Boala Parkinson

Prof. Dr. Bogdan O. Popescu

Disciplina de Neurologie – Spitalul
Clinic Colentina
U.M.F. „Carol Davila” Bucuresti
1817
Modularea mișcării de către
ganglionii bazali
 Substanța neagră și 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 în boala Parkinson
Conceptul de neurodegenerare. Mecanisme
patogenice comune ale bolilor
neurodegenerative
• Neurodegenerare = un proces de pierdere neuronală continuă,
pe o perioadă lungă de timp, care afectează anumite ppuplații
neuronale specifice în SNC, cu o evoluție clinică progresivă

• Apoptoză neuronală (vs. necroză)

• 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 – generalități
• De obicei debutează la sfârșitul decadei a șasea sau
începutul decadei a șaptea
• Boala Parkinson duce la un declin progresiv al controlului
mișcărilor voluntare, afectând inițierea mișcării, viteza
mișcării și precizia acesteia
• Simptome parkinsoniene se pot întâlni în până la 15%
dintre cei cu vârstă între 65-74 și aproape la 30% din cei
peste 75 de ani
• BP afectează peste 1,000,000 de persoane in UE atât
bărbați cât și femei, cu aprox. 50.000 de cazuri noi pe an
• Imensa majoritate a cazurilor de BP sunt sporadice
• ~5% PD – mutații genetice – moștenite (mai rar spontane)
 Etiologia BP (I)
• Necunoscută, ca în toate bolile neurodegenerative
(susceptibilitate genetică + factori de mediu)
• Semnele și simptomele motorii sunt determinate
de pierderea neuronilor dopaminergici din SN din
mezencefal, unul din centrele cerebrale de control
al mișcării voluntare
• Semnele non-motorii – degenerarea altor arii din
trunchiul cerebral sau cortex
• Marca neuropatologică a bolii Parkinson – corpii
Lewy (depozite anormale de alfa-sinucleină)
 Etiologia BP (II)
• Boala Parkinson ≠ parkinsonism
• Moartea celulară care duce la parkinsonism poate fi provocată
de o serie de alte condiții patologice:
– Infecție
– Trauma
– Toxice
– Medicație anti-dopaminergică - haloperidol (Haldol), clorpromazine
(tioridazină)
• Când nu se poate identifica o asemenea cauză pentru pierderea
neuronilor nigrali – se diagnostichează un parkinsonism
primar, neurodegenerativ (BP sau parkinsonism atipic)
• Parkinsonism atipic sau “Parkinson plus” – paralizia
supranucleară progresivă, atrofia multisistemică,
degenerescența cortico-bazală
 Boala Parkinson și parkinsonismul
Parkinsonism +alte semne
Parkinsonism pur Pseudoparkinsonism
clinice
Paralizia supranucleară
Boala Parkinson Tremorul esențial
progresivă
Parkinsonismul
Atrofia multisistemică Parkinsonismul vascular (aterosclerotic)
medicamentos

Parkinsonismul Calcificările masive de

postencefalitic ganglioni bazali

Parkinsonismul indus de
TCC repetate
MPTP

Alte toxine, ex. Mangan,

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

• Tremorul – de obicei cu debut la mb superior, de obicei întâi

pe o parte și mai târziu pe cealaltă (asimetria!). Clasic –
“numărat bani”, 3 Hz

• Bradichinezia – reducerea globală a vitezei de mișcare,

uneori freezing (blocaj motor), hipomimie, facies fijat, clipire
rară

• Rigiditatea – un tip specific de hipertonie musculară

• Instabilitatea posturală/dezechilibrul, uneori festinație

 Simptome ale BP - nonmotorii

• Depresie
• Anxietate
• Dizartrie, festinația vorbirii, fără intonație, egal
• Tulburări de somn – variate
• Modificări emoționale – frică, iritabilitate și
insecuriate
• Tulburări micționale – incontinență, poliurie
• Constipație
• Disfuncție sexuală
 Alte simptome ale BP
• Modificarea scrisului, literele devin din ce în ce mai mici
(micrografie)
• Tulburare cognitivă, până la demență
• Halucinații
• Modificări ale TA
• Hiperhidroză
• Seboree
• Edeme mb inferioare
• Durere – intens și frecvent
• Astenie marcată
• Disestezie
 Stadializarea Hoehn și Yahr a BP
• Stage 1 : afectare unilaterală, mb superior în semiflexie cu
tremor, pacientul se înclină de obicei spre partea afectată

• Stage 2: afectare bilaterală cu modificări minime posturale,

mers cu pași mici, târșâiți.

• Stage 3: Modificări importante de mers; dizabilitate generală

moderată; instabilitate posturală cu tendința la cădere.

• Stage 4: Dizabilitate importantă; ambulație limitată, necesită

asistență.

• Stage 5: Invaliditate completă, pacientul este imobilizat în

scaun cu rotile sau la pat, nu poate merge nici cu sprijin.
 Diagnosticul bolii Parkinson
• B. Parkinson trebuie diferențiată de:
– Parkinsonismul de diferite etiologii
– Parkinsonismul atipic
• Se bazează pe răspunsul la levod-dopa și pe
căitarea altor semne neurologice, care nu fac
parte din tabloul clinic al b. Parkinson
• BP se caracterizează prin:
– Manifestări cardinale motorii
– Semne non-motorii caracteristice
 Semnele motorii cardinale
• Bradykinesia, hypokinesia, akinesia
– Dificultate în inițierea mișcării(akinesia)
– Lentoarea mișcării(bradykinesia)
– Mișcări spontane diminuate(hypokinesia)
– Tind să apară împreună
– Fluctuații spontane ale mobilității
– Semnele motorii sunt mai pronunțate pe o parte – asimetrie (în
special în stadiile precoce)
– Faciesul fijat (hypomimia), gură întredeschisă, clipit rar,
disfagie, salivație excesivă (drooling)
– Vorbirea: hipofonie (diminuare a volumului vocii), voce
îngroșată, dizartrie, voce monotonă, fără intonație
(dizartrofonie), dificlutate în a iniția vorbirea, accelerare către
sfârșitul frazei (festinația 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
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)
 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/
Parkinson’s Disease Nonpharmacologic therapy
functional impairment

No treatment has
been shown to be
neuroprotective22 Education

MAOB Inhibitors
(RAS) have only mild
Support
symptomatic benefit11 Services

Exercise22

Dopamine Levodopa††
Nutrition
Agonists11 (+/- 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. 36
 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

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
(often precede/coincide with Motor Symptoms) 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

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 (60–90 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’
 Duration of L-dopa treatment and
frequency of dyskinesia
Patients with dyskinesia (%)

Duration of L-dopa treatment (years)

Kostic et al. Neurology 1991;41:202–5

Treatment with levodopa has dramatically reduced disability
and mortality associated with Parkinson’s disease

100
disability and death (%)

80
Patients with severe

60 Untreated patients

Levodopa/carbidopa-
40 treated patients

20

0
1–5 6–10 11–15

Years since diagnosis

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

Hoehn et al. J Neural Trans 1983;19:253
Chronic therapy with conventional levodopa is associated
with the development of wearing-off and dyskinesia

Early disease Mid-stage disease Advanced disease

Dyskinesia

Clinical effect

Clinical effect
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 Parkinson’s 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
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 Parkinson´s 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 Parkinson´s disease and they are
still widely used. They are believed to work by counteracting an imbalance which
exists in Parkinson´s 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