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PD CTR
www.saigata-nh.go.jp/saigata/rinken/neuropat/
Scenariul Heiko Braak
despre stadializarea BP si
posibila etiologie a BP
Definitia Bolii Parkinson
Parkinsonismul
indus de TCC repetate
MPTP
Alte toxine, ex.
Mangan, Anoxia cerebral
pesticide
Simptomele cardinale ale
parkinsonismului criteriile de
diagnostic UK Brain Bank
Tremorul de obicei cu debut la mb superior, de
obicei nti pe o parte i mai trziu pe cealalt
(asimetria!). Clasic numrat bani, 3 Hz
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 thalamo-
cortical drive is inhibited)
The Pope in 1979,
age 59, with
President Jimmy
Carter. The
Pope'sshoulders
stoop, PD begins.
Neurodegeneration: AD and
PD
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. 44
Drugs that replace
dopamine
Levodopa (L-dopa), is the most effective treatment for the
symptoms of PD
L-dopa is a derivative of dopamine, and is converted into
dopamine by the brain
It may be started when symptoms begin, or when they
become serious enough to interfere with work or daily living
L-dopa therapy usually remains effective for all duration of
the disease
Following this, many patients develop motor fluctuations,
including peak-dose "dyskinesias" (abnormal movements
such as twisting, or restlessness), rapid loss of response
after dosing (known as the "on-off" phenomenon), and
unpredictable drug response
Higher doses are usually tried, but may lead to an increase
in dyskinesias
Side effects of L-dopa include:
nausea and vomiting
low blood pressure upon standing (orthostatic hypotension) - causes
dizziness
these effects usually lessen after several weeks of therapy.
Dopamine
Enzyme inhibitors (I)
Dopamine is broken down by several enzyme systems
in the brain and elsewhere in the body, and blocking
these enzymes is a key strategy to prolonging the
effect of dopamine
The two most commonly prescribed forms of L-dopa
contain a drug to inhibit the amino acid
decarboxylase (an AADC inhibitor), one type of
enzyme that breaks down dopamine
These combination drugs are Sinemet, Nakom,
Isicom (L-dopa plus carbidopa) and Madopar (L-
dopa plus benzaseride). Controlled-release
formulations also aid in prolonging the effective
interval of an L-dopa dose
Enzyme inhibitors (II)
The enzyme monoamine oxidase B (MAO-B)
inhibitors selegiline and rasagiline may be
given as add-on therapy for L-dopa. Research
indicates rasagiline may have a neuroprotective
effect, sparing nigral cells from damage by free
radicals. Because of this, and the fact that it has
few side effects, it is also frequently prescribed
early in the disease before L-dopa is begun
Entacapone and tolcapone, two inhibitors of
another enzyme system called catechol-O-
methyltransferase (COMT), may soon reach the
market as early studies suggest that they
effectively treat PD symptoms with fewer motor
fluctuations and decreased daily L-dopa
requirements.
Typical pattern of wearing-off
328 Neurologists
300 patients with PD treated with
74 Movement Disorder Specialists
carbidopa/levodopa
54 PCPs
Managing Managing
dyskinesia #1 for wearing-off #1
Movement for PD patients
Disorder and PCPs
Specialists
g-off
Wearin
Dyskinesia
Within two years 12% of neurologists recognize
wearing-off but 54% modify the levodopa regimen
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
sweating
Fatigue
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
Anxiety 66 88
Drenching sweats 64 59
Slowness of thinking 58 83
Fatigue 56 75
Akathisia 54 63
Irritability 52 88
Hallucinations 49 25
Olanow 2004
Altered neuronal firing patterns
Downstream dysregulation of
genes, proteins and second
messenger systems
Development of
dyskinesia
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
* *
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
UPDRS III scores
12.0
Levodopa with DDCI and entacapone
Traditional levodopa plus placebo
6.0
0.0
-6.0
Baseline 1 2 3 4 5
(N=484) (N=410) (N=101) (N=90) (N=44) (N=37)
Years
Delayed start analysis of 3 long-term studies
Over 5 years, early initiation of levodopa with a DDCI and entacapone resulted in a
significant benefit compared with a delayed start in treatment
Nissinen et al (2006 Feb)- Early initiation of entacapone leads to superior 5 year efficacy compared
to delayed initiation in PD patients receiving traditional ldopa/DDCI therapy
World Parkinson Congress- Poster, Washington
