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Boala Parkinson
Conf. Dr. Bogdan O. PopescuDisciplina de Neurologie Spitalul
Clinic ColentinaU.M.F. Carol Davila Bucuresti
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1817
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Substantia nigra and Parkinsons disease
The pathological changes in certain neurological diseases provide insights about the function of thebasal 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: Themesencephalon 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'sdisease. (From Bradley et al., 1991.)
PD CTR
http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.biblist.1266http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.biblist.12667/28/2019 Boala Pakinson
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SN in Parkinsons disease
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Patogeneza bolii Parkinson
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Corpii Lewy
www.saigata-nh.go.jp/saigata/rinken/neuropat/
http://www.saigata-nh.go.jp/saigata/rinken/neuropat/http://www.saigata-nh.go.jp/saigata/rinken/neuropat/http://www.saigata-nh.go.jp/saigata/rinken/neuropat/http://www.saigata-nh.go.jp/saigata/rinken/neuropat/7/28/2019 Boala Pakinson
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Scenariul Heiko Braak desprestadializarea BP si posibila etiologie a
BP
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Definitia Bolii Parkinson
Boala Parkinson (BP) este o afectiuneneurodegenerativa progresiva, marcata, din
punct de vedere motor, de semne precumtremorul de repaus, rigiditatea, bradikinezia siinstabilitatea posturala.
Apare din cauza mortii celulare progresive aunor celule din regiuni bine determinate aleSNC, inclusiv substanta neagra din mezencefal.
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PD description
Usually beginning in a person's late fifties or early sixties
Parkinson disease causes a progressive decline inmovement control, affecting the ability to controlinitiation, speed, and smoothness of motion
Symptoms of PD are seen in up to 15% of those ages65-74, and almost 30% of those ages 75-84
PD affects approximately 1,000,000 people in theUnited States, both men and women, with as many asfifty thousand new cases each year
Most cases of PD are sporadic 1-5% PD genetic mutations inherited
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PD etiology (I)
The immediate cause of PD: degeneration of brain cells in the area known as the substantianigra , one of the movement control centers of the brain
Damage to this area leads to the cluster of symptoms known as "parkinsonism"
In PD, degenerating brain cells contain Lewy bodies, which help identify the disease
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PD etiology (II)
The cell death leading to parkinsonism may be causedby a number of conditions: Infection Trauma Poisoning Drugs given for psychosis, such as haloperidol (Haldol) or
chlorpromazine (thorazine) When no cause for nigral cell degeneration can be
found, the disorder is called idiopathic parkinsonism, orParkinson disease Parkinsonism may be seen in other degenerative
conditions, known as the "parkinsonism plus"syndromes, such as progressive supranuclear palsy
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PD etiology (III)
The substantia nigra , or "black substance," is one of the principal movement control centers in the brain
By releasing dopamine , it helps to refine movementpatterns throughout the body
The dopamine released by nerve cells of substantianigra stimulates another brain region, the corpusstriatum
Without enough dopamine, the corpus striatum cannotcontrol its targets, and so on down the line
Ultimately, the movement patterns of walking, writing,reaching for objects, and other basic programs cannotoperate properly, and the symptoms of parkinsonismare the result.
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PD etiology (IV) There are some known toxins that can cause parkinsonism, most
notoriously a chemical called MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) , found as an impurity in someillegal drugs.
Parkinsonian symptoms appear within hours of ingestion, andare permanent
MPTP may exert its effects through generation of toxicmolecular fragments called free radicals, and reducing freeradicals has been a target of several experimental treatments forPD using antioxidants
It is possible that early exposure to some as-yet-unidentifiedenvironmental toxin or virus leads to undetected nigral celldeath, and PD then manifests as normal age-related declinebrings the number of functioning nigral cells below the thresholdneeded for normal movement
It is also possible that, for genetic reasons, some people aresimply born with fewer cells in their substantia nigra than
others, and they develop PD as a consequence of normal decline.
