorul esenial
progresiv
Parkinsonismul
Atrofia multisistemic Parkinsonismul vascular (aterosclerotic)
medicamentos

Parkinsonismul Calcificrile masive de ganglioni


postencefalitic bazali

Parkinsonismul indus de
TCC repetate
MPTP

Alte toxine, ex. Mangan,


Anoxia cerebral
pesticide
Simptomele cardinale ale parkinsonismului
criteriile de diagnostic UK Brain Bank

Tremorul de obicei cu debut la mb superior, de obicei nti pe


o parte i mai trziu pe cealalt (asimetria!). Clasic numrat
bani, 3 Hz

Bradichinezia reducerea global a vitezei de micare, uneori


freezing (blocaj motor), hipomimie, facies fijat, clipire rar

Rigiditatea un tip specific de hipertonie muscular

Instabilitatea postural/dezechilibrul, uneori festinaie


Simptome ale BP - nonmotorii

Depresie
Anxietate
Dizartrie, festinaia vorbirii, fr intonaie, egal
Tulburri de somn variate
Modificri emoionale fric, iritabilitate i
insecuriate
Tulburri micionale incontinen, poliurie
Constipaie
Disfuncie sexual
Alte simptome ale BP
Modificarea scrisului, literele devin din ce n ce mai mici
(micrografie)
Tulburare cognitiv, pn la demen
Halucinaii
Modificri ale TA
Hiperhidroz
Seboree
Edeme mb inferioare
Durere intens i frecvent
Astenie marcat
Disestezie
Stadializarea Hoehn i Yahr a BP
Stage 1 : afectare unilateral, mb superior n semiflexie cu tremor,
pacientul se nclin de obicei spre partea afectat

Stage 2: afectare bilateral cu modificri minime posturale, mers


cu pai mici, trii.

Stage 3: Modificri importante de mers; dizabilitate general


moderat; instabilitate postural cu tendina la cdere.

Stage 4: Dizabilitate important; ambulaie limitat, necesit


asisten.

Stage 5: Invaliditate complet, pacientul este imobilizat n scaun


cu rotile sau la pat, nu poate merge nici cu sprijin.
Diagnosticul bolii Parkinson
B. Parkinson trebuie difereniat de:
Parkinsonismul de diferite etiologii
Parkinsonismul atipic
Se bazeaz pe rspunsul la levod-dopa i pe
citarea altor semne neurologice, care nu fac
parte din tabloul clinic al b. Parkinson
BP se caracterizeaz prin:
Manifestri cardinale motorii
Semne non-motorii caracteristice
Semnele motorii cardinale
Bradykinesia, hypokinesia, akinesia
Dificultate n iniierea micrii(akinesia)
Lentoarea micrii(bradykinesia)
Micri spontane diminuate(hypokinesia)
Tind s apar mpreun
Fluctuaii spontane ale mobilitii
Semnele motorii sunt mai pronunate pe o parte asimetrie (n
special n stadiile precoce)
Faciesul fijat (hypomimia), gur ntredeschis, clipit rar, disfagie,
salivaie excesiv (drooling)
Vorbirea: hipofonie (diminuare a volumului vocii), voce
ngroat, dizartrie, voce monoton, fr intonaie (dizartrofonie),
dificlutate n a iniia vorbirea, accelerare ctre sfritul frazei
(festinaia vorbirii)
Cardinal manifestations of PD (II)
Postural changes

Stooped posture
Flexed and
adducted posture
of the arms
Postural instability
Cardinal manifestations of PD (III)
Gait disturbances
Appear in the early stages of the disease
Small-stepped gait, shuffling, limping
Reduced arm swinging
Difficulty in initiating gait
Freezing of gait = complete arrest of gait when the
patient is confronted by doorway or a narrow path
between furniture
Difficult to stand up from a seated position or to
turn over in bed
Cardinal manifestations of PD (IV)
Impairment of fine motor control
Impairs activities of daily living (fastening buttons,
writing micrographia, eating with knife and fork,
shaving, hair-combing)
Difficult to perform two activities in parallel e.g.
walking and talking
Specimens of Adolf Hitler's handwriting,
from 1929, when he did not have PD,
to 1934 when he had it but it was not diagnosed,
to 1944- 1945, when he obviously had PD,
script becomes smaller, more cramped
Hitler's signature in 1929, 11 years after encephalitis, no
evidence of PD. Hitler is 40.
Hitler's signature in 1934, 16 years after encephalitis, beginning
PD. Hitler is 45.
Hitler's signature in 1945, 27 years after encephalitis, advanced
PD. Hitler is 56
PD famous people
Adolf Hitler had post encephalitic PD, PD that developed after a
viral infection during the Great Encephalitis, Sleeping Sickness,
Epidemic of 1918 - 1926. Hitler, in 1938, was Time Man of the
Year.

