BOLILE GANGLIONILOR BAZALI

- SINDROAMELE HIPOKINETICE -

- BOALA PARKINSON -

Dr. MIHAI VASILE, SUUB - NEUROLOGIE

MOTILITATE ORGANIZAREA CAILOR DESCENDENTE
Cate structuri sunt implicate direct in
controlul motilitatii ?
6
Cortex motor
Talamus
Trunchiul cerebral
Maduva spinarii
2 structuri subcorticale:
Cerebel
Ggl. Bazali (striat, pallidum, structurile asociate)

CELE 2 CONTROLEAZA MAI MULTE FUNCTII PRIN INTERMEDIUL

PROIECTIILOR TALAMOCORTICALE:
TONUSUL MUSCULAR
POSTURA
COORDONAREA
MOTOR PATHWAYS
 ASEMANARI INTRE CEREBEL SI GANGLIONII BAZALI

LUENTEAZA ACTIVITATEA CORTICALA VIA TALAMUS

ATURI CU CORTEXUL CEREBRAL PRIN BUCLE DE FEEDBACK

CIRCUITE INTERNE CE MODULEAZA ACTIVITATEA ACESTOR BUCLE DE FEE

RENTELE CARE MODULEAZA ACTIVITATEA LOR:

FIBRELE CATARATOARE PENTRU CEREBEL

TERMINATIILE DOPAMINERGICE PENTRU GGL. BAZALI

 ROLUL GANGLIONILOR BAZALI

Denny-Brown si Yanagisawa comparatia rolului ggl. bazali cu o

vama

In timpul proiectarii unui anumite activitati motorii

Un set de activitati este facilitat

Alt set de miscari nenecesare este inhibat

Alte comparatii pentru activitatea ggl bazali este de frana si

schimbator

Inhibitia tonica (frana) previne ca structurile pentru

care trimit eferente sa genereze o activitate motorie

nedorita

functia de schimbator capacitatea de a selecta care

 MOTOR FUNCTIONS OF BASAL GANGLIA
ONTROL:

OLUNTARY MOVEMENT (INITIATION AND SELECTION):

SELECT AND MAINTAIN PURPOSEFUL MOTOR ACTIVITY WHILE

SUPPRESS USELESS OR UNWANTED PATTERNS OF MOVEMENT

USCULAR TONE:

REGULATE THE BALANCE BETWEEN EXCITATORY AND

INHIBITORY TO NEURONS INNERVATING SKELETAL MUSCLES

ODY POSTURE:

MONITOR AND COORDINATE THE SLOW SUSTAINED CONTRACTIONS,

ESPECIALLY PERTAINING TO POSTURE AND SUPPORT

SO:
DOES NOT DIRECTLY INFLUENCE EFFERENT MOTOR NEURONS
MODIFIES ONGOING ACTIVITY IN THE MOTOR PATHWAYS
 BASAL GANGLIA - FUNCTIONS
OTHER FUNCTIONS:

learning (motor learning)

cognition
emotional function

More recently an additional term - ventral striatum has been

introduced to describe those parts of the basal ganglia
closest to limbic structures and that are involved in
cognitive and behavioural functions

nucleus accumbens has a rich dopaminergic

innervation
arising from the ventral tegmental area and dense
innervation from the basolateral complex of the
amygdala

the amygdala embriologically derived from

CORTICAL AND SUBCORTICAL LOOPS OF BASAL GANGLIA

RED - EXCITATORY
BLUE - INHIBITORY
 INNER CIRCUITS OF BASAL GANGLIA

The basal ganglia input structures then relay signals, via direct and
indirect routes to the principal output nuclei, namely, the
internal globus pallidus and the substantia nigra pars
reticulata.

The output nuclei project:

directly to:
the thalamus
midbrain
medulla
and indirectly (via the thalamus)
to target cortical and limbic regions from which the basal
ganglia input originated
INPUT NUCLEI: CORTEX
DIRECT PATHWAY LIMBIC REG.
STRIATUM OUTPUT
NUCLEI:
GPi THALAMUS
NC. LUYS INDIRECT PATHWAY SNr MIDBRAIN
(HYPERDIRECT MEDULLA
PATHWAY)
 OUTPUT OF BASAL GANGLIA TO INFERIOR STRUCTURES

Basal ganglia output is directed not only to thalamocortical

projections but also to brainstem nuclei following at least two
pathways:

To superior colliculus (SC) regulate eye and eyelid

movements

To pedunculopontine tegmental nc.(PPn) influence

locomotion, regulation of sleep cycle, attention, arousal,
startle, prepulse inhibition, and many other behavioral reactions
INNER CIRCUITS OF BASAL GANGLIA CLASSIC MODEL
CORTEX

indirect
pathway Dopamine
GPe STRIATUM

direct
pathway
SNpc

STN Gpi/SNpr

THALAMUS
 MODULATION OF STRIATUM
Dopamine input to the striatum arises from the SNpc and the
ventral tegmental area (VTA)
the SNpc projects to most of the striatum;
the VTA projects to the ventral striatum

the SNpc and VTA are made up of large dopamine-containing

cells

the SNpc receives input from the striatum. This input is

GABAergic and inhibitory

the SNpc and VTA dopamine neurons project to caudate and

putamen in a topographic manner but with overlap
SNpc dopamine neurons fire in relation to behaviorally
significant events and reward
These signals are likely to modify the responses of striatal
neurons to inputs that occur in conjunction with the dopamine
signal
Result - reinforcement of motor and other behavior
 DOPAMINE

The action of dopamine on

striatal neurons depends on the
type of dopamine receptor
involved

Five types of G protein

coupled dopamine receptors
have been described (D1-D5) and
grouped into two families based
on their linkage to adenylcyclase
activity and response to agonists

the D1 family includes D1 and

D5 receptors

the D2 family includes D2, D3,

and D4 receptors
INPUT

OUTPUT
 BASAL GANGLIA: MOVEMENT MODULATION
THROUGH DISINHIBITION

Output nuclei of the basal ganglia are inhibitory

Output nuclei maintain a high tonic level of

discharge, suppressing activity in target regions

Phasic decrease in firing rate transiently releases

target regions from inhibition.

Disinhibited thalamocortical circuit discharges,

promoting movement.
 CIRCUITS IN BASAL GANGLIA
2 disynaptic pathways:
hyperdirect
CORTEX direct
1 polysynaptic pathway:
indirect
Hyperdirect Direct
(faster, divergent) (slower, focused)

STN STRIATUM
THALAMUS

SURROUND FOCUSED
INHIBITION Gpi/SNr FACILITATION

the winner takes it all.

desinhibition is the model proposed for basal ganglia mechanism
the spiny striatal neurons are GABA-ergic (inhibitory) they inhibit the nigro and
pallidal fibers which is also inhibitory so there is double inhibitory chain
 DESINHIBITION IS THE PRINCIPLE MECHANISM OF ACTION
OF BASAL GANGLIA

the tonically active inhibitory output of the basal ganglia acts as a brake
on motor pattern generators (MPGs) in the cerebral cortex (via the
thalamus) and brainstem

When a movement is initiated by a particular MPG, basal ganglia output

neurons projecting to competing MPGs increase their firing rate, thereby
increasing inhibition and applying a brake on those generators

Other basal ganglia output neurons projecting to the generators involved

in the desired movement decrease their discharge, thereby removing
tonic inhibition and releasing the brake from the desired motor patterns.