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Pure Parkinsonism Parkinsonism with otherfeatures Pseudoparkinsonism
Parkinson's disease Progressive supranuclear palsy Essential Tremor
Drug-inducedparkinsonism Multiple system atrophy Vascular (aterosclerotic) parkinsonism
Postencephaliticparkinsonism Basal ganglia calcification
MPTP parkinsonism Repetitive head trauma
Other toxins, e.g.manganese Cerebral anoxia
Parkinsons disease and parkinsonism
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PD symptoms Tremors , usually beginning in the hands, often occurring on one
side before the other. The classic tremor of PD is called a "pill-rolling tremor," because the movement resembles rolling a pillbetween the thumb and forefinger. This tremor occurs at afrequency of about three per second.
Slow movements (bradykinesia) occur, which may involveslowing down or stopping in the middle of familiar tasks such as
walking, eating, or shaving. This may include freezing in placeduring movements (akinesia).
Muscle rigidity or stiffness, occuring with jerky movementsreplacing smooth motion.
Postural instability or balance difficulty occurs. This may leadto a rapid, shuffling gait (festination) to prevent falling.
In most cases, there is a "masked face," with little facialexpression and decreased eye-blinking = hypomimia
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PD symptoms non-motor (II)
Depression Anxiety Speech changes , including rapid speech without
inflection changes Sleep problems , including restlessness and nightmares Emotional changes , including fear, irritability, and
insecurity Bladder disorders incontinence, polyuria, urinary
urgency Constipation Sexual dysfunction
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Stages of Parkinsons disease (Hoehn and Yahr)
Stage 1 : unilateral involvement; blank faces; affected arm insemiflexed position with tremor; patient lean to unaffected side.
Stage 2: bilateral involvement with early postural changes; slow,shuffling gait with decreased excursion of legs.
Stage 3: pronounced gait disturbances; moderate generalizeddisability; postural instability with tendency to fall .
Stage 4: significant disability; limited ambulation with assistance.
Stage 5: complete invalidism; patient confined to bed or chair;cannot stand or walk even with assistance.
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Diagnosis of Parkinsons disease
Parkinsons disease to be differentiated from: Parkinsonisms of different etiologies Atypical parkinsonism
Mainly based on typical neurological findingsand to response to levodopa (l-dopa)
PD is characterized by: Disturbances of motor function (cardinal
manifestations) Accompanying manifestations (non-motor signs)
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Cardinal manifestations of PD (I)
Bradykinesia, hypokinesia, akinesia Difficult initiation of movement ( akinesia ) Sluggishness of movement ( bradykinesia ) Diminished spontaneous movement ( hypokinesia ) Tend to occur together Spontaneous fluctuations of mobility Motor disturbances more pronounced on one side (especially
early stages) Mask like facies (hypomimia), defective mouth closure, reduced
blinking, dysphagia, salivation (drooling) Speech: hypophonia (diminished in volume), hoarse voice, poorly enunciated, monotonous in pitch (disarthrophonia), hard toinitiate speech, may repeat syllables involuntary acceleration of speech toward the end of a sentence (festination)
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Cardinal manifestations of PD (II)
Postural changes
Stooped posture Flexed andadducted postureof the arms
Postural instability
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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 pathbetween furniture
Difficult to stand up from a seated position or toturn over in bed
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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.
1945, 56 yo1938, 49 yo
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Why tremor?
The exact anatomical basis of parkinsonian tremor isnot known
In animals, experimental lesions to the SN do not result
in tremor neither do lesions in the striatopallidal partsof the basal ganglia From 8 MPTP intoxicated patients, only 4 developed
tremor
Ward et al. produced parkinsonian tremor in monkeysby lesions in the ventromedial tegmentum of themidbrain concluded that probably lesions toreticulospinal pathway induce parkinsonian tremor
alternatively the tegmento-thalamic projection
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Cardinal manifestations of PD (VI)
Rigidity Elevated muscle tone is felt by the patient as muscle
tension of spasm and by examiner as resistance topassive movements across the joints
Examination reveal cogwheel rigidity (repeated,ratchet-like oscillations of resistance to passivemovements across the wrist, elbow, etc., which arebrought out by alternating passive flexion andextension)
Pathophisiology: lesions to nigrostriatal system (lessdopamine normal thalamo-cortical drive isinhibited)
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The Pope in 1979, age
59, with President Jimmy Carter. ThePope's shouldersstoop, PD begins.