1938, 49 yo 1945, 56 yo
Cardinal manifestations of PD (V)
Tremor
Only half of patients have tremor early in the course
of the disease; the rest usually develops as the
disease progresses
Typically more pronounced in the hands (pill-rolling
tremor), seen mainly at rest, improving or
disappearing with voluntary movements and during
sleep
Frequency 5 Hz
Often asymmetrical
Exacerbated by even mild stress
Why tremor?
The exact anatomical basis of parkinsonian tremor is
not known
In animals, experimental lesions to the SN do not result
in tremor neither do lesions in the striatopallidal parts
of the basal ganglia
From 8 MPTP intoxicated patients, only 4 developed
tremor
Ward et al. produced parkinsonian tremor in monkeys
by lesions in the ventromedial tegmentum of the
midbrain concluded that probably lesions to
reticulospinal pathway induce parkinsonian tremor
alternatively the tegmento-thalamic projection
Cardinal manifestations of PD (VI)
Rigidity
Elevated muscle tone is felt by the patient as muscle
tension of spasm and by examiner as resistance to
passive movements across the joints
Examination reveal cogwheel rigidity (repeated,
ratchet-like oscillations of resistance to passive
movements across the wrist, elbow, etc., which are
brought out by alternating passive flexion and
extension)
Pathophisiology: lesions to nigrostriatal system (less
dopamine normal thalamo-cortical drive is
inhibited)
The Pope in 1979, age
59, with President
Jimmy Carter. The
Pope's shoulders
stoop, PD begins.
Neurodegeneration: AD and PD

The Pope and


President Ronald
Reagan defeated
Communism
The Pope in 1988, age
68, 2 years after PD
diagnosed. The Pope is
with President Ronald
Reagan. The Pope died
of complications of
PD. President Reagan
died of complications of
Alzheimer disease.
The Pope in 1992,
age 72, 13 years
after PD began, 6
years after PD
diagnosed. The
Pope is with
President
George Herbert
Walker Bush and
Barbara Bush
The Pope in 1999, age
79, 20 years after PD
began, 13 years he was
diagnosed. The Pope is
with President Clinton
and Hillary Clinton
The Pope in 2004, age
84, 25 years after PD
began, 18 years after PD
diagnosed. The Pope is
with President George W
Bush
PD treatment

There is no cure for Parkinson disease. Most


drugs treat the symptoms of the disease only,
although drugs like rasagiline and dopamine
agonists may slow degeneration of the substantia
nigra.
PD treatment physical exercise
Regular, moderate exercise has been shown to
improve motor function without an increase in
medication for a person with PD
Exercise helps maintain range of motion in stiff
muscles, improve circulation, and stimulate appetite
An exercise program designed by a physical therapist
has the best chance of meeting the specific needs of the
person with PD
A physical therapist may also suggest strategies for
balance compensation and techniques to stimulate
movement during slowdowns or freezes.
PD treatment - nutrition
PD patients may lose interest in food, especially if depressed, and may have
nausea from the disease or from medications, especially those known as
dopamine agonists
Slow movements may make it difficult to eat quickly, and delayed gastric
emptying may lead to a feeling of fullness without having eaten much
Increasing fiber in the diet can improve constipation, soft foods can reduce
the amount of needed chewing, and a prokinetic drug such as cisapride or
domperidone can increase the movement of food through the digestive
system.
PD patients may need to limit the amount of protein in their diets the
main drug used to treat PD, L-dopa, is an amino acid, and is absorbed by the
digestive system by the same transporters that pick up other amino acids
broken down from proteins in the diet. Limiting protein, under the direction
of the physician or a nutritionist, can improve the absorption of L-dopa.
No evidence indicates that vitamin or mineral supplements can have any
effect on the disease other than in the improvement of the patient's general
health
No antioxidants used to date have shown promise as a treatment a large,
carefully controlled study of vitamin E demonstrated that it could not halt
disease progression
PD treatment - drugs
The pharmacological treatment of Parkinson disease is
complex
While there are a large number of drugs that can be
effective, their effectiveness varies with the patient,
disease progression, and the length of time the drug has
been used
Dose-related side effects may preclude using the most
effective dose, or require the introduction of a new
drug to counteract them
There are six classes of drugs currently used to treat
PD.
Drug classes to treat PD

