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Boala Parkinson

Conf. 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

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 pur

Parkinsonism +alte
semne clinice

Pseudoparkinsonism

Boala Parkinson

Paralizia supranuclear
progresiv

Tremorul esenial

Parkinsonismul
medicamentos

Atrofia multisistemic

Parkinsonismul vascular
(aterosclerotic)

Parkinsonismul
postencefalitic

Calcificrile masive de
ganglioni bazali

Parkinsonismul
indus de
MPTP

TCC repetate

Alte toxine, ex.


Mangan,
pesticide

Anoxia cerebral

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 becomessmaller, more cramped
Hitler's signature in 1929, 11years 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

PD famous people
Adolf Hitlerhad 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 thalamocortical drive is inhibited)

The Pope in 1979,


age 59, with
President Jimmy
Carter. The
Pope'sshoulders
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
GeorgeHerbe
rt Walker
Bush and
Barbara Bush

The Pope in 1999,


age 79, 20 years
after PD began, 13
years he was
diagnosed. The
Pope is
withPresident
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 dopadecarboxylase 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/
functional impairment

Parkinsons Disease

Nonpharmacologic therapy

No treatment has been


shown to be
neuroprotective22

Education

MAOB Inhibitors
(RAS) have only mild
symptomatic benefit11

Support
Services
Exercise22

Dopamine
Agonists11

Levodopa
(+/- COMT inhibitor)

Nutrition

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 (Ldopa 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-Omethyltransferase (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
74 Movement Disorder Specialists
54 PCPs

300 patients with PD treated with


carbidopa/levodopa

All physicians surveyed treated


patients with PD

Sampled through the National


Parkinsons Foundation

PRELUDE survey: Importance of wearing-off


for patients and healthcare professionals

What is the biggest challenge with levodopa therapy?

Managing
dyskinesia #1 for
Movement
Disorder
Specialists

Managing
wearing-off #1
for PD patients
and PCPs

g-off
Wearin

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

Rajput et al. 2002

A predictable decline in motor function at the end of


dose in a patient with previously stable response
receiving 3 or more daily levodopa doses
25% of patients had wearing-off after 4.9 years

Parkinson Study Group,


2000

A perception of loss of mobility or dexterity, usually


taking place gradually over minutes and usually
bearing close resemblance to the timing of
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


emergence of one or more PD signs or
symptoms before the next scheduled
antiparkinsonian medication dosage.

Stacy et al, 2004

Wearing-off happens when a dose that


previously used to help your symptoms
does not last as long and your next dose is
needed sooner. Symptoms of wearing-off
include changes in movement and mobility,
thoughts and feelings, sensations and
sense of well being.
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 wearingoff and specifically ask about the occurrence of such
changes.
Stacy, 2003

Identification of Wearing Off


Symptoms

Wearing-Off

Non-Motor Symptoms
(often precede/coincide with Motor Symptoms)

SENSORY
Pain
Paresthesias
Sensory loss
Akathisia
Fatigue
PSYCHIATRIC
Anxiety
Paranoia
Hallucinations
Depression
Panic
Cognitive changes

AUTONOMIC
pallor
BP changes
shortness of breath
tachycardia
sweating
facial flushing
laryngeal stridor
papillary dilation
drooling
dysphagia
belching
abdominal bloating
urinary frequency
micturition disturbances

Motor Symptoms
Tremor
Rigidity
Akinesia/Bradykinesia
Postural Instability/Balance

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

Of

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

Clinical Effect

Increased likelihood of peak-dose dyskinesia

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

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

UPDRS III scores

18.0

12.0

Levodopa with DDCI and entacapone


Traditional levodopa plus placebo

6.0

0.0

-6.0
Baseline
(N=484)

1
(N=410)

2
3
(N=101)
(N=90)
Years

4
(N=44)

5
(N=37)

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 improvements in PDQ-8


Significant improvement in
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
improved by 0.92.2

1.5
ADL change

Celomen

UKIrish

Combined

-1

*
Stalevo
*p<0.05, **p<0.01

**

Change in levodopa dose (mg)

50
40

Daily levodopa dosage reduced


by 2240 mg relative to
placebo

Combined Celomen and UKIrish

30
20
10

0
-10
-20
-30
0

Time (months)
Levodopa/DDCI plus placebo

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 function 5
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

Plasma drug
concentrations

Motor
complications

On

Off

Dose

Dose

Patients symptoms
well controlled

Dose
Patients symptoms
not well controlled

Patients with dyskinesia (%)

Duration of L-dopa treatment and


frequency of 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

Patients with severe


disability and death (%)

100
80
60

Untreated patients

40

Levodopa/carbidopatreated 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

16
14
12
10
8
6
4
2
0
2
4

Change in UPDRS total score

Improvement

Levodopa/carbidopa
versus pramipexole1

Levodopa/DDCI versus
dopamine agonists
improvement in UPDRS total
after 4 or 5 years
Treatment
regimen

12 18 24 30 36 42 48
Time (months)

Improvement versus
levodopa/DDCI

Pramipexole1

5.9 points on total UPDRS


score (p=0.003) at 4 years

Ropinirole2

4.48 points on UPDRS


motor score (p=0.008)
at 5 years

Cabergoline3

2.9 points on UPDRS motor


score (p<0.001) at 5 years

Pramipexole
Levodopa/carbidopa
p=0.003

DDCI-=dopa-decarboxylase inhibitor;
UPDRS=Unified Parkinsons Disease Rating Scale

Figure adapted from 1Holloway et al. Arch Neurol 2004;61(7):1044;


2
Rascol et al. N Engl J Med 2000;342(20):1484;
3
Bracco et al. CNS Drugs 2004;18(11):733

Most patients eventually require the superior efficacy of


levodopa for symptom control

Patients requiring
supplemental levodopa (%)

80
60

72%

53%

40
20
0
2

Years after randomization

Need for levodopa in patients


initiated with a dopamine agonist
(ropinirole)3,4
80
Patients requiring
supplemental levodopa (%)

Need for levodopa in patients


initiated with a dopamine agonist
(pramipexole)1,2

66%

60
40
20
4%

0.5

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

Levodopa

Mid-stage disease

ON
OFF
2

Time (hours)

Long duration of
clinical benefit

Low incidence of
dyskinesias

Levodopa

6
Levodopa

Time (hours)

Dyskinesia
Wearing-off

Time (hours)

Diminished duration of

Clinical response mirrors

Increased incidence of

ON-time is associated with

clinical benefit leads to


wearing-off
dyskinesias

Dyskinesia threshold
Response threshold

Advanced disease

Clinical effect

Clinical effect

Clinical effect

Early disease

levodopa plasma
pharmacokinetic profile

dyskinesias and wearing-off

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


ability to regulate and
maintain steady levels of
dopamine in the brain is
reduced due to
progressing
neuronal loss

The short half-life


(6090 min) of conventional
levodopa leads to peaks
and profound troughs in
plasma levodopa levels,
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)
Activated

Striatum
Substantia nigra

Nigrostriatal neurons
degenerate

Conventional
levodopa

Unactivated

Conventional levodopa
Activated

Unactivated

*
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 antiParkinson'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