PARKINSON DISEASE TREATMENT

UPDATE

By
Agus Soedomo
Department of Neurology
Medicine Faculty,
Sebelas Maret University/Moewardi General
Hospital Surakarta
MOVEMENT DISORDERS
Is defined as a neurologic syndromes in
which there is either an excess of
movement or a paucity of voluntary and
automatic movements, unrelated to
weakness or spastic

(Fahn.S.,et al, Handbook of Movement

Disorders, 1998)
 ABNORMAL MOVEMENTS

Voluntary Mov Involuntary Mov

* Exaggerated Gestures * Chorea/Atetosis

* Mannerism * Dystonia
* Compulsive Mov * Myoclonus
* Guarding * TICS
* Tremors
(Parkinsonism)
 PARKINSONISM
Secondary causes Degenerative disorders

stroke trauma NPH Parkinsons Atypical

medications infections toxins Disease Parkinsonism

PSP CBD MSA DLBD

SND SDS OPCA

NPH : Normal Pressure Hydrocephalus
PSP : Progressive Supranuclear Palsy
CBD : Cortico Basal Degeneration
DLBD : Diffuse Lewy Body Disease
MSA : Multiple System Atrophy
SND : Striato Nigral Degeneration
SDS : Shy - Drager Syndrome
OPCA : Olivo Pontoserebeller Atrophy
PARKINSONISM
Suatu sindroma yang ditandai oleh tremor
waktu istirahat, rigiditas, bradikinesia dan
hilangnya refleks postural, akibat
penurunan kadar dopamin dengan
berbagai macam sebab = SINDROMA
PARKINSON
PENYAKIT PARKINSON
Adalah bagian dari Parkinsonism yang
secara patologis ditandai oleh degenerasi
ganglia basalis terutama di Substansia
Nigra Pars Kompakta (SNc) yang disertai
adanya inklusi sitoplasmik eosinofilik
(Lewy Bodies) = PARKINSONISM PRIMER /
IDIOPATIK

(KONSENSUS NASIONAL PERDOSSI, 2001)

 CORTICAL AREAS

Thalamus Basal Ganglia

Cerebelum

Brainstem
Spinal Cord

PYRAMIDAL & EXTRA PYRAMIDAL TRACT

(SCHEMATIC)
Pathophysiology of the Basal Ganglia in PD
(Inbalance direct and indirect pathway)
Normal Parkinsonism
Cortex Cortex

Striatum Striatum
D2 D1

SNc SNc

Gpe Gpe
VL VL
STN STN

Gpi/SNr Gpi/SNr
BS/SC BS/SC
 DYSKINESIA
Cortex

Striatum
D2 D1

SNc

GPe VL

STN
GPi/SNr
BS/SC
PATHOPHYSIOLOGY GANGLIA BASAL In PD
(Imbalance of Neurotransmitter)
Ach Dop
A. Normal