1. MAO inhibitors (rasagiline, selegiline)


2. Dopaminergic agonists, non-ergot (ropinirol,
pramipexol, rotigotine) + apomorphine
3. Levo-dopa
4. Levo-dopa enzymatic degradation inhibitors:
a. dopa-decarboxylase inhibitor (benserazide or
carbidopa) and b. COMT inhibitors (entacapone)
5. Anticholinergics
6. Amantadine (NMDA inhibitor)
Levo-dopa

Is never used nowadays without a dopa-


decarboxylase inhibitors, always in
combination (Sinemet, Madopar, Nakom,
etc.)
Triple combination in one tablet: levo-dopa
+ carbidopa + entacapone) - Stalevo
Algorithms and Practice Parameters for
Initial Treatment of PD*
Pharmacologic therapy/
Parkinsons Disease Nonpharmacologic therapy
functional impairment

No treatment has
been shown to be
neuroprotective2 Education

MAOB Inhibitors
(RAS) have only mild Support
symptomatic benefit1 Services

Exercise2

Dopamine Levodopa
Nutrition
Agonists1 (+/- COMT inhibitor)

Comined treatment

Based on: Olanow, CW et al. Neurology 2001; 56 S5, S1-88 and on AAN practice parameters.
Levodopa provides superior motor benefit but greater risk of dyskinesia; no evidence of a benefit of initiating treatment with
extended release levodopa versus immediate release (1)
1. Miyasaki et al. 2002 Neurology 58, 11-17; 2. Suchowersky et al. 2006 Neurology 66, 976-982. 44
Drugs that replace dopamine
Levodopa (L-dopa), is the most effective treatment for the
symptoms of PD
L-dopa is a derivative of dopamine, and is converted into dopamine
by the brain
It may be started when symptoms begin, or when they become
serious enough to interfere with work or daily living
L-dopa therapy usually remains effective for all duration of the
disease
Following this, many patients develop motor fluctuations, including
peak-dose "dyskinesias" (abnormal movements such as twisting, or
restlessness), rapid loss of response after dosing (known as the "on-
off" phenomenon), and unpredictable drug response
Higher doses are usually tried, but may lead to an increase in
dyskinesias
Side effects of L-dopa include:
nausea and vomiting
low blood pressure upon standing (orthostatic hypotension) - causes dizziness
these effects usually lessen after several weeks of therapy.
Dopamine
Enzyme inhibitors (I)
Dopamine is broken down by several enzyme systems in the
brain and elsewhere in the body, and blocking these enzymes
is a key strategy to prolonging the effect of dopamine
The two most commonly prescribed forms of L-dopa contain
a drug to inhibit the amino acid decarboxylase (an AADC
inhibitor), one type of enzyme that breaks down dopamine
These combination drugs are Sinemet, Nakom, Isicom (L-
dopa plus carbidopa) and Madopar (L-dopa plus
benzaseride). Controlled-release formulations also aid in
prolonging the effective interval of an L-dopa dose
Enzyme inhibitors (II)
The enzyme monoamine oxidase B (MAO-B)
inhibitors selegiline and rasagiline may be given as
add-on therapy for L-dopa. Research indicates
rasagiline may have a neuroprotective effect, sparing
nigral cells from damage by free radicals. Because of
this, and the fact that it has few side effects, it is also
frequently prescribed early in the disease before L-dopa
is begun
Entacapone and tolcapone, two inhibitors of another
enzyme system called catechol-O-methyltransferase
(COMT), may soon reach the market as early studies
suggest that they effectively treat PD symptoms with
fewer motor fluctuations and decreased daily L-dopa
requirements.
Typical pattern of wearing-off

Daily fluctuations in wearing-off


The PRELUDE survey

Objective: To understand perceptions of levodopa therapy among


clinicians and patients

Physician survey Patient survey

328 Neurologists
300 patients with PD treated with
74 Movement Disorder Specialists
carbidopa/levodopa
54 PCPs

All physicians surveyed treated


Sampled through the National
patients with PD
Parkinsons Foundation
PRELUDE survey: Importance of wearing-off
for patients and healthcare professionals

What is the biggest challenge with levodopa therapy?