STALEVO:
Fluctuators- Quality of Life
Significant improvement in quality of life with Stalevo
Subjects global self assessment also showed an improvement (p=0.02) compared with
placebo
30
1
20
10
0
0
*
-10
-20
-30
-1 0 2 4 6
* ** Time (months)
Stalevo Levodopa/DDCI plus placebo
*p<0.05, **p<0.01
1. Poewe et al- Austrian-German CELOMEN Study Group (2002 ) Efficacy and safety of entacapone
in parkinsons disease patientswith suboptimal levodopa response, Acta Neurol Scand 105: 2345-255
2. Brooks etl al- UK-IRISH (2003). Entacapone is beneficial in both fluctuating and non-fluctuating
patients with Parkinsons disease. J Neurol Neurosurg Psych. 74: 10711079
The use of STALEVO
A) in Fluctuators:
Improves ON time with current levodopa regimen by 1.4- 1.6 hours (6.8
- 16% mean change from baseline)1-3
Sustains current levodopa efficacy/dose regimen for at least the next 3
years4 Earlier Stalevo start results in improved long-term function 5
Improves QOL & ADL6,7
Motor
complications
concentrations
Plasma drug
On
Off
100
disability and death (%)
80
Patients with severe
60 Untreated patients
Levodopa/carbidopa-
40 treated patients
20
0
15 610 1115
8
6 score (p=0.003) at 4 years
4
Ropinirole2 4.48 points on UPDRS
2
0 motor score (p=0.008)
2 at 5 years
4 Cabergoline3 2.9 points on UPDRS motor
0 6 12 18 24 30 36 42 48 score (p<0.001) at 5 years
Time (months)
Pramipexole
Levodopa/carbidopa
p=0.003
Figure adapted from 1Holloway et al. Arch Neurol 2004;61(7):1044;
DDCI-=dopa-decarboxylase inhibitor; 2
Rascol et al. N Engl J Med 2000;342(20):1484;
UPDRS=Unified Parkinsons Disease Rating Scale 3
Bracco et al. CNS Drugs 2004;18(11):733
Most patients eventually require the superior efficacy of
levodopa for symptom control
Patients requiring
53%
40 40
20 20
4%
0 0
2 4 0.5 5
Years after randomization Years after randomization
Figure adapted from 1Holloway et al. Arch Neurol 2004;61(7):1044;
Figure adapted from 2PSG. JAMA 2000;284(15):1931;
Figure adapted from 3Rascol et al. NEJM 2000;342:1484;
Figure adapted from 4Rascol et al. Mov Disord 1998;13(1):39
Chronic therapy with conventional levodopa is associated
with the development of wearing-off and dyskinesia
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)
Dyskinesia threshold
Response threshold Figure adapted from Obeso et al. Neurology 2000;55(4 Suppl):S13
In Parkinsons disease, conventional levodopa delivery
leads to pulsatile stimulation of the brain
Unactivated
PD (untreated)
Striatum Activated
Conventional levodopa
Nigrostriatal neurons
degenerate Activated
Conventional
levodopa 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
Wearing-off Dyskinesia
Summary
Anticholinergic drugs can improve movement symptoms of Parkinson's
disease, but with adverse mental effects, and there is not enough evidence to
compare the different drugs.
Anticholinergics were the first drugs available for Parkinsons disease and they are
still widely used. They are believed to work by counteracting an imbalance which
exists in Parkinsons disease between two chemicals in the brain which transmit
messages between nerve cells. However, anticholinergic drugs have been
associated with unfavourable side effects. They are used alone, or with other anti-
Parkinson's drugs. The review of trials found that anticholinergics can improve
movement problems in people with Parkinson's disease, but also cause adverse
mental effects (such as confusion, memory problems, restlessness and
hallucinations). There is not enough evidence to compare the different
anticholinergic drugs.
Other drugs
Amantadine (Symmetrel) is sometimes used
as an early therapy before L-dopa is begun,
and as an add-on later in the disease.
Has an evidence-based antidiskinetic effect
Its anti-parkinsonian effects are mild, and are
not seen in all patients
Multiple mechanisms of action, probably the
main one being the antiglutamatergic effect
Clozapine (Clozaril) is effective especially
against psychiatric symptoms of late PD,
including psychosis and hallucinations;
newer quetiapine (Seroquel)
Duodopa
Intestinal gel containing levo-dopa
Avoids absorbtion problems
Can be titrated precisesly by the pump
Usually substitutes all other PD treatments
High efficacy
Disadvantage: pateints have to carry the pump with
them
Advantage: can be used when DBS is
contraindicated (e.g. cognitive disturbance,
depression)
PD prognosis