Thus, the intended movement is enabled, and competing movements

are prevented from interfering with the desired one
 PATHOPHISIOLOGY OF MOVEMENT DISORDERS (I)

Loss of dopamine input to the striatum results in a loss of normal pauses of GPi discharge
during voluntary movement.
excessive inhibition of motor pattern generators and ultimately bradykinesia
abnormal synchrony of GPi neuronal discharge and loss of the normal
spatial and temporal focus of GPi activity

Broad lesions of the GPi or SNpr:

disinhibit both desired and undesired motor patterns leading to inappropriate
activation of competing motor patterns but normal generation of the desired
movement
lesions of the GPi cause co-contraction of multiple muscle groups and difficulty
in turning off unwanted motor patterns, similar to dystonia, but they do not affect
movement initiation
lesions of the SNpr cause unwanted saccadic eye movements that interfere with
the ability to maintain visual fixation but do not impair the initiation of voluntary
saccades
 PATHOPHISIOLOGY OF MOVEMENT DISORDERS (II)

Lesions of the putamen may cause dystonia due to the loss of focused
inhibition in the GPi

Lesions of the STN produce continuous involuntary movements of the

contralateral limbs (hemiballism or hemichorea);Despite the involuntary
movements, voluntary movements can still be performed

Although structural lesions of the putamen, GPi, SNpr, or STN produce

certain types of unwanted movements or behaviors, they do not produce tics

Tics are more likely to arise from abnormal activity patterns, most likely
in the striatum
Catecholamine (dopamine neurons )
 DA can be metabolized by:

monoamine oxidase (MAO) to 3,4-dihydroxyphenylacetic acid (DOPAC)

MAO exists in two forms, MAO-A and MAO-B, both found in the
mitochondria of neurons and glia (Bortolato et al., 2008).

catechol-Omethyltransferase (COMT) to 3-methoxytyramine (3-MT)

(also called 3-O-methydopamine)

COMT is a membrane-bound enzyme (Bonifacio et al., 2007).

and by both enzymes serially to homovanillic acid (HVA)

Physiologically, DA action is terminated by reuptake back into the

dopaminergic nerve terminal by action of the dopamine transporter (DAT)

Once in the cytosol, it can be taken back up into synaptic vesicles by VMAT2.
 DOPAMINE CAN NOT CROSS THE BLOOD BRAIN BARRIER
ONLY LEVODOPA CAN PASS
 Extrapyramidal syndromes can be classified into:

HYPERTONIC-HYPOKINETIC

elevated muscle tone + paucity of movement

HYPOTONIC- HYPERKINETIC

diminished muscle tone + exccess of movement

 DEFINITIONS/TERMS

MOVEMENT DISORDERS:

INVOLUNTARY MOVEMENTS OF HYPOKINESIA, HYPERKINESIA OR

ABNORMAL EXECUTION OF MOVEMENTS IN THE PRESENCE OF
CLEAR CONSCIOUSNESS

OLD TERM - EXTRAPYRAMIDAL DISORDERS

CENTRAL MOTOR DISTURBANCES NOT INVOLVING THE
CORTICOSPINAL PATHWAYS

DYSKINESIAS UNNATURAL MOVEMENTS IMPLIES:

PAUCITY OF MOVEMENTS (BRADYKINESIA/ HYPOKINESIA)
LOSS OF MOVEMENTS (AKINESIA) OR
EXCESS OF SPONTANEOUS MOVEMENTS (HYPERKINESIAS)

IN CLINICAL PRACTICE IS USED IATROGENIC DISORDERS CAUSED

BY EXPOSURE TO DOPAMINE ANTAGONISTS OR LEVODOPA
 MOVEMENT DISORDERS DIAGNOSIS

THERE ARE INVOLUNTARY MOVEMENTS ?

INDISTINGUISHABLE WITH EXAGGERATED PURPOSEFUL MOV.

GESTURES/ MANNERISMS

DIFFERENTIATE FROM:
ABN. MOV. IN ALTERED COUNSCIOUSNESS EPILEPSY
ABNORMAL MOV. IN THE ABNORMAL THOUGHTS /CONTENTS

WHAT ARE THE NATURE OF THIS MOVEMENTS ?

MAIN FEATURES:
SPEED
RHYTMICITY
DURATION
PATTERN
SUPPRESIBILITY
REGION FOCAL/ SEGMENTAL/ HEMIBODY/ GENERALISED

WHAT ARE THE CAUSE ?

ANCILLARY INVESTIGATIONS
 CLASSIFICATION OF MOVEMENT DISORDERS

HYPERKINESIAS
HYPOKINESIAS

TREMOR
PARKINSONISM
DYSTONIA/ATHETOSIS
CATATONIA
CHOREA/ BALLISM
STIFF SYNDROME
TICS
+ FREEZING PHENOMENON
MYOCLONUS
STEREOTYPY
AKHATISIA
ATAXIA
Dr. Mihai Vasile- "Patologia
ganglionilor bazali", seria X
Dr. Mihai Vasile- "Patologia
ganglionilor bazali", seria X
Dr. Mihai Vasile- "Patologia
ganglionilor bazali", seria X
Dr. Mihai Vasile- "Patologia
ganglionilor bazali", seria X
Dr. Mihai Vasile- "Patologia
ganglionilor bazali", seria X
HYPERKINESIAS
 CLINICAL MANIFESTATIONS OF BASAL GANGLIA DISORDERS:
NEGATIVE SYMPTOMS:
BRADYKINESIA
HYPOKINESIA
ABSENCE OF POSTURAL REFLEXES

POSITIVE SYMPTOMS:
TREMOR
RIGIDITY
INVOLUNTARY MOVEMENTS
CHOREA
ATHETOSIS
HEMIBALLISMUS
DYSTONIA

OTHER MANIFESTATIONS:

PHONATION AND ARTICULATION TROUBLES

BOALA PARKINSON

ASPECTE GENERALE
 ISTORIC

Sindromul parkinsonian a fost descris medicul britanic James

Parkinson in
An Essay on the Shaking Palsy publicat in 1817

Involuntary tremulous motion, with lessened muscular power,

in parts not in
action and even when supported, with a propensity to bend the
trunk forwards,
and to pass from a walking to a running pace: the senses and
intellects being
uninjured

paralysis agitans 1841 Marshalls textbook Diseases

and Derangements
of the Nervous System

denumirea de Boala Parkinson a fost data 60 de ani mai

tarziu de catre
 BOALA PARKINSON PERSPECTIVE ISTORICE

James Parkinson, 1817

Shaking Palsy 1960 introducerea
Jean-Martin Charcot, 1867 tratamentului
cu Levodopa
Clasificare clinica si diagnostic diferential
Propune titulatura de boala Parkinson 1980 descrierea complicatiilor
Primul tratament alcaloizi de beladona motorii
Friedrich Heinrich Levy, 1912 ale tratamentului cu
Incluziuni intracitoplasmatice corpi Levy Levodopa

Constantin Trtiakoff, 1919 1990 studii genetice si

Degenerarea celulara in substanta neagra imagistice,
Herbert Ehringer and Oleh Hornykiewicz, 1960 cautarea markerilor
biologici
Deficitul dopaminergic in striat
tratamentul chirurgical

Parkinson J. An Essay on the Shaking Palsy; 1817.

Lewy FH. In: Handbuch der Neurologie; 1912:920-33.
Trtiakoff C. PhD Thesis, University of Paris; 1919.
Ehringer H, Hornykiewicz O. Klin Wochenschr 1960;38:1236-9.
Dr. Mihai Vasile- "Patologia ganglionilor bazali", seria X
 PATOLOGIA BOLII PARKINSON-
MACROSCOPIC
Normal Boala Parkinson

substantia nigra normala Depigmentare substantia nigra

A: Rostral (R), intermediate (I) and caudal (C) transverse

planes of the mesencephalon on a sagittal MRI of the
brainstem.
B: MRI of the intermediate transverse plane. Arrows show
the emergence of the third cranial nerve fibres.
Damier P, Brain 1999;122:1421-36.
Images courtesy of JJ Hauw, Department of Neuropathology, Hpital de la Piti-Salptrire, Paris, France.
Dr. Mihai Vasile- "Patologia ganglionilor bazali", seria X
 Pathology of Parkinsons Disease Microscopy
Gibb WR, Lees AJ. Neuropathol Appl Neurobiol 1989;15:27-44.