Managing Managing
dyskinesia #1 for wearing-off #1
Movement for PD patients
Disorder and PCPs
Specialists

Dyskinesia
Within two years 12% of neurologists recognize
wearing-off but 54% modify the levodopa regimen

The large discrepancy in the numbers (54% Vs 12%) highlights


the difficulty in identifying the first signs of wearing-off
Comtan Diagnostic survey, 2002
No universal definition of wearing-off

Study, year Definition and Incidence

A predictable decline in motor function at the end of


dose in a patient with previously stable response
Rajput et al. 2002 receiving 3 or more daily levodopa doses
25% of patients had wearing-off after 4.9 years
A perception of loss of mobility or dexterity, usually
taking place gradually over minutes and usually
Parkinson Study Group, bearing close resemblance to the timing of
2000 antiparkinsonian medications
38% of patients had wearing-off after only 2 years

The lack of a universal definition of wearing-off may be reflected


in its reported incidence in patients PSG, 2000
Rajput et al., 2002
Useful definitions of wearing-off

For the physician: For the patient:


Wearing-off refers to the predictable Wearing-off happens when a dose that
emergence of one or more PD signs or previously used to help your symptoms
symptoms before the next scheduled does not last as long and your next dose is
antiparkinsonian medication dosage. needed sooner. Symptoms of wearing-off
include changes in movement and mobility,
thoughts and feelings, sensations and
sense of well being.

Stacy et al, 2004 PinK working group


Consensus definition of wearing-off

In September 2004, a wearing-off working group meeting of


leading international Movement Disorder Specialists arrived
at a consensus definition.

A generally predictable recurrence of motor


or non motor symptoms that
precedes a scheduled dose and usually
improves with antiparkinsonian
medication.
Symptoms of wearing-off
Challenges in identification of wearing-off

Because patients may not be aware that the


changes they are experiencing are related to their PD
and are treatable, they may not spontaneously discuss
their symptoms

It is, therefore, important that physicians treating


PD be aware of the many different symptoms of wearing-
off and specifically ask about the occurrence of such
changes.
Stacy, 2003
Identification of Wearing Off
Symptoms

Wearing-Off

Non-Motor Symptoms Motor Symptoms


(often precede/coincide with Motor Symptoms)

SENSORY AUTONOMIC
Pain pallor Tremor
Paresthesias BP changes
Rigidity
Sensory loss shortness of breath
Akathisia tachycardia Akinesia/Bradykinesia
Fatigue sweating
facial flushing Postural Instability/Balance
PSYCHIATRIC laryngeal stridor
Anxiety papillary dilation
Paranoia drooling
Hallucinations dysphagia
Depression belching
Panic abdominal bloating
Cognitive changes urinary frequency
micturition disturbances

Blanchet (2003) CJNS, 30(1): S19-S26


Non-motor fluctuations (NMF)

1976: Marsden and Parkes recognized NMF in fluctuating PD

1993: Riley and Lang proposed a classification that is often used


today

1996: Hillen and Sage studied the frequency of NMF in a


fluctuating population
Using an open-ended question they identified NMF in 17% of fluctuating
patients

2002: Witjas et al studied the frequency and disability caused by


NMF in advanced PD patients
Using a structured questionnaire they identified NMF in 100% of patients
experiencing motor fluctuations
Marsden and Parkes, 1976
Riley and Lang, 1993
Hillen and Sage, 1996
Witjas et al, 2002
Non-motor fluctuations in wearing-off

In a study of 50 patients with advanced PD and motor fluctuations:


All patients with motor off periods had at least one non-motor fluctuation
Most non-motor fluctuations were associated with the off state

Non-motor fluctuation Frequency (%) Frequency during off state (%)

Anxiety 66 88

Drenching sweats 64 59

Slowness of thinking 58 83

Fatigue 56 75

Akathisia 54 63

Irritability 52 88

Hallucinations 49 25

Witjas et al. 2002


Causes of wearing-off
Causes of Wearing Off:
Impact of striatal dopamine levels

Dopaminergic neurons die, growing lack of buffering capacity


Striatal pulsatility increasingly mirrors exogenous delivery

Olanow 2004
Altered neuronal firing patterns

Pulsatile stimulation of striatal


dopamine receptors

Downstream dysregulation of
genes, proteins and second
messenger systems

Altered basal ganglia firing


patterns

Development of
dyskinesia

Obeso et al. 2000


Pulsatility

1. Pulsatile stimulation contributes to the development of


complications related to dopaminergic therapy
Pulsatile stimulation of brain dopamine receptors results from:
progressive PD pathology
the use of dopaminergic agents with short half-lives
2. Levodopa has a relatively short half-life (6090 min)