B. Dyskinesia
D
 C. D Parkinsonism

B. Therapy : Dopamine Antagonist (Neuroleptic)

Ach Agonist (Phisostigmine, Choline
Chlorida, Deonal)
C. Therapy : Dopamine Agonist
Ach Antagonist
EPIDEMIOLOGY PD
80% Parkinsonism
1% Population over the age of 65 yrs
Prevalence : 160 cases/100.000 pop
Incidence : 20 cases/100.000/yr
An accelerated from of aging 80% : 40 -
70 yrs (+ 60 yrs)
CLINICAL FEATURES of PD
Primary Features (TRAP)
Resting Tremor
Cogwheel Rigidity
Bradikinesia / Akinesia
Postural Instability
Semi flextion postures
Freezing
Secondary Features
Affective disturbances
Cognitive symptoms
Autonomic dysfunction
Sensory complaint
DIAGNOSIS (GELB & HUGHES)
* Best Clinical Predictors
- asymmetry of onset
- presence of resting tremor
- good response to levodopa therapy
1* Possible PD
If one of the salient features (TRAP),
asymmetry
2* Probable PD
Combination of any two of TRAP,
asymmetry
3* Definite PD
Combination of three of TRAP,
bilaterally
HOEHN AND YAHR STAGING of PD
Stage One :
1. Unilateral mild signs and symptoms
2. Friends have noticed the features
Stage Two :
1. Bilateral features
2. Posture and gait affected
Stage Three :
1. Worsening bilateral features
2. Balance difficulties
Stage Four :
1. Unable to live alone independently
2. Tremor may be less
Stage Five :
1. Invalidism complete
2. Requires constant nursing care
SCHWAB AND ENGLAND ADL
100% : Completely independent
90% : Completely independent with some
slowness, difficulty or impairment
80% : Independent in most chores
conscious of difficulty and slowing
70 % : Not completely independent
3 to 4 times difficulty with chores
60% : Some dependency, very slowly
50% : More dependent
difficulty with everything
40% : Very dependent, with all chores
30% : Much help needed
20% : Nothing alone, severe invalid
10% : Totally dependent, helpless
0% : Vegetative functions are not
functioning
TREATMENT
Goal :
* Reverse the functional disability
* Abolition of all symptoms and signs
Categories :
* Symptomatic
- to abolition symptoms and signs
* Protective :
- to interfere with the pathophysiologic
mechanism
* Restorative :
- to provide new neurons
- to stimulate growth and function of
remaining cells
 EARLY PD

Non pharmacologic Pharmacologic

Intervention Intervention

Group Support Neuroprotective

Education Antioxydants

Nutrition Dopamin agonist

Exercise Selegiline (?)

Functional impairment
 Functional impairment

Yes No

Age < 60 yr Age > 60 yr

Tremor Predominant

Amantadine Anticholinergic Dopamine agonist Levodopa Amantadine

CR

Response to therapy
 ADVANCING PD

Good response Poor or No Response

Lowest dose to maintain

Symptoms control

Unsatisfactory Wearing off Dyskinesia

Control of Symptoms

- Increase dose - COMT inhibitor - Decrease

- Consider other Diagnosis - Combination DA Levodopa dose
agonist + levodopa - Add or increase
- Add Levodopa DA agonist
Anticholinergic Agents
- The oldest class of drugs
- Has a few side effects
- Trihexyphenidyl 3-15 mg/day
Dopaminergic + Decarboxylase Inhibitor
- More 95% - peripher
- Less 1% - BBB - cerebral circulation
- Carbidopa + Levodopa 10/100, 25/100, 25/250 per
day
- Benseraside + Levodopa 50/100 perday

(Boewe et al, 1998, Waters, 1999)

DOPAMINE AGONIST
Secondary most effective class of drugs
Less risk of developing dyskinesia
As adjuctive therapy
Bromocryptine mesylate, 5 - 40 mg/day
apomorphine, 10 - 80 mg/day

(Ramaber, 2000)
MAO - B Inhibitor
* Can reduce the production of free radical
* As neuroprotection

Selegiline, 10 mg/day
MNDA ANTAGONIST / GLUTAMATE
ANTAGONIST
Enhancement dopamine release
Blocking dopamine re-uptake
Stimulation dopamine receptors
Limited to mild or early disease
Amantadine 100-300 mg/day, 1-3 dd
Side Effect
- Depression - Dry mouth - Insomnia
- Heart failure - Bloured vision
- Legs edema - Hallucination
COMT INHIBITOR
Increase the amount Levodopa
to cross BBB
Improved reduced using
levodopa to 1/2 dose/day
Entacapone : 200 mg
Tolcapone : black - box warning
COMPLICATION
EARLY Honeymoon period