Loss of pigmented dopaminergic neurons, the deficit of

dopamine at the striatum, the site of axonal projections
Normal Parkinsons disease
PD develops clinically when the leve
of dopamine synaptic loss in striatum
reaches 80 -90 % or 60-70 % loss of
cell in SNc
Normal substantia nigra Degeneration of nigral cells

Histopathological hallmark: Levy bodies Levy bodies,are concentric hyaline dense

eosinophilic cytoplasmic inclusions and a
pale halo containing hyperphosphorylated
neurofilament proteins, lipids, iron,
ubiquitin, and alphasynuclein (Jellinger
2002)

In PD alfa synuclein is deposited in

neuronal cell bodies and processed as LBs
Images courtesy of JJ Hauw,
Department of Neuropathology Early it was assumed that LBs cause
Hpital de la Piti-Salptrire, neuronal cell death, but now LB represent a
Paris, France.
cytoprotective mechanism; can occur in
other disorders: Alzheimer,
Levy bodies

Mechanisms of neuronal loss in PD:

oxydative stress

mytochodrial dysfunction

excitotoxicity

glial cell activation and

apoptosis
 Levy bodies and PD

The role of Levy bodies in the pathogenic process is discussed

controversially.

Parkinsonism can occur in the absence of Levy bodies, for

instance in some cases of familial PD or in drug induced
parkinsonism (Davis et al, 1979; Langston et al,1999;
Nuytemans et al, 2010)

On the other hand, Levy body pathology is sometimes found at

autopsy in individuals without reported symptoms of
parkinsonism (Jellinger, 2009; Adler et al, 2010).
The manifestation of non-motor symptoms, some of which even precede th
motor symptoms, reflect the fact that the neurodegenerative process is no
limited
to the SNc but has a much wider impact
 Neuropathological staging of Parkinsons disease (Braak
Staging)
Based on autopsy findings in PD patients, Braak et al.
reported that the intracerebral formation of Levy inclusion
bodies and Levy neurites has a topographically predictable
progression from medulla oblongata to pons,
mesencephalon, mesocortex and finally to neocortex
.
Braak staging - 6 stages based on the presence of Levy
bodies and Levy neurites

Stage 1 (Medulla oblongata)

Lesions initially occur in the dorsal glossopharyngeal/vagal motor

nucleus and frequently in the anterior olfactory nucleus

Stage 2 ( Medulla oblongata + pontine tegmentum)

This include the pathology of stage 1 with lesions in caudal

raphe nuclei, gigantocellular reticular nucleus, and coeruleus
subcoeruleus complex.
Stage 3 (Midbrain)

Pathology of stage 2 plus midbrain lesions, particularly in the pars compacta of

the substantia nigra.

Stage 4 (basal prosencephalon and mesocortex)

Pathology of stage 3 with lesion at prosencephalon. Cortical involvement is confined

to the temporal mesocortex (transentorhinal region) and allocortex (CA2-
plexus). The neocortex is however, unaffected.
Stage 5 (Neocortex)

Stage 5 and above involved the neocortex. Its lesion include those of
stage 4 plus lesions in high order sensory association areas of
the neocortex and prefrontal neocortex.
Stage 6 (Neocortex)

Pathology of stage 5 plus lesions in first order sensory

association areas of the neocortex and premotor areas,
occasionally mild changes in primary sensory areas and the primary
A. Sauerbier et al. / Parkinsonism and Related Disorders 22 (2016)
A. Sauerbier et al. / Parkinsonism and Related Disorders 22 (2016)
A. Sauerbier et al. / Parkinsonism and Related Disorders 22 (2016)
EARLY DIAGNOSIS OF PD PREMOTOR/ PRESYMPTOMATIC PD
 GENE IN PD

The majority of PD cases are sporadic

Abnormal gene mutations have been discovered to cause or be associated with
familial form of PD
Many (20) loci have been identified for PD (PARK 1-20)
Other risk factors for PD:
Age
Toxins organochlorites pesticides
 PD genes identified in familial PD
( no more than 10% of cases )

The major breakthrough in recent years in PD research has

been the mapping of 16 genetic loci, named PARK116, and
the subsequent cloning of several genes involved in familial
PD

Wongi Seol - BMB reports 2010; 43(4): 233-244

Corti O et al - Physiol Rev 2011; 91: 11611218
 Possible correlations:
genetic - pathophysiological - phenotypical

Different model systems strongly suggest that mitochondrial dysfunction plays a

central role in clinically similar, early-onset autosomal recessive PD forms
caused by parkin and PINK1, and possibly DJ-1 gene mutations

Autosomal recessive PD is characterized by:

1) early disease onset, in most cases before age 40
2) benign, slowly progressive disease course
3) excellent response to levodopa but early levodopa-induced
dyskinesias
4) minimal cognitive decline and minimal dysautonomia

It is consistent with neurodegeneration mainly restricted to the

dopaminergic
neurons of the SNc, as confirmed by the neuropathological analyses of the
few cases
that have come to autopsy

In contrast, alpha-synuclein accumulation in Lewy bodies defines a spectrum

of disorders ranging from typical late-onset PD to PD dementia and including
Corti O et al - Physiol Rev 2011; 91: 11611218
sporadic and autosomal dominant PD forms due to mutations in SCNA and
Parkinsons disease
 WHAT IS PARKINSONS DISEASE ?

Progressive multifocal neurodegenerative disease

mutiple synaptic systems impairment

dopaminergic ( not only the nigro-striatal circuit )
non-dopaminergic: Ach, NA, 5-HT, others

CNS ( including RETINA ) and peripheral autonomic nervous system

Symptomatology:

early: non-motor, non-dopaminergic, not certain for diagnosis!

diagnosis possible only: motor parkinsonism ! ( st. III Braak ! )

motor symptoms: DA-ergic & non-DA-ergic !

non-motor symptoms: DA-ergic & non-DA-ergic !

Complications: motor & non-motor

* DA-ergic dysfunction related
* also: Ach-ergic, Glu-ergic, serotonin-ergic
 PIDEMIOLOGIE:

BP este una din cele mai frecvente boli neurodegenerative (1% peste 6

debutul intre 40-70 de ani cu un varf de incidenta in decada a sasea

evolutie progresiva pe o perioada lunga

prevalenta creste odata cu varsta:

sub 40 de ani prevalenta este mica : 3-4/100000 locuitori

peste 70 de ani prevalenta creste peste la 500/100000 locuitori
prevalenta medie a bolii este de 200-300/100000 locuitori

boala este mai frecventa in randul barbatilor

factori precipitanti
traume fizice - boxeri
traume psihice, frigul, extenuare fizica
personalitate rigida
factori de mediu: mediul rural, intoxicatii cu pesticide
rasa caucaziana
genetici
 BOALA PARKINSON

- DIAGNOSTIC POZITIV SI DIFERENTIAL -

 DEBUTUL CLINIC AL BOLII PARKINSON

DEBUT CU TREMOR DE REPAUS

DEBUT CU DURERI MUSCULARE (RIGIDITATE)

DEBUT CU TULBURARI DE MERS (HIPOKINEZIE)

DEBUT CU TULBURARI DE SOMN/ SDR. RLS

DEBUT CU TULBURARI DE SCRIS (MICROGRAFIE)