The therapeutic hypothesis:


Strategies that provide levodopa to the brain in a less
pulsatile and more continuous manner may reduce the risk
of motor complications

Obeso et al. 2000


Wearing-Off

ON

Off

L-Dopa Dosing
Management of wearing-off
The Management of Wearing-off:
Dopamine Agonists

The dopamine agonists are a viable option, but many patients are already on a
dopamine agonist when they are given levodopa

Furthermore the dopamine agonists do not change the


pharmacokinetic/pharmacodynamics of levodopa and therefore do not address the
underlying issue of pulsatility associated with traditional levodopa therapy

Providing a dopamine agonist to patients already on levodopa may reduce levodopa


efficacy through competitive inhibition of dopamine on the post-synaptic striatal
receptor

CALM-PD (PSG), 4 yr Pramipexole vs. Levodopa, 2004


A) Levodopa Modification
1. Increase Dose

Increased likelihood of peak-dose dyskinesia


Clinical Effect
A) Levodopa Modification
2. Increase Dose Frequency

The challenge of CDS with levodopa:


Increasing the frequency of oral levodopa doses- troughs

* *

*Data from different fluctuating patients With permission from F. Stocchi


2. Increase Dose Frequency

Pharmacokinetic evidence of significant pulsatility with hourly dosing

Fluctuating patient ON
OFF

With permission from F. Stocchi


A) Levodopa Modification
3. CR Preparations

The challenge of CDS with CR levodopa


Erratic/Variable Absorption and/or control
Slow time to ON
Absent ON
A History of Levodopa Delivery

1961 Levodopa introduced, 1% converted to Dopamine in the brain.

1963 DDCI introduced, 10% of Levodopa converted to Dopamine

2001 Entacapone introduced, increased Levodopa exposure ~35%

Entacapone

Carbidopa or
Benserazide
Levodopa/carbidopa/entacapone
Fluctuators: Efficacy

In patients with fluctuations:

Mean daily ON-time increased by 1.4 1.6 hours

Efficacy (mean motor UPDRS scores) improved by 1.9 - 3.2

Daily levodopa dosage reduced by 42 - 112 mg


relative to placebo

1. Rinne et al- Nordic NOMECOMT Study Group (1998) Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations, Neurol 51: 1309-1314
2. PSG- North American SEESAW Study (1997) Entacapone improves motor fluctuations in levodopa-treated parkinsons disease patients, Ann Neurol 42: 747-755
3. Poewe et al- Austrian-German CELOMEN Study Group (2002 ) Efficacy and safety of entacapone in parkinsons disease patientswith suboptimal levodopa response, Acta Neurol Scand 105: 2345-255
4. Brooks etl al- UK-IRISH (2003). Entacapone is beneficial in both fluctuating and non-fluctuating patients with Parkinsons disease. J Neurol Neurosurg Psych. 74: 10711079
Levodopa/carbidopa/entacapone
Sustained Duration of Efficacy
or Long Duration Dose Stability
Earlier management of wearing-off improves long-term patient function
18.0
UPDRS III scores

12.0
Levodopa with DDCI and entacapone
Traditional levodopa plus placebo
6.0

0.0

-6.0
Baseline 1 2 3 4 5
(N=484) (N=410) (N=101) (N=90) (N=44) (N=37)
Years
Delayed start analysis of 3 long-term studies
Over 5 years, early initiation of levodopa with a DDCI and entacapone resulted in a
significant benefit compared with a delayed start in treatment
Nissinen et al (2006 Feb)- Early initiation of entacapone leads to superior 5 year efficacy compared
to delayed initiation in PD patients receiving traditional ldopa/DDCI therapy
World Parkinson Congress- Poster, Washington
STALEVO:
Fluctuators- Quality of Life
Significant improvement in quality of life with Stalevo

IB-01 Gershanik et al. (2003) Opticom. Onofrj et al. (2004)

Significant improvement in Significant improvements in PDQ-8


independent of dosing frequency
PDQ-39 versus baseline at 20
weeks 1. Gershanik et al (2003) Efficacy and safety of levodopa with entacapone in parkinsons disease
patients suboptimally controlled with levodopa alone, Prog Neuro-Psych & Bio-Psych, 27: 963-971
2. Onofrj et al. (2004) Combining entacapone with levodopa/DDCI improves clinical status and
quality of life regarless of dosing frequency, J Neurol Transam, 111: 1053-1063
Levodopa/carbidopa/entacapone
Non-Fluctuators- Quality of Life