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Neurodegeneration: AD and PD
The Pope andPresident RonaldReagan defeatedCommunism
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The Pope in 1988, age68, 2 years after PDdiagnosed. The Pope is
with President RonaldReagan. The Pope diedof complications of PD. President Reagan
died of complications of Alzheimer disease.
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The Pope in 1992,age 72, 13 yearsafter PD began, 6years after PDdiagnosed. ThePope is withPresidentGeorge Herbert
Walker Bush andBarbara Bush
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The Pope in 1999, age79, 20 years after PDbegan, 13 years he was
diagnosed. The Pope is with President Clintonand Hillary Clinton
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The Pope in 2004, age84, 25 years after PDbegan, 18 years after PD
diagnosed. The Pope is with President George W Bush
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PD treatment
There is no cure for Parkinson disease. Most
drugs treat the symptoms of the disease only,although drugs like rasagiline and dopamineagonists may slow degeneration of the substantianigra.
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PD treatment physical exercise
Regular, moderate exercise has been shown toimprove motor function without an increase inmedication 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 therapisthas 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 stimulatemovement during slowdowns or freezes.
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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 asdopamine 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 ordomperidone can increase the movement of food through the digestivesystem.
PD patients may need to limit the amount of protein in their diets themain drug used to treat PD, L-dopa, is an amino acid, and is absorbed by thedigestive system by the same transporters that pick up other amino acidsbroken 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 generalhealth
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
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PD treatment - drugs
The pharmacological treatment of Parkinson disease iscomplex
While there are a large number of drugs that can beeffective, their effectiveness varies with the patient,disease progression, and the length of time the drug hasbeen used
Dose-related side effects may preclude using the mosteffective dose, or require the introduction of a new drug to counteract them
There are six classes of drugs currently used to treatPD.
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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)
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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
Alg ith d P ti P t f
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43
Algorithms and Practice Parameters for Initial Treatment of PD*
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 withextended release levodopa versus immediate release (1)1. Miyasaki et al. 2002 Neurology 58, 11-17; 2. Suchowersky et al. 2006 Neurology 66, 976-982.
Parkinson s Disease Pharmacologic therapy/functional impairment Nonpharmacologic therapy
Education
SupportServices
Exercise 2
NutritionDopamineAgonists 1Levodopa
(+/- COMT inhibitor)
Comined treatment
No treatment hasbeen shown to beneuroprotective 2
MAOB Inhibitors(RAS) have only mildsymptomatic benefit 1
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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 dopamineby the brain
It may be started when symptoms begin, or when they becomeserious enough to interfere with work or daily living
L-dopa therapy usually remains effective for all duration of thedisease Following this, many patients develop motor fluctuations , including
peak-dose "dyskinesias" (abnormal movements such as twisting, orrestlessness), 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 indyskinesias
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.
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Dopamine
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Enzyme inhibitors (I)
Dopamine is broken down by several enzyme systems in thebrain and elsewhere in the body, and blocking these enzymesis a key strategy to prolonging the effect of dopamine
The two most commonly prescribed forms of L-dopa containa drug to inhibit the amino acid decarboxylase (an AADCinhibitor), one type of enzyme that breaks down dopamine
These combination drugs are Sinemet, Nakom, Isicom (L-dopa plus carbidopa ) and Madopar (L-dopa plusbenzaseride ). Controlled-release formulations also aid inprolonging the effective interval of an L-dopa dose
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Enzyme inhibitors (II)
The enzyme monoamine oxidase B (MAO-B)inhibitors selegiline and rasagiline may be given asadd-on therapy for L-dopa. Research indicatesrasagiline 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 alsofrequently prescribed early in the disease before L-dopais begun
Entacapone and tolcapone, two inhibitors of anotherenzyme system called catechol-O-methyltransferase( COMT ), may soon reach the market as early studiessuggest that they effectively treat PD symptoms withfewer motor fluctuations and decreased daily L-dopa
requirements.