DEBUT LA TINERI CU FENOMENE DISTONICE FORME GENETICE/B

ALTE MANIFESTARI NON-MOTORII LA DEBUT :

HIPOSMIE
TULBURARI DE COMPORTAMENT MOTOR ASOCIAT SOMNULUI REM
CONSTIPATIE
DEPRESIE
MERS PARKINSONIAN
 CRITERIILE DE DIAGNOSTIC CLINIC BOALA PARKINSON
UK PARKINSON DISEASE BRAIN BANK (cf. Hughes et al, 1992) -

Specificitate de
82%

asul 1: Diagnosticul de parkinsonism:

Bradikinezie (obligatorie)

+ cel putin unul din :

rigiditate
tremor de repaus
hipokinezie
instabilitate posturala nedatorata altor afectiun
Pasul 2. Criterii de excludere Boala Parkinson:

istoric de AVC repetate cu parkinsonism progresiv

istoric de traumatisme craniene repetate

istoric de encefalita

tratament neuroleptic la debut simptome

remisiune prelungita
strict unilateral dupa 3 ani de la debut
raspuns negativ la levodopa > 1g/zi pentru 3 luni
semne cerebeloase
paralizie supranucleare a privirii
semne disautonomice precoce
dementa precoce si apraxie
semn Babinski
tumora / hidrocefalie pe CT nevoia de examinare imagistica (cel
putin CT cerebral
Pasul 3: Criterii predictive pozitive (cel putin 3
necesare):

debut unilateral al simptomatologiei (tremor/

bradikinezie)
tremor de repaus
evolutie pregresiva
durata bolii > 10 ani
persisenta asimetriei semnelor clinice
raspuns bun la medicatia dopaminergica
(levodopa) > 5 ani
diskinezii severe induse de tratamentul cu
Levodopa
 TABLOUL CLINIC
AL
SINDROMULUI PARKINSONIAN
 BRADYKINESIA:

SLOWNESS OF INITIATION WITH PROGRESSIVE REDUCTION IN SPEED

AND AMPLITUDE OF REPETITIVE ACTION

IN CLINICAL SETTINGS MAY BE TESTED IN A NUMBER OF WAYS:

REPETITIVE FINGER TAPPING
SEQUENTIAL FINGER TAPPING
RAPID ALTERNATING MOVEMENTS AT THE WRIST
REPETITIVE HAND OPENING
FOOT TAPPING
LOOK AT THE PROGRESSIVE DIMINUATION OF AMPLITUDE OF MOV.
REQUIRE MORE THAN 15 SECONDS OF OBSERVATION

MICROGRAPHIA
ARCHIMEDES SPIRAL DRAWING
 HYPOKINESIA (AKINESIA):

POVERTY OF MOVEMENT
REDUCTION OF AUTOMATIC MOVEMENTS
DISINCLINATION TO USE AN AFFECTED PART AND TO ENGAGE IT FREELY
IN ALL THE NATURAL ACTIONS OF THE BODY
INCIDENTAL OBSERVATION OF PATIENTS:
REDUCTION IN SPONTANEOUS MOVEMENTS eg.ARM SWING DURING
WALK
REDUCTION OF BLINKING
HYPOMIMIA
DROOLING OF SALIVA (IMPAIRED SWALLOWING)
REDUCED GESTICULATION
TENDENCY TO MOVE EN BLOC (WHEN STANDING FROM A SEATED
POSITION)
 EXTRAPYRAMIDAL RIGIDITY:

ABNORMALLY INCREASED RESSITANCE TO MOVEMENT THAT IS

INDEPENDENT OF THE VELOCITY OF THE MOVEMENT
CAN HAVE A
LEAD PIPE QUALITY (CONSISTENT THROUGHOUT THE MOVEMENT)
COGWHEEL QUALITY (JERKY, INCONSISTENT RESISTANCE)
NEGRO SIGN (RIGIDITY WITH TREMOR)
WHEN RELEASED THE LIMB DOES NOT RESUME ITS ORIGINAL POSITION
INVOLVES ALL MUSCLE GROUPS BUT TENDS TO BE MORE PROMINENT
IN THE FLEXOR MUSCLES OF TRUNK AND LIMBS
MAY MANIFEST AS PAIN:
FROZEN SHOULDER OR LOW BACK PAIN
TREMOR:

AN INVOLUNTARY RHYTMICAL OSCILLATION OF A BODY PART

REST TREMOR:
OCCUR IN A BODY PART THAT IS NOT VOLUNTARILY ACTIVATED AND
IS COMPLETELY SUPPORTED AGAINST GRAVITY
ACTION TREMOR:
PRODUCED BY ANY VOLUNTARY CONTRACTION OF MUSCLE
INCLUDING:
POSTURAL TREMOR:
WHILE VOLUNTARILY MAINTAINING A POSITION AGAINST GRAVITY
APPEARS TO BE EXACERBATED DURING SPECIFIC POSTURES
KINETIC TREMOR
SIMPLE KINETIC TREMOR/ TASK SPECIFIC
INTENTION TREMOR APPEARS OR INCREASE IN AMPLITUDE
DURING TARGET DIRECTED MOVEMENT
ISOMETRIC TREMOR:
RESULT OF FORCED MUSCLE CONTRACTION
 TREMOR PARKINSONIAN:

typical rest tremor

assymetric

has a frequency between 4 and 6 Hz

almost always most prominent in the distal part of an extremity

in the hand - called a pill-rolling tremor
head tremor is rare in PD
inner tremor.
exacerbated during provocations - walking and counting backwards
resumed during sleep

Atypical onset of PD:

isolated postural tremor may be the initial presentation of PD,

latency of a few seconds (up to a minute) before the tremor
reemerges during postural holding (reemergent tremor)
ETIOLOGY OF TREMOR:

PD:
ASYMMETRIC, PILL ROLLING REST TREMOR
FREQUENCY: 4-6 HZ
RE-EMERGENT POSTURAL DISTAL TREMOR > KINETIC
HAND TREMOR WHEN WALKING
LEG TREMOR AT REST / OROLINGUAL TREMOR

ET:
ACTION TREMOR (KINETIC>POSTURAL)
BILATERAL, SYMMETRIC/ ASYMMETRIC
REST TREMOR THAT DECREASE IN DEPENDANT ARM WALKING
PURE HEAD TREMOR

DYSTONIC:
ACTION TREMOR
HEAD TREMOR IS COMMON
DYSTONIC POSTURING
WITHOUT BRADYKINESIA
 POSTURE IN PD:

As the disease advances, the patient begins to assume a flexed posture:

particularly of the neck, thorax, elbows, hips, and knees

walk with the arms flexed at the elbows and the forearms placed in
front of the body, and with decreased armswing.

With the knees slightly flexed, the patient tends to shuffle the feet,
which stay close to the ground and are not lifted up as high as they
would be in normal motion

with time there is loss of heel strike, which would normally occur
when the foot moving forward is placed onto the ground.