Improved QOL in non-fluctuating patients with Stalevo

US-01 randomized DB trial in non-fluctuators (n=750)


No difference in primary viable (UPDRS Part III Motor score)
Significant improvements in QoL vs placebo (p<0.05)
PDQ-39 Total Score
PDQ-39 Mobility Domain
PDQ-39 Activities of Daily Living Domain
SF-36 Physical Component score

Subjects global self assessment also showed an improvement (p=0.02) compared with
placebo

Olanow et al. (2004) Double-Blind, placebo-controlled study of entacapone in levodopa-treated


patients with stable parkinsons disease: Arch Neruol 61: 1563-1568
STALEVO:
Non-Fluctuators- ADL
Mean ADL UPDRS scores Daily levodopa dosage reduced
improved by 0.92.2 by 2240 mg relative to
placebo
1.5 50

Change in levodopa dose (mg)


Combined Celomen and UKIrish
Celomen UKIrish Combined 40
ADL change

30
1
20

10

0
0
*
-10

-20

-30
-1 0 2 4 6
* ** Time (months)
Stalevo Levodopa/DDCI plus placebo
*p<0.05, **p<0.01
1. Poewe et al- Austrian-German CELOMEN Study Group (2002 ) Efficacy and safety of entacapone
in parkinsons disease patientswith suboptimal levodopa response, Acta Neurol Scand 105: 2345-255
2. Brooks etl al- UK-IRISH (2003). Entacapone is beneficial in both fluctuating and non-fluctuating
patients with Parkinsons disease. J Neurol Neurosurg Psych. 74: 10711079
The use of STALEVO
A) in Fluctuators:

Improves ON time with current levodopa regimen by 1.4- 1.6 hours (6.8
- 16% mean change from baseline)1-3
Sustains current levodopa efficacy/dose regimen for at least the next 3
years4 Earlier Stalevo start results in improved long-term function5
Improves QOL & ADL6,7

B) In Non-Fluctuators, emerging evidence suggests

Improves QOL & ADL8,9


Reduces levodopa pulsatility which, over time, is thought to be
responsible for development of dyskinesias10.

1. Rinne et al- Nordic NOMECOMT Study Group (1998) Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations, Neurol 51: 1309-1314
2. PSG- North American SEESAW Study (1997) Entacapone improves motor fluctuations in levodopa-treated parkinsons disease patients, Ann Neurol 42: 747-755
3. Poewe et al- Austrian-German CELOMEN Study Group (2002 ) Efficacy and safety of entacapone in parkinsons disease patientswith suboptimal levodopa response, Acta Neurol Scand 105: 2345-255
4. Larsen et al NOMESAFE Study Group (2003), The tolerability and efficacy of entacapone over 3 years in patients with parkinsons disease, Eur J Neur, 10: 137-146
5. Nissinen et al (2006 Feb)- Early initiation of entacapone leads to superior 5 year efficacy compared to delayed initiation in PD patients receiving traditional ldopa/DDCI therapy , WPC Poster, Washington
6. Onofrj et al. (2004) Combining entacapone with levodopa/DDCI improves clinical status and quality of life regarless of dosing frequency, J Neurol Transam, 111: 1053-1063
7. Gershanik et al (2003) Efficacy and safety of levodopa with entacapone in parkinsons disease patients suboptimally controlled with levodopa alone, Prog Neuro-Psych & Bio-Psych, 27: 963-971
8. Brooks etl al- UK-IRISH (2003). Entacapone is beneficial in both fluctuating and non-fluctuating patients with Parkinsons disease. J Neurol Neurosurg Psych. 74: 10711079
9. Olanow et al. (2004) Double-Blind, placebo-controlled study of entacapone in levodopa-treated patients with stable parkinsons disease: Arch Neruol 61: 1563-1568
10. Stocchi and Olanow (2004), Continuous dopaminergic stimulation in early and advanced PD, Neurol Sci 62 (Suppl 1): S57-S64
Limitations of multiple dosing for
Parkinsons disease

Multiple daily doses of a short-acting agent can lead to:


fluctuations in plasma drug concentration throughout
the day
decline in plasma drug concentration at night
wearing off of symptom control during the night
May contribute to lack of control of nocturnal symptoms
of PD
Variation of absorption rate with food intake
Limitations of multiple dosing for
Parkinsons disease