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Typical pattern of wearing-off
Daily fluctuations in wearing-off
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PRELUDE survey : Importance of wearing-off for patients and healthcare professionals
Managingdyskinesia #1 for
MovementDisorder
Specialists
Managingwearing-off #1for PD patients
and PCPs
Dyskines ia
What is the biggest challenge with levodopa therapy?
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Within two years 12% of neurologists recognizewearing-off but 54% modify the levodopa regimen
Comtan Diagnostic survey, 2002
The large discrepancy in the numbers (54% Vs 12%) highlightsthe difficulty in identifying the first signs of wearing-off
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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 responsereceiving 3 or more daily levodopa doses25% of patients had wearing-off after 4.9 years
Parkinson Study Group,2000
A perception of loss of mobility or dexterity, usuallytaking place gradually over minutes and usuallybearing close resemblance to the timing of antiparkinsonian medications38% of patients had wearing-off after only 2 years
No universal definition of wearing-off
The lack of a universal definition of wearing-off may be reflected
in its reported incidence in patients PSG, 2000Rajput et al., 2002
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Useful definitions of wearing-off
Wearing -off happens w hen a dose that
p rev ious ly used to he lp your symptom s does no t las t as long and yo ur next dos e is
needed so oner. Symp toms of wear ing-off
includ e changes in mov ement and m obi l i ty,
thoug hts and feelings , sensat ions and
sense of well being.
PinK working group
Wearing -off refers to th e predictable
emergence of one or more PD s igns or sym ptom s before the next scheduled
antiparkinsonian medication dosage.
For the ph ysic ian : For the pat ien t :
Stacy et al, 2004
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Consensus definition of wearing-off
A generally predictable recurrence of motor o r n o n m o t o r s y m p t o m s t h at
precedes a sc hedu led do se and u su a lly imp roves wi th an t ipark inso n ian
medication.
In September 2004, a wearing-off working group meeting of leading international Movement Disorder Specialists arrived
at a consensus definition.
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Symptoms of wearing-off
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Challenges in identification of wearing-off
Because patients may not be aware that thech anges th ey are exp eriencin g are related to th eir PD and are t reatable, they m ay not s pon taneou sly d iscu ss their symptoms
It is, therefore, important that physicians treating PD be aware of th e m any different sym ptom s of w earing- o ff and sp ec if ical ly ask about the occu r rence of s uch changes.