Camptocormia is characterized by extreme flexion of the thoracolumbar

spine that increases during walking and resolves in supine position
 TULBURARILE DE MERS DIN BOALA PARKINSON

CONTINUE: PAROXISTICE:

VARIAZA DOAR CA SEVERITATE:

FREEZING
FESTINATIE
VITEZA MICA DE DEPLASARE
DEZECHILIBRU
DISTANTA MICA INTRE PASI
TARASTE PICIOARELE
POSTURA ANTEFLECTATA A TRUNCHIULUI
+ INSTABIL
+ TEMATOR
+ DISKINEZII/ DISTONII Proba tandemului normala
Baza de sustinere ingusta
 Loss of postural reflexes occurs later in the disease:

has difficulty righting himself or herself after being pulled off

balance

A simple test (the pull test) for the righting reflex:

the examiner stand behind the patient and give a firm tug on the
patients shoulders towards the examiner
explaining the procedure in advance
directing that the patient should try to maintain his balance
by taking a step backwards

A combination of loss of postural reflexes

and stooped posture can lead to
festination, whereby the patient walks
faster and faster, trying to catch up with his
or her center of gravity to prevent falling
Alterations in cholinergic rather than
dopaminergic neurotransmission have
been implicated in disturbed balance and
falls associated with PD
 The freezing phenomenon:
predominantly affects a patients gait
begins either with:
start-hesitation that is, the feet take short, sticking, shuffling
steps when the patient initiates walking
turning-hesitation while walking

when the patient walks through a crowded space

trying to move a distance in a short period of time
stopping before reaching the final destination
when the patient perceives an obstacle in the walking path

Other motor abnormalities :

reemergence of primitive reflexes (Myerson sign)

inability to perform multiple tasks simultaneously
the bulbar symptoms (dysarthria, hypophonia, dysphagia, and sialorrhea)
are thought to result from orofacial-laryngeal bradykinesia and rigidity
 SIMPTOMELE NON-MOTORII IN BOALA PARKINSON
(I)
Autonomic symptoms:
Neuropsychiatric symptoms:
Bladder disturbances
Depression, apathy, anxiety
Urgency
Anhedonia
Nocturia
Attention deficit Frequency
Hallucinations, illusions, delusions Sweating
Dementia Orthostatic hypotension

Obsessional behaviour (can be drug- Falls related to orthostatic

hypotension
induced) and repetitive behaviour
Sexual dysfunction
Confusion
Hypersexuality (likely to be drug-
Delirium (could be drug-induced)
induced)
Panic attacks
Erectile impotence
Dry eyes
Adapted from Chaudhuri KR, et al. Lancet Neurol 2006;5:235-45.
SIMPTOMELE NON-MOTORII IN BOALA PARKINSON
(II)

Sleep disorders:

Restless legs and periodic limb movements

Rapid eye movement (REM) sleep behaviour disorder
and REM loss of atonia
Non-REM sleep-related movement disorders
Excessive daytime somnolence
Vivid dreaming
Insomnia
Sleep-disordered breathing
 SIMPTOMELE NON MOTORII IN BOALA PARKINSON
(III)
Gastrointestinal symptoms:
(overlap with autonomic symptoms) Sensory Symptoms:
Drooling Pain
Ageusia Paraesthesia
Olfactory disturbance
Dysphagia and choking
Other symptoms:
Reflux, vomiting
Nausea Fatigue
Diplopia
Constipation Blurred vision
Seborrhoea
Unsatisfactory voiding of bowel Weight loss
Faecal incontinence Weight gain (possibly drug-
induced)

Adapted from Chaudhuri KR, et al. Lancet Neurol 2006;5:235-45.

SINDROM PARKINSONIAN AVANSAT
AKINEZIE
Neuroimaging in Parkinsons
Disease
Diagnosis of Parkinsons disease (PD) is mainly
clinical

MRI can be helpful in detecting other causes of

parkinsonism such as vascular parkinsonism

Neuroimaging of the nigrostriatal dopaminergic

pathway:
Single photon emission computed tomography
(SPECT) with [123I]-2-carbomethoxy-3-(4-
iodophenyl)tropane (-CIT) and positron emission
tomography (PET) with 6-[18F]fluoro-L-dopa (F-
DOPA)
Mostly used in therapeutic trials measuring
disease progression
Tolosa E, et al. Lancet Neurol 2006;5:75-86.
Samii A, et al. Lancet 2004;363:1783-94.
SPECT may be helpful to distinguish PD from
hers tests:

Response to LEVODOPA (how ameliorate the motor synptoms?)

Biomarkers in serum and CSF
Transcranian ecography of substantia nigra hyperecogenity
DIFFERENTIAL DIAGNOSIS OF PD
Degenerative
Parkinsonisms
Parkinson's disease
Hereditary forms
Sporadic
Multiple system atrophy (MSA)
Diffuse Lewy body disease
Progressive supranuclear palsy (PSP)
Corticobasal degeneration
Frontotemporal dementia with
parkinsonism
Pallidal degenerations
Alzheimer disease
Spinocerebellar ataxias (types 2,3,17)
Degenerative
Parkinsonisms
Huntington's disease
Juvenile presentation
Later in disease course
Wilson disease
Acquired hepatolenticular
degeneration
Parkinsonism Dementia Complex of
Guam
Neuroferritinopathy
Basal Ganglia calcification
Gauchers disease
GM1 gangliosidosis
Chediak-Higashi disease
Chorea-acanthocytosis
Secondary
Parkinsonisms
Post-encephalitic
Post-traumatic
Vascular Drug-induced
Hydrocephalus DA-receptor blockers
Space-occupying Antipsychotics
Anti-emetics
lesion CA-channel blockers
Toxic Anticonvulsants
Phenytoin
Manganese Valproic acid
MPTP Antiarrhythmics
Carbon monoxide Amiodarone
Cyanide
Others
Lithium
Carbon disulfide
Parkinsonism and Intracellular
Proteins
Synucleinopathie
s Tauopathies
Parkinson's disease Progressive
Genetic supranuclear palsy
-synuclein
mutation
Corticobasal
Parkin mutations degeneration
UCH-L1 mutation PDC Guam
Others
Multifactorial Post-encephalitic
Multiple system FTDP 17
atrophy Post-traumatic
Diffuse Lewy body
disease
ATYPICAL PARKINSONISM
EVOLUTION AND PROGNOSIS
OF
PARKINSONS DISEASE
 EVOLUTIA BOLII PARKINSON

Lorraine Kalia, Anthony Lang- Parkinsons disease,2015, Lancet

 Parkinsons Disease Scales and
Scores
Hoehn and Yahr Staging
Stage Four
of
Parkinsons
Stage One Disease 1.2. Severe symptoms
Can still walk to a limited
1. Signs and symptoms on one
side only extent
2. Symptoms mild 3. Rigidity and bradykinesia
3. Symptoms inconvenient but 4. No longer able to live alone
not disabling 5. Tremor may be less than
4. Usually presents with tremor earlier stages
of one limb
Stage Five
5. Friends have noticed changes
in posture, locomotion and facial 1. Cachectic stage
expression 2. Invalidism complete
Stage Two 3. Cannot stand or walk
1. Symptoms are bilateral 4. Requires constant nursing
2. Minimal disability care
3. Posture and gait affected
Stage Three
1.Significant slowing of body
movements
2.Early impairment of Hoehn MM, Yahr MD. Neurology 1967;17:427-42.
equilibrium on walking or
standing
TREATMENT OF PARKINSON DISEASE
Purpose of treatment in PD:

Symptomatic treatment of motor features

Prevention of motor complications

Symptomatic control of motor complications

Symptomatic treatment of non-motor features

Prevention of disease progression: disease modification

(neuroprotection)
 DOPAMINE CAN NOT CROSS THE BLOOD BRAIN BARRIER
ONLY LEVODOPA CAN PASS
 Non-dopaminergic
Drug Therapy Symptomatic treatment of
motor Symptoms agents
Dopaminergic agents Anticholinergic
Levodopa
Levodopa + carbidopa
agents:
Levodopa + benserazide
COMT inhibitors* Trihexyphenidyl
(entacapone, tolcapone)
Dopamine agonists Benztropine
Non-ergot
Pramipexole NMDA

