Documente Academic
Documente Profesional
Documente Cultură
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
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
• 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
– 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
PD treatment
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. 32
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
Limitations of multiple dosing for
Parkinson’s disease
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
1–5 6–10 11–15
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 Parkinson’s 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
*
*Levodopa dose; PD=Parkinson's disease Adapted from Olanow et al. Lancet Neurol 2006;5(8):677
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 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