Stacy , 2003
Identification of Wearing Off
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Identification of Wearing Off Symptoms
Wearing-Off
Non-Motor Symptoms(often precede/coincide with Motor Symptoms)
Motor Symptoms
AUTONOMICpallor BP changesshortness of breathtachycardiasweatingfacial flushinglaryngeal stridor papillary dilationdroolingdysphagiabelchingabdominal bloatingurinary frequencymicturition disturbances
Tremor R igidityAkinesia/BradykinesiaP ostural Instability/Balance
Blanchet (2003) CJNS, 30(1): S19-S26
SENSORYPainParesthesiasSensory lossAkathisiaFatigue
PSYCHIATRICAnxietyParanoiaHallucinationsDepressionPanicCognitive changes
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Non-motor fluctuations (NMF)
1976: Marsden and Parkes recognized NMF in fluctuating PD
1993: Riley and Lang proposed a classification that is often usedtoday
1996: Hillen and Sage studied the frequency of NMF in afluctuating population
Using an open-ended question they identified NMF in 17% of fluctuatingpatients
2002: Witjas et al studied the frequency and disability caused byNMF in advanced PD patients
Using a structured questionnaire they identified NMF in 100% of patientsexperiencing motor fluctuations
Marsden and Parkes, 1976Riley and Lang, 1993Hillen and Sage, 1996Witjas et al, 2002
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Non-motor fluctuations in wearing-off
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
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
Witjas et al. 2002
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Causes of Wearing Off
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Causes of Wearing Off :Impact of striatal dopamine levels
Olanow 2004
Dopaminergic neurons die, growing lack of buffering capacity Striatal pulsatility increasingly mirrors exogenous delivery
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Obeso et al. 2000
Altered neuronal firing patterns
Pulsatile stimulation of striataldopamine receptors
Downstream dysregulation of genes, proteins and second
messenger systems
Development of dyskinesia
Altered basal ganglia firingpatterns
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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-lives2. 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 riskof motor complications
Obeso et al. 2000
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Wearing -Off
L-Dopa Dosing
Off
ON
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Management of wearing-off
The Management of Wearing-off :
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g gDopamine Agonists
The dopamine agonists are a viable option, but many patients are already on adopamine agonist when they are given levodopa
Furthermore the dopamine agonists do not change thepharmacokinetic/pharmacodynamics of levodopa and therefore do not address theunderlying issue of pulsatility associated with traditional levodopa therapy
Providing a dopamine agonist to patients already on levodopa may reduce levodopaefficacy through competitive inhibition of dopamine on the post-synaptic striatalreceptor
CALM-PD (PSG), 4 yr Pramipexole vs. Levodopa, 2004
A) Levodopa Modification
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A) Levodopa Modification1. Increase Dose
C l i n i c a
l E f f e c t
Increased likelihood of peak-dose dyskinesia
A) Levodopa Modification
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The challenge of CDS with levodopa:Increasing the frequency of oral levodopa doses- troughs
With permission from F. Stocchi* Data f rom different f luctuat ing pat ients
* *
A) Levodopa Modification2. Increase Dose Frequency
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Pharmacokinetic evidence of significant pulsatility with hourly dosing
With permission from F. Stocchi
ON
OFF
Fluctuating patient
2. Increase Dose Frequency
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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%
Carbidopa or Benserazide
Entacapone
Levodopa/carbidopa/entacapone
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Levodopa/carbidopa/entacaponeFluctuators: 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 mgrelative 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 Parkinson s disea se. J Neurol Neurosurg Psych. 74: 1071 1079
Levodopa/carbidopa/entacapone
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Earlier management of wearing-off improves long-term patient function
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
-6.0
0.0
6.0
12.0
18.0
Baseline (N=484)
1 (N=410)
2 (N=101)
3(N=90)
4(N=44)
5(N=37)
Years
U P D R S I I I s c o r e s
Levodopa with DDCI and entacapone
Traditional levodopa plus placebo
Sustained Duration of Efficacy or Long Duration Dose Stability
Nissinen et al (2006 Feb)- Early initiation of entacapone leads to superior 5 year efficacy comparedto delayed initiation in PD patients receiving traditional ldopa/DDCI therapyWorld Parkinson Congress- Poster, Washington
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STALEVO :
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Mean ADL UPDRS scores improved by 0.9 2.2
Daily levodopa dosage reduced by 22 40 mg relative to
placebo
Stalevo Levodopa/DDCI plus placebo*p
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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 3years 4 Earlier Stalevo start results in improved long-term function 5
Improves QOL & ADL6,7
B) In Non-Fluctuators, emerging evidence suggests
Improves QOL & ADL 8,9
Reduces levodopa pulsatility which, over time, is thought to beresponsible for development of dyskinesias 10.