Ropinirole
antagonists
Rotigotine
Apomorphine Amantadine
Piribedil
Ergot
Bromocriptine * catechol-O-methyltransferase inhibitors;
always used in conjunction with levodopa
Pergolide
apomorphine is available for subcutaneous
Cabergoline injections and may be useful in patients with
levodopa-related motor fluctuations
Dihydroergocryptin

monoamine oxidase type-B
e
N-methyl-D-aspartate
Lisuride
Selective MAO-B
inhibitors
Selegiline
Schapira AHV, Olanow CW. In: Principles of Treatment in Parkinsons Disease; 2005.
Rasagiline
Main Mechanisms of Action of Therapeutic
Interventions in Parkinsons Disease
Action
Prolong Prolong
Promote dopamine Activate specific
Drugs dopamine levodopa
synthesis receptors
availability bioavailability

Dopaminergic Levodopa DAs MAO-B inhibitors COMT inhibitors

Antiglutamatergic Amantadine*

Trihexyphenidyl
Anticholinergic
Benztropine

Lesion DBS Transplantation

Thalamotomy Thalamus Foetal
Surgery
Pallidotomy Pallidum mesencephalic
Subthalamic nucleotomy Subthalamic nucleus cells

Physical therapy
Rehabilitation
Occupational therapy
procedures
Speech therapy
Abbreviations: DAs, dopamine agonists; MAO-B, monoamine * mechanism of action not fully known, the antiglutamatergic
oxidase B; COMT, catechol-O-methyltransferase; DBS, deep action being only part of the drug's effect
brain stimulation
only drugs commonly used are listed

experimental
Rascol O, et al. Lancet 2002;359:1589-98. 111
Goetz CG, et al. Mov Disord 2005;20:523-39.
 LEVODOPA

Oral levogyral precursor of dopamine

dopamine cannot cross the digestive barrier or blood-brain barrie
Is utilised from 1960 in PD
always utilised with inhibitors of dopa- decarboxylase (benserazide/ carbidop
in order to diminish her perriferic dopaminergic adverse effects
In vivo, levodopa is synthesized from L-tyrosine by the enzyme
tyrosine hydroxylase (TH)
L-tyrosine is an essential amino acid in the brain ( it cannot be
synthesized from L-phenylalanine, as it can in the rest of the body )
 Levodopa is then captured by the terminals of the surviving nigrostriatal neurons
and also probably by the
microglia and serotoninergic neurons
Levopoda is decarboxylated to dopamine
Once synthesized, DA is taken up into synaptic vesicles by the vesicular monoamine
transporter 2 (VMAT2).
Released dopamine binds to the dopaminergic receptors after reuptake into the
 METABOLISATION OF DOPAMINE

DA can be metabolized by:

1. monoamine oxidase (MAO) to 3,4-dihydroxyphenylacetic acid
(DOPAC)
2. catechol-O-methyltransferase (COMT) to 3-methoxytyramine (3-
MT) (also called 3-O-methydopamine),
3. both enzymes serially to homovanillic acid (HVA).

MAO exists in two forms:MAO-A and MAO-B, both found in the

mitochondria of neurons and glia

COMT is a membrane-bound enzyme

. Physiologically, DA action is terminated by reuptake back into

the dopaminergic nerve terminal by action of the dopamine
transporter (DAT).

. Once in the cytosol, it can be taken back up into synaptic vesicles by

VMAT2.

. Dopamine neurons have MAO-A but virtually no COMT, DA not taken

Advantages of L-dopa Therapy:
First of the dopaminergic drugs
The vast majority of patients who start treatment with L-dopa
experience good to excellent functional benefit
Tolerability is usually good.
The antiparkinsonian effect is maintained throughout the course
of the illness.
L-dopa is not toxic to humans.
There is evidence to show that L-dopa extends life expectancy.
L-dopa improves quality of life.
L-dopa is the drug of choice for treatment of elderly patients,
and in the presence of neuropsychiatric problems.
L-dopa today remains the gold standard and the most effective
drug for the symptomatic treatment of Parkinson's disease.
Responsiveness to L-dopa

1. as a diagnostic criterion:

. observation that striatal dopamine is depleted in patients with

Parkinson disease
the remaining diseased nigral cells are still capable of
producing
some dopamine by taking up its precursor, L-dopa

. number of neurons in the striatum is not diminished, and they

remain receptive to ingested dopamine acting through the residual
nigral neurons

2. But.

. over time, the number of remaining nigral neurons becomes

inadequate and the receptivity to dopamine of the striatal target
neurons becomes excessive, possibly as a result of denervation
hypersensitivity;
this results in both a reduced response to L-dopa and to
Limitations of L-dopa Therapy:
Absorption delayed or diminished by large neutral amino acids
or agents that slow transit time, antacids and anticholinergics1,2
Short half-life causes pulsatile stimulation of dopamine
receptors

Development of motor and nonmotor fluctuations.

Dyskinesias

Limited or no response of some symptoms (e.g., freezing of gait,

dysautonomia, dysarthria).

Occurrence of nonmotor dopaminergic adverse effects (less

frequently than with other drugs): nausea, neuropsychiatric problems

including hallucinosis, sleepiness, autonomic problems.

Long-term challenges:
Symptoms less responsive to levodopa
Motor
postural instability, gait disorders, speech
problems
Mental changes
dementia, depression, anxiety, apathy

Autonomic nervous system dysfunction

orthostatic hypotension, constipation, sexual
dysfunction, urinary problems, sweating
Sensory phenomenon
pain, dysesthesias

Sleep disturbances
sleep fragmentation, sleep apnea, REM

behavioral disorder, restless leg syndrome

 Long-term challenges:
Symptoms unresponsive to
levodopa

Degeneration of nigrostriatal pathway & other pigmented cell groups

Lang et al. 1998
 LEVODOPA

With dopa decarboxylase inhibitors (benserazide/ carbidopa)

decarboxylation of L-dopa to dopamine - diminished in peripheral
tissues
permits a greater proportion of L-dopa to reach nigral neurons
at the same time, reduces the peripheral side effects of L-dopa
and
dopamine (nausea, hypotension, etc.)

combinations of carbidopa-levodopa are available in a 1:10

or 1:4 ratio
the benserizide-levodopa combination in a 1:4 ratio

DOSE:
the initial dose of levodopa-carbidopa is typically one-half to one of a
100/25 mg
tablet given two or three times daily
increased slowly until optimum improvement is achieved
usually up to four tablets (administered five or more times daily)
as the disease advances
 Long-acting preparations of levodopa-carbidopa

SINEMET CR
MADOPAR HBS

INDICATIONS:

EARLY MORNING AKINESIA (OFF STATE)

CRAMPS OVER NIGHT WITH INSOMNIA

EARLY MORNING DYSTONIA

 HONEY- MOON PERIOD IN PD

up to 5 years after early diagnosis (but stage 3 Braak !!!, not so

early course of disease)

in the early stages of the disease the response to levodopa is

sustained, despite its relatively short half life (,1.5 hours)
the preserved capacity of the presynaptic nerve terminals to
store dopamine
suprasensitivity of dopamine receptors after chronic
denervation

patients do not notice any deterioration in their symptoms of

Parkinsons disease even if they miss out a few doses
 ADVANCED DISEASE - LEVODOPA

As the disease progresses,with continued loss of substantia nigra, the

beneficial effect of each dose of levodopa progressively gets shorter

Patients notice deterioration in their symptoms an hour or two

before their next due dose, the so-called end of dose
deterioration or wearing off.

