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1817
PD
CTR
SN n boala Parkinson
Corpii Lewy
www.saigata-nh.go.jp/saigata/rinken/neuropat/
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)
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
Anoxia cerebral
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
Cardinal manifestations of
PD (IV)
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
Neurodegeneration: AD and
PD
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
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
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.
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
Parkinsons Disease
Nonpharmacologic therapy
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
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
Patient survey
328 Neurologists
74 Movement Disorder Specialists
54 PCPs
Managing
dyskinesia #1 for
Movement
Disorder
Specialists
Managing
wearing-off #1
for PD patients
and PCPs
g-off
Wearin
Dyskinesia
Symptoms of wearing-off
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
Frequency (%)
Anxiety
66
88
Drenching sweats
64
59
Slowness of thinking
58
83
Fatigue
56
75
Akathisia
54
63
Irritability
52
88
Hallucinations
49
25
Causes of wearing-off
Olanow 2004
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
Wearing-Off
ON
Of
L-Dopa Dosing
Management of wearing-off
The dopamine agonists are a viable option, but many patients are already on a
dopamine agonist when they are given levodopa
A) Levodopa Modification
1. Increase Dose
Clinical Effect
A) Levodopa Modification
2. Increase Dose Frequency
The challenge of CDS with levodopa:
Increasing the frequency of oral levodopa doses- troughs
Fluctuating patient
ON
OFF
A)
Levodopa Modification
3. CR Preparations
Entacapone
Carbidopa or
Benserazide
Levodopa/carbidopa/entacapone
Fluctuators: Efficacy
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
12.0
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)
STALEVO:
Fluctuators- Quality of Life
Significant improvement in quality of life with Stalevo
IB-01 Gershanik et al. (2003)
Levodopa/carbidopa/entacapone
Non-Fluctuators- Quality of Life
Improved QOL in non-fluctuating patients with Stalevo
Subjects global self assessment also showed an improvement (p=0.02) compared with
placebo
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
**
50
40
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
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
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
Plasma drug
concentrations
Motor
complications
On
Off
Dose
Dose
Patients symptoms
well controlled
Dose
Patients symptoms
not well controlled
100
80
60
Untreated patients
40
Levodopa/carbidopatreated patients
20
0
15
610
1115
16
14
12
10
8
6
4
2
0
2
4
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
Ropinirole2
Cabergoline3
Pramipexole
Levodopa/carbidopa
p=0.003
DDCI-=dopa-decarboxylase inhibitor;
UPDRS=Unified Parkinsons Disease Rating Scale
Patients requiring
supplemental levodopa (%)
80
60
72%
53%
40
20
0
2
66%
60
40
20
4%
0.5
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
Increased incidence of
Dyskinesia threshold
Response threshold
Advanced disease
Clinical effect
Clinical effect
Clinical effect
Early disease
levodopa plasma
pharmacokinetic profile
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
Wearing-off
Dyskinesia
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
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
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