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 Parkinson s disea se. J Neurol Neurosurg Psych. 74: 1071 1079
9. Olanow et al. (2004) Double-Blind, placebo-controlled study of entacapone in levodopa-treated patients with stable parkinsons disease: Arch Neruol 61: 1563-156810. Stocchi and Olanow (2004), Continuous dopaminergic stimulation in early and advanced PD, Neurol Sci 62 (Suppl 1): S57-S64
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Limitations of multiple dosing for Parkinson s 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 symptomsof PD
Variation of absorption rate with food intake
Li i i f l i l d i f
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P l a s m a
d r u g
c o n c e n
t r a
t i o n s
Dose Dose Dose
Motor complications
Off
On
Patients symptomswell controlled
Patients symptoms notwell controlled
Limitations of multiple dosing for Parkinson s disease
Duration of L dopa treatment and
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P a t i e n
t s w
i t h d y s
k i n e s i a
( % )
Kostic et al. Neurology 1991;41:202 5
Duration of L-dopa treatment (years)
Duration of L-dopa treatment andfrequency of dyskinesia
Treatment with levodopa has dramatically reduced disabilityand mortality associated with Parkinson s disease
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y
Years since diagnosis
P a
t i e n
t s w i t
h s e v e r e
d i s a
b i l i t y a n d
d e a
t h ( % )
0
20
40
60
80
100
1 5 6 10 11 15
Untreated patients
Levodopa/carbidopa-treated patients
Figure adapted from Poewe et al. Neurol 1996;47:S146;Hoehn et al. J Neural Trans 1983;19:253
Levodopa consistently provides better symptom controlcompared with dopamine agonists
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DDCI-=dopa-decarboxylase inhibitor;UPDRS=Unified Parkinson s Disease Rating Scale
p p g
Pramipexole Levodopa/carbidopa p=0.003
Levodopa /ca rb idopa ver sus p ramipexo le 1
4 2
0 2 4
12 24 42 C h a n g e
i n U P D R S t o
t a l s c o r e 16 14 12 10
8 6
6 18 36 48 Time (months)
I m p r o v e m e n
t
Figure adapted from 1Holloway et al. Arch Neurol 2004;61(7):1044;2
Rascol et al. N Engl J Med 2000;342(20):1484;3Bracco et al. CNS Drugs 2004;18(11):733
Treatmentregimen
Improvement versuslevodopa/DDCI
Pramipexole 1 5.9 points on total UPDRSscore (p=0.003) at 4 years
Ropinirole 2 4.48 points on UPDRSmotor score (p=0.008)at 5 years
Cabergoline3
2.9 points on UPDRS motor score (p
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Need fo r levodo pa in pat ien ts in i t i ated w i th a dop amine agon is t
(pramipexole) 1,2
Need for levod op a in pat ien ts in i t i ated w i th a dop amine agon is t
( rop in iro le) 3,4
Years after randomization Years after randomization
P a
t i e n
t s r e q u
i r i n g
s u p p
l e m e n
t a l l e v o
d o p a
( % )
53%
72%
0
20
40
60
80
2 4
Figure adapted from 1Holloway et al. Arch Neurol 2004;61(7):1044;Figure adapted from 2PSG. JAMA 2000;284(15):1931;
Figure adapted from3
Rascol et al. NEJM 2000;342:1484;Figure adapted from 4Rascol et al. Mov Disord 1998;13(1):39
P a
t i e n
t s r e q u
i r i n g
s u p p
l e m e n
t a l l e v o
d o p a
( % )
4%
66%
0
20
40
60
80
50.5
Chronic therapy with conventional levodopa is associatedwith the development of wearing-off and dyskinesia
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Response thresholdDyskinesia threshold
Early diseaseMid-stage disease Advanced disease
Long duration of clinical benefit
Low incidence of dyskinesias
Diminished duration of clinical benefit leads towearing-off
Increased incidence of dyskinesias
Clinical response mirrorslevodopa plasmapharmacokinetic profile
ON-time is associated withdyskinesias and wearing-off
Levodopa2 4 6
C l i n
i c a
l e f f e c
t
ON
OFF
Levodopa2 4 6
C l i n
i c a
l e f f e c
t
Time (hours)
Levodopa2 4 6
C l i n i c a
l e
f f e c
t
Figure adapted from Obeso et al. Neurology 2000;55(4 Suppl):S13
Time (hours)Time (hours)
Wearing-off
Dyskinesia
In Parkinson s disease, conventional levodopa deliveryleads to pulsatile stimulation of the brain
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In Parkinson s disease, theability to regulate and
maintain steady levels of dopamine in the brain is
reduced due toprogressingneuronal loss
Deep troughs in plasma levodopa levels lead to pulsatilestimulation of the brain
The short half-life(60 90 min) of
conventional levodopaleads to peaks and