With further progression of the disease, more unpredictable

ONcomplications, such as motor fluctuations, on/ off phenomena, and
STATE :
dyskinesias appear
OFF STATE :
well being reappearance of parkinsonian symptoms
mobile - without motor symptoms
Imobile
fully ambulatory/ independent
predictable/ unpredictable
Symptoms:
pain, stiffness, paresthesia, cognitive
symptoms (depression, anxiety,
difficulty with concentration, mental slowin
inner restlessness, and inner tremulousnes
L-DOPA response in PD

Obeso et al. 2000

MECHANISMS OF L-DOPA MOTOR COMPLICATIONS
Development of motor
complications:
Impact of levodopa levels on the
striatum
plications related to dopaminergic therapy

or and nonmotor fluctuations

kinesia
ropsychiatric problems
hallucinosis and behavioural disorders
(e.g. dopaminergic dysregulation, punding, hypersexu
essive daytime sleepiness
edema
COMPLICATIILE MOTORII ALE BOLII
PARKINSON
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.
Typical pattern of
wearing-off

Daily fluctuations in wearing-off

Non-motor fluctuations in wearing-off
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

Non-motor Frequency during off

Frequency (%)
fluctuation state (%)
Anxiety 66 88
Drenching
64 59
sweats
Slowness of
58 83
thinking
Fatigue 56 75
Akathisia 54 63
Irritability 52 88
Witjas et al. 2002
Hallucinations 49 25 Witjas et al. 2002
 Delayed on/no on:
prolongation of the time required for the
antiparkinsonian drug effect to appear

insufficient dose
dosing with high-protein meals
delayed gastric emptying.
INVOLUNTARY MOVEMENTS INDUCED BY L-DOPA (DYSKINESIAS)

choreiform (brief, jerky movements, usually affecting limbs)

athetoid (twisting movements affecting limbs, face, or trunk)

initially, dyskinesias arise as a result of high levodopa dosage

and can be reduced or ameliorated by the dose reduction.

as the disease advances, they can occur regularly at the time of

peak plasma levels of levodopa (peak dose dyskinesia)

uncommonly, dyskinesia can occur at peak levels as well as

when the effect of an individual dose is waning, giving rise to
the sequence of dyskinesia- improvement- dyskinesia, also called
 OTHER MOTOR COMPLICATIONS IN PD :

dystonias (painful muscle contractions causing unusual

postures)

early morning painful foot dystonia (painful curling

movements of foot) is a common form of dystonia

dystonias are not clearly linked with chronic levodopa

treatment

early morning dystonias often respond favourably to an

additional levodopa dose or a controlled release preparation
of levodopa taken on a previous night.
DOPAMINE AGONISTS
Dopamine Agonists Pharmacological
Advantages

Pharmacological profile of dopamine agonists

Advantages over levodopa

Direct dopamine-receptor stimulation (thereby

partially bypassing the depleted nigral neurons)
No need for conversion to dopamine
No interference with food for absorption
Longer half-life compared with levodopa
(pramipexole, ropinirole, rotigotine, pergolide,
cabergoline)
Putative neuroprotective action (pramipexole,
Poewe W. In: Principles of Treatment in Parkinsons Disease; 2005.
ropinirole)
Clinical Pharmacology of Dopamine
Agonists
Dopamine receptor Interaction with other
Drug Half-life (h)
interaction receptors
NA 5-HTP(Ser)
Non-ergot
Pramipexole D2 - 10
Ropinirole D2 - - 6
Rotigotine D2 > D1 + + 5-7 (td)
Apomorphine D2/D1 - - 0.5 (sc)
Ergot
Bromocriptine D2 + + 3-6
Pergolide D2 > D1 + + 15
Cabergoline D2 + + 65

All mentioned D2-family agonists have D 3/D2 subtype affinity ratio > 1 except for bromocriptine.
Abbreviations: NA, noradrenaline; 5-HT, 5-hydroxytryptophan; td, transdermal; sc, subcutaneous
Poewe W. In: Principles of Treatment in Parkinsons Disease; 2005.
Kyniyoshi S and Jankovic J. In: Parkinsons Disease; 2005.
Jenner P. Neurology 2005;65(2 Suppl 1):S3-5.
Clinical Importance of D2 Selectivity

All dopamine agonists stimulate D2

receptors
stimulation of D2 receptors is thought
to mediate improvement of cardinal
motor symptoms1

Stimulation of D1 receptors results in

dyskinesias in experimental animal
models2
1. Guttman M, Jaskolka J. Parkinsonism Relat Disord 2001;7:231-4.
2. Fici GJ, et al. Life Sci 1997; 60:1597-603.
Clinical Implications of D3 Preference
D3 receptors in the mesolimbic dopamine
system may be involved in cognition, mood
and behaviour1,2
Preferential stimulation of D3 receptors (D3
preference) may explain the antidepressive
and anti-anhedonic properties of dopamine
agonists pramipexole/3,4

1. Guttman M, Jaskolka J. Parkinsonism Relat Disord 2001;7:231-4.

2. Missale C, et al. Physiol Rev 1998;78:189-225.
3. Piercey FM. Clin Neuropharmacol 1998;21:141-51.
4. Willner P. Int Clin Psychopharm 1997;12(Suppl 3):S7-14.
 LIMITATIONS OF DOPAMINE AGONISTS

dopamine agonists may be poorly tolerated, especially by

frail older patients
excessive daytime sleepiness
sudden sleep attacks and road traffic accidents
hypotension

may be less potent antiparkinsonian drugs than levodopa

supplemental levodopa was required in a number of

patients to control Parkinsons disease

may induce Impulse Control Disorders (ICD) (OR: 2-3.5)

the 4 most common ICDs are:
compulsive spending / shopping
pathological gambling,
compulsive sexual behaviour,
compulsive eating
Other - dopaminergic dysregulation syndrome (DDS)
compulsive consumption of dopaminergic drugs in which a patient
increases both dose amounts and frequencies at the expense of
exacerbating motor fluctuations and dyskinesias )
 LIMITATIONS OF DOPAMINE AGONISTS

dopamine agonists may be poorly tolerated, especially by

frail older patients
excessive daytime sleepiness
sudden sleep attacks and road traffic accidents
hypotension

may be less potent antiparkinsonian drugs than levodopa

supplemental levodopa was required in a number of

patients to control Parkinsons disease

may induce Impulse Control Disorders (ICD) (OR: 2-3.5)

the 4 most common ICDs are:
compulsive spending,
pathological gambling,
compulsive sexual behaviour,
compulsive eating
Other - dopaminergic dysregulation syndrome (DDS)
compulsive consumption of dopaminergic drugs in
which a patient increases both dose amounts and
Other Drug Therapies for
Parkinsons Disease
Other Drug Therapies for Parkinsons
Disease

Other dopaminergic agents

MAO-B* inhibitors

Compounds interacting with

receptors other than dopaminergic
receptors may be useful in some
patients
Anticholinergics
Amantadine
* monoamine oxidase B
Cersosimo MG, Koller WC. In: Principles of Treatment in Parkinsons Disease; 2005.
 Other Dopaminergic Agents MAO-B*
Inhibitors (1)
Selegiline and rasagiline
Selective MAO-B inhibitors; however, selectivity is lost at high
doses
Risk of tyramine-induced hypertension (the cheese effect)
at high doses
Symptomatic effect in Parkinsons disease
Neuroprotective effect in the laboratory

Mechanisms of action:

Irreversible inhibition of MAO-B, which catalyses the

oxidative deamination of neuroactive amines
Prolongation of dopamine availability