Motor
complications
concentrations
Plasma drug

On

Off

Dose Dose Dose


Patients symptoms Patients symptoms not
well controlled well controlled
Duration of L-dopa treatment and
frequency of dyskinesia
Patients with dyskinesia (%)

Duration of L-dopa treatment (years)

Kostic et al. Neurology 1991;41:2025


Treatment with levodopa has dramatically reduced disability
and mortality associated with Parkinsons disease

100
disability and death (%)

80
Patients with severe

60 Untreated patients

Levodopa/carbidopa-
40 treated patients

20

0
15 610 1115

Years since diagnosis

Figure adapted from Poewe et al. Neurol 1996;47:S146;


Hoehn et al. J Neural Trans 1983;19:253
Levodopa consistently provides better symptom control
compared with dopamine agonists

Levodopa/carbidopa Levodopa/DDCI versus


versus pramipexole1 dopamine agonists
improvement in UPDRS total
16
after 4 or 5 years
Change in UPDRS total score

14 Treatment Improvement versus


12 regimen levodopa/DDCI
10
Improvement

8 Pramipexole1 5.9 points on total UPDRS


6 score (p=0.003) at 4 years
4
2 Ropinirole2 4.48 points on UPDRS
0 motor score (p=0.008)
2 at 5 years
4 Cabergoline3 2.9 points on UPDRS motor
0 6 12 18 24 30 36 42 48
score (p<0.001) at 5 years
Time (months)
Pramipexole
Levodopa/carbidopa
p=0.003
Figure adapted from 1Holloway et al. Arch Neurol 2004;61(7):1044;
DDCI-=dopa-decarboxylase inhibitor; 2Rascol et al. N Engl J Med 2000;342(20):1484;

UPDRS=Unified Parkinsons Disease Rating Scale 3Bracco et al. CNS Drugs 2004;18(11):733
Most patients eventually require the superior efficacy of
levodopa for symptom control

Need for levodopa in patients Need for levodopa in patients


initiated with a dopamine agonist initiated with a dopamine agonist
(pramipexole)1,2 (ropinirole)3,4
80 80
72%
supplemental levodopa (%)

supplemental levodopa (%)


66%
Patients requiring

Patients requiring
60 53% 60

40 40

20 20

4%
0 0
2 4 0.5 5
Years after randomization Years after randomization
Figure adapted from 1Holloway et al. Arch Neurol 2004;61(7):1044;
Figure adapted from 2PSG. JAMA 2000;284(15):1931;
Figure adapted from 3Rascol et al. NEJM 2000;342:1484;
Figure adapted from 4Rascol et al. Mov Disord 1998;13(1):39
Chronic therapy with conventional levodopa is associated
with the development of wearing-off and dyskinesia

Early disease Mid-stage disease Advanced disease

Clinical effect

Clinical effect
Dyskinesia
Clinical effect

ON

OFF Wearing-off

2 4 6 2 4 6 2 4 6
Levodopa Levodopa Levodopa
Time (hours) Time (hours) Time (hours)

Long duration of Diminished duration of Clinical response mirrors


clinical benefit clinical benefit leads to levodopa plasma
Low incidence of wearing-off pharmacokinetic profile
dyskinesias Increased incidence of ON-time is associated with
dyskinesias dyskinesias and wearing-off

Dyskinesia threshold
Response threshold Figure adapted from Obeso et al. Neurology 2000;55(4 Suppl):S13
In Parkinsons disease, conventional levodopa delivery
leads to pulsatile stimulation of the brain

In Parkinsons disease, the The short half-life


ability to regulate and (6090 min) of
maintain steady levels of conventional levodopa
dopamine in the brain is leads to peaks and
reduced due to profound troughs in
progressing plasma levodopa levels,
neuronal loss which are further worsened
by intermittent dosing

Deep troughs in plasma levodopa levels lead to pulsatile


stimulation of the brain

Olanow et al. Lancet Neurol 2006;5(8):677


In Parkinsons disease, deep troughs in plasma levodopa
levels lead to pulsatile stimulation of dopamine receptors

Dopamine receptor state


Normal
Activated

Unactivated

PD (untreated)
Striatum Activated

Substantia nigra Unactivated

Conventional levodopa
Nigrostriatal neurons
degenerate Activated

Conventional
levodopa Unactivated

*
*Levodopa dose; PD=Parkinson's disease Adapted from Olanow et al. Lancet Neurol 2006;5(8):677
Normal movement
Parkinsonian state
Parkinsonian state with
intermittent levodopa
Parkinsonian state with
continuous levodopa
Motor complications associated with chronic levodopa therapy
may be due to pulsatile stimulation of dopamine receptors

Deep troughs in plasma levodopa levels can lead to pulsatile


stimulation of the dopamine receptors, which, in turn,
may result in

Wearing-off Dyskinesia

How can we avoid deep troughs in


plasma levodopa?