profound troughs inplasma levodopa levels,which are further worsened
by intermittent dosing
Olanow et al. Lancet Neurol 2006;5(8):677
In Parkinson s disease, deep troughs in plasma levodopalevels lead to pulsatile stimulation of dopamine receptors
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Conventionallevodopa
Activated
Unactivated
Normal
Substantia nigra
Striatum
Dopamine receptor state
Nigrostriatal neuronsdegenerate
PD (untreated)Activated
Unactivated
Conventional levodopa
Activated
Unactivated
*Levodopa dose; PD=Parkinson's disease
*
Adapted from Olanow et al. Lancet Neurol 2006;5(8):677
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Normal movement
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Parkinsonian state
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Parkinsonian state withintermittent levodopa
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Parkinsonian state withcontinuous levodopa
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Motor complications associated with chronic levodopa therapymay be due to pulsatile stimulation of dopamine receptors
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Deep troughs in plasma levodopa levels can lead to pulsatilestimulation of the dopamine receptors, which, in turn,
may result in
Wearing-off Dyskinesia
How can we avoid deep troughs inplasma levodopa?
Obeso et al. Neurology 2000;55(4 Suppl):S13;Olanow et al. Lancet Neurol 2006;5(8):677
Dopamine agonists
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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
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Anticholinergics
Anticholinergics maintain dopamine balance as levelsdecrease
Side effects of anticholinergics (dry mouth,constipation, confusion, and blurred vision) are usually too severe in older patients or in patients withdementia.
Anticholinergics rarely work for very long
They are often prescribed for younger patients whohave predominant shaking. Trihexyphenidyl (Artane) isthe drug most commonly prescribed.
Acetylcholine in PD
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Acetylcholine in PD
Acetylcholine neurotransmitter involved inmany brain functions (e.g. memory)
In the striatum : balance between acetylcholine
and dopamine is critical for smooth motorfunction ( striatal cholinergic interneurons inhibit the medium spiny neurons)
In PD acetylcholine unchanged, dopamine reduced tilts the balance
Drugs that block acetylcholine transmissionrestore the balance
The Cochrane Database of Systematic Reviews 2006 Issue 1Copyright 2006 The Cochrane Collaboration. Published by John Wiley & Sons,
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Ltd.Anticholinergics for symptomatic management of Parkinsons disease
Katzenschlager R, Sampaio C, Costa J, Lees A
SummaryAnticholinergic drugs can improve movement symptoms of Parkinson's
disease, but with adverse mental effects, and there is not enough evidence tocompare the different drugs.
Anticholinergics were the first drugs available for Parkinsons disease and they arestill widely used. They are believed to work by counteracting an imbalance whichexists in Parkinsons disease between two chemicals in the brain which transmitmessages between nerve cells. However, anticholinergic drugs have beenassociated with unfavourable side effects. They are used alone, or with other anti-
Parkinson's drugs. The review of trials found that anticholinergics can improvemovement problems in people with Parkinson's disease, but also cause adversemental effects (such as confusion, memory problems, restlessness andhallucinations). There is not enough evidence to compare the differentanticholinergic drugs.
Other drugs
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Other drugs
Amantadine (Symmetrel) is sometimes used as an early therapy before L-dopa is begun, and as an add-on laterin 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 psychosisand hallucinations; newer quetiapine (Seroquel)
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Duodopa
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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 iscontraindicated (e.g. cognitive disturbance,depression)
PD prognosis
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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).
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