Moderate Wearing off

Dyskinesia

Advanced
MOTOR FLUCTUATIONS
Variations in clinical status that
occur over the course the day
PROBLEM SOLUTION
* Wearing off * CR Levodopa
Benefit for only * DA agonist
a few hours * More frequent
dose
* COMT Inhibitor
PROBLEM SOLUTION
* On * DA agonist (apomorphine)
symptomatic benefit * Liquid levodopa
Off sudden loss of * Clozapine
benefit
* Yo-yo * DA agonist
Sudden change * Levodopa booster
from severe dyskinesias * Clozapine
to severe parkinson
symptoms
* Dose failure * Dietary adjustment
(after protein meal) * Evening : cisapride,
domperidone
DYSKINESIA
Abnormal involuntary movements
occuring in association with medication
therapy
PROBLEM SOLUTION
* Peak Dose * Reduce dose
as the blood level * Other medications
of levodopa is highest * DA agonist
- chorei form, twisting * Add anticholinergic
- non-patterned
- turning movement
PROBLEM SOLUTION
* Wearing-off dystonia * DA agonist
low or falling dopamine * LA levodopa
level
- foot inversion
- plantar flexion
- calf pain
* Diphasic dyskinesia * as yo-yo
(D-I-D dystonia)
- dystonia + chorea
FREEZING

Momentary inability to move ones feet

during ambulation
Attempting to march, stepping over an
object, walking over masking tape
MAJOR NEUROPSYCHIATRIC
DISORDERS
PROBLEM SOLUTION
1. Dementia - Anticholin esterase inhibitor
(20%) - Reassesed all medications
- Avoid anticholinergic
2. Depression * TCA
(40 - 60%) * SSR I
3. Hallucinations - Stop * DA Agonist
* Anticholinergic
* Amantadine
- Reduce dose levodopa
- Clozapine
4. Sleep disorders - Clonazepam
- CR Levodopa
- TCA
5. Day time sleepiness - Increased activity
- Caffeine
CONCLUSION
PD is a degenerative disease / age related
disorders, one of the most movement
disorders
Pathophysiology of ganglia basal in PD
can occur by imbalance direct and
indirect pathway or by imbalance of
neurotransmitter
Diagnosis of PD is clinically by primary
features and secondary features
Treatment in PD is symptomatic,
protective, and restorative catagories
continued
In early stage, PD have good response to
levodopa therapy. In advanced stage
there are any complications : motor
fluctuation, dyskinesia, and major
neuropsychiatric disorders
SHY DRAGER SYNDROME (SDS)
Parkinsonism (usually levodopa unres-
ponsive)
Impotence (men) autonomic failure
Labil blood pressure
Rectal incontinence
Fasciculation
Vocal cord paralysis with stridor
Gliosis in the intermedio lateral columns SC,
cerebellum, SNC, & dorsal vagus nucleus
 DOPAMINE METABOLISM PATHWAY
semi quinone quinone

O2 O2.- polymerization
O2.- O2 O2.-
O2 Dopac
neuromelanin
O2 + H2O R-CHO
+
NH3 Fe2+ Fe3+
MAO-A, MAO-B
Levodopa DA + CO2 H2O2 OH
2H+ + O2.- SOD 2GSH NO2.
GSSG lipids
Mithochondria and H 2O ONOO
oxidases lipid peroxides
Continued
ONOO

Arg NO
NOS
O2-
OLIVO PONTO CEREBELLAR ATROPHY
(OPCA)
Parkinsonism (usually levodopa
unresponsive)
Ataxia cerebellar deficits
Nystagmus
Oculo matordis turbances
Facial dystoma in response to levodopa
Degeneration : pons, inferior olives,
cerebellar & SNC
STRIATONIGRAL DEGENERATION (SND)
Parkinsonism (levodopa unresponsive)
Early falling
Corticospinal tract signs autonomic
Severe neckflexion NFD
Vocal cord paralysis with stredor
Neuronal lost in striatum, SNC
PROGRESIVE SUPRANUCLEAR PALSY
(PSP)
Rigidity and bradikinesia
Postural instability
Gait disturbances
Speech and swallowing difficulty
Supra nuclear gaze palsy
Dementia
Neuronal degeneration in pallidum,
subthalamic nucleus
CORTICO BASAL DEGENERATION (CBD)
Parkinsonism : bradikinesia + rigidity
Cortical dysfunction (apraxia, cortical
sensory loss)
Asymmetry
Alien - limb phenomenon
Asymmetric
Asymmetric atrophy of frontal and
parietal lobes
DIFFUSE LEWY BODY DISEASE (DLBD)
Dementia in early disease
Autonomic abnormalities
Lewy bodies : cortex, limbus, hypothalamus,
brainstem nuclei