Obeso et al. Neurology 2000;55(4 Suppl):S13;


Olanow et al. Lancet Neurol 2006;5(8):677
Dopamine agonists
Dopamine works by stimulating receptors on the surface of
corpus striatum cells
Drugs that also stimulate these cells are called dopamine
agonists, or DAs
DAs may be used before L-dopa therapy, or added on to avoid
requirements for higher L-dopa doses late in the disease
DAs available in the United States as of early 1998, include
bromocriptine (Permax, Parlodel), pergolide (Permax), and
pramipexole (Mirapex), cabergoline (Dostinex) and ropinirole
(Requip), lisuride (Dopergine) and apomorphine.
Side effects of all the DAs are similar to those of dopamine,
plus confusion and hallucinations at higher doses.
Main advantages:
Continuous dopaminergic stimulation
DA treatment complicate with dyskinesias and motor fluctuations less
thatn levo-dopa
Anticholinergics
Anticholinergics maintain dopamine balance as levels
decrease
Side effects of anticholinergics (dry mouth,
constipation, confusion, and blurred vision) are usually
too severe in older patients or in patients with
dementia.
Anticholinergics rarely work for very long
They are often prescribed for younger patients who
have predominant shaking. Trihexyphenidyl (Artane) is
the drug most commonly prescribed.
Acetylcholine in PD
Acetylcholine neurotransmitter involved in
many brain functions (e.g. memory)
In the striatum: balance between acetylcholine
and dopamine is critical for smooth motor
function (striatal cholinergic interneurons
inhibit the medium spiny neurons)
In PD acetylcholine unchanged, dopamine
reduced tilts the balance
Drugs that block acetylcholine transmission
restore the balance
The Cochrane Database of Systematic Reviews 2006 Issue 1
Copyright 2006 The Cochrane Collaboration. Published by John Wiley & Sons,
Ltd.
Anticholinergics for symptomatic management of Parkinsons disease
Katzenschlager R, Sampaio C, Costa J, Lees A

Summary
Anticholinergic drugs can improve movement symptoms of Parkinson's
disease, but with adverse mental effects, and there is not enough evidence to
compare the different drugs.

Anticholinergics were the first drugs available for Parkinsons disease and they are
still widely used. They are believed to work by counteracting an imbalance which
exists in Parkinsons disease between two chemicals in the brain which transmit
messages between nerve cells. However, anticholinergic drugs have been
associated with unfavourable side effects. They are used alone, or with other anti-
Parkinson's drugs. The review of trials found that anticholinergics can improve
movement problems in people with Parkinson's disease, but also cause adverse
mental effects (such as confusion, memory problems, restlessness and
hallucinations). There is not enough evidence to compare the different
anticholinergic drugs.
Other drugs
Amantadine (Symmetrel) is sometimes used as an early
therapy before L-dopa is begun, and as an add-on later
in the disease.
Has an evidence-based antidiskinetic effect
Its anti-parkinsonian effects are mild, and are not seen
in all patients
Multiple mechanisms of action, probably the main one
being the antiglutamatergic effect
Clozapine (Clozaril) is effective especially against
psychiatric symptoms of late PD, including psychosis
and hallucinations; newer quetiapine (Seroquel)
Duodopa
Intestinal gel containing levo-dopa
Avoids absorbtion problems
Can be titrated precisesly by the pump
Usually substitutes all other PD treatments
High efficacy
Disadvantage: pateints have to carry the pump
with them
Advantage: can be used when DBS is
contraindicated (e.g. cognitive disturbance,
depression)
PD prognosis

Despite medical treatment, the symptoms of


Parkinson disease worsen over time, and
become less responsive to drug therapy
Late-stage psychiatric symptoms are often the
most troubling, including difficulty sleeping,
nightmares, intellectual impairment (dementia),
hallucinations, and loss of contact with reality
(psychosis).
Prevention of PD

There is no known way to prevent Parkinson


disease