Possible enhancement of catecholaminergic neurons by other

mechanisms
Effect
* monoamine onB mitochondrial
oxidase membrane,
Cersosimo anti-apoptotic
MG, et al. In: Principles effect
of Treatment in Parkinsons and2005.
Disease;
Horstink M, et al. Eur J Neurol 2006;13:1170-85.
reduction of oxidative stress with potential neuroprotective
 Non-Dopaminergic Antiparkinsonian
Drugs Anticholinergics
Mechanism of action:
State of relative cholinergic sensitivity due to dopamine
depletion
Cholinergic drugs exacerbate and anticholinergic agents
(e.g. trihexyphenidyl, benztropine) improve parkinsonian
symptoms
Typically used in younger patients with Parkinsons disease in
whom tremor is the major symptom
However:
Little data on potency and tolerance
Common side effects that limit their usefulness
Cognitive side effects: memory impairment, acute
confusion, hallucinations, sedation, dysphoria
Peripheral antimuscarinic side effects: dry mouth,
constipation, accommodation impairment, nausea, urinary
retention, impaired sweating, tachycardia
Contraindicated in Cersosimo
patients MG, et with prostate
al. In: Principles of Treatmenthypertrophy,
in Parkinsons Disease; 2005.
Samii A, et al. Lancet 2004;363:1783-94.
closed-angle glaucoma, tachycardia,
Horstink M, gastrointestinal
et al. Eur J Neurol 2006;13:1170-85.
Non-Dopaminergic Antiparkinsonian Drugs
Amantadine

Mechanism of action
Although the exact mechanism of action is not established,
amantadine seems to have dopaminergic, anticholinergic
and antiglutamatergic activities
Mild and transitory improvement of parkinsonian
symptoms
More effective in the control of bradykinesia and rigidity than
tremor
Generally considered unsuitable for monotherapy in
Parkinson's disease
Mostly used as Cersosimo
an adjunct MG, et al. In: Principles of Treatment in Parkinsons Disease; 2005.
Samii A, et al. Lancet 2004;363:1783-94.
Horstink M, et al. Eur J Neurol 2006;13:170-85.
Ameliorate dyskinesias l-DOPA induced
CONTINOUS DOPAMINERGIC STIMULATION
 AGONISTI DOPAMINERGICI TRANSDERMICI

NONINVAZIVI
2 medicamente:
ROTIGOTINA
LISURID

ROTIGOTINA:
agonist selectiv liposolubil nonergolinic de receptori D2
doza e direct proportionala cu suprafata plasturelui
administrare unica zilnica
se poate utiliza in stadiile initiale ale bolii ca monoterapie
studii care au aratat beneficii si in stadiile tardive cu complicatii motorii la Le
amelioreaza simptome non-motorii (somnul, durerea,)si QoL

LISURID:
agonist puternic ergolinic dopaminergic si serotoninergic
capsule/injectabil/ plasture
in stadiile initiale sau cu fluctuatii motorii
 APOMORPHINE

a nonergot derivative, is a potent, directly acting

dopamine receptor agonist

high affinity to D4 receptors, lower affinity to D2, D3,

D5, and a lowest affinity to D1-like dopamine, serotonin
and
provides rapid, effective relief of off episodes iv
adrenoreceptors.
injections
effect begins within 20 minutes after dosing and lasts
approximately 100 minutes.

therapeutic rescue doses are 26 mg, and patients

typically require approximately three rescue doses
per day

Side effects: hypotension, nausea

Domperidone is a peripherally active dopamine

receptor blocker and is useful in preventing
gastrointestinal upset
from levodopa and the dopamine agonists.
 DUODOPA:

Duodopa is a combination of Levodopa (20 mg/ml) and

Carbidopa (5 mg/ml) applied in form of a gel into the
duodenum

a test application period of Duodopa via a nasoduodenal

catheter
system is generally used
a percutaneous, endoscopic gastrostomy (PEG) is
performed and Duodopa is delivered via a portable pump
and a duodenal catheter
Adverse events are mainly due to technical reasons like:
 DUODOPA

mpa duodenala cu eliberare controlata de Levodopa

ziva
tarea endoscopica a unei jejunostome transgastric pe care se administreaza
ODOPA/CARBIDOPA gel cu eliberare controlata de o pompa
oada de testare a efectelor terapeutice sonda nasogastrica cateva saptamani
are doza optima : 1 saptamana
catii:
rme severe cu fluctuatii motorii/diskinezii
traindicatii: dementa severa
te terapeutice:
mulare dopaminergica continua
ntrol bun simptomatic
ecte predictibile
mai depinde de timpul de golire gastrica
da wearing-off
onoterapie
tine diskinezii
bleme tehnice:
oma (infundare/scurgeri/peritonita)
obilizare jejunostoma
Surgery
Surgical Procedures for Parkinsons Disease

Ablative procedure Deep brain stimulation Restorative procedure

Thalamotomy VIM nucleus of thalamus Cell-based therapies
Unilateral pallidotomy GPi Human foetal nigral cells
Subthalamotomy Porcine foetal nigral cells
STN Retinal pigmented epithelial cells
Stem cells
Trophic factors
Gene therapies

Abbreviations: VIM, ventrointermediate; GPi, globus pallidus pars interna; STN, subthalamic nucleus

In practice:
Potential benefit for advanced disease not controlled with medical therapy
Ablative procedures have been largely abandoned
Effects not superior to optimised medical therapy
Non-dopaminergic features not affected

Goetz CG, et al. Mov Disord 2005;20:523-39.

Pahwa R, et al. Neurology 2006;66:983-95.
 TRATAMENTUL CHIRURGICAL

STIMULAREA CEREBRALA PROFUNDA (DBS)

STIMULAREA NC. SUBTALAMIC:

stimulare de inalta frecventa pulsatila mono/bipolara a nucleului subta

generator cu baterie implantat subcutanat
ajustari frecvente ale frecventei de stimulare (initial la 3 luni)
programarea optima poate fi stabilita cam la 1 an de zile
pacientii vor trebui sa reia administrarea medicatiei simptomatice
comlicatii chirurgicale:
delirium
hemoragie
infectie
reactii adverse:
psihiatrice: depresie/ tendinta la suiccid/tulburari cognitive
crestere ponderala
diplopie, sindrom parestezic
dezavantaje:
cost crescut
dupa 4-5 ani trebuie schimbata bateria generatorului
interferenta cu unele aparate magnetice
 APOMORFINA DUODOPA DBS

INDICATII Boala severa Boala severa Boala severa

Fluctuatii motorii Fluctuatii motorii Fluctuatii
severe severe motorii severe
Diskinezii Diskinezii Diskinezii
Akinezie nocturna Akinezie nocturna Tremor sever
CONTRAINDICAT Dementa severa Dementa severa Varsta>70 ani
II Tendinta la Contraindicatii Dementa
halucinatii chirurgie
abdominala
Necomplianta/ Necomplianta/ Depresie/anxiet
Fara suport Fara suport ate
Contraindicatii
chirurgie
cerebrala
NU SUNT Depresia Depresia/anxietate
CONTRAINDICAT a
II Varsta Halucinatiile Halucinatiile
Dementa Varsta
usoara/moderata Dementa
usoara/moderata
 EVIDENCE BASED MEDICINE

TRATAMENTUL BOLII PARKINSON

NITIAL AL BOLII PARKINSON

are motorie/ crestere calitate a vietii/prevenire complicatii motorii/

tector/ educatie pentru sanatate

tanar (< 65 ani):

omatologie usoara
sau
ADINA sau
LINERGIC (pentru tremor)

omatologie moderata:
ST DOPAMINERGIC SELECTIV SI NONERGOLINIC
in care se doreste o ameliorare rapida motorie (profesional): LEVODOP
in care nu raspund/ reactii adverse dopaminergice severe: LEVODOPA d

u tremor:
ci de AGONIST DOPAMINERGIC (ROPINIROL/PRAMIPEXOL)
ANOLOL 40-120 mg/zi
 EVIDENCE BASED MEDICINE STADIIILE MODERATE ALE BOLII
PARKINSON
TRATAMENTUL BOLII PARKINSON

oducerea la un moment dat a terapiei cu Levodopa (daca nu a fost initiat)

a fost sub selegilina/ IMAO-B/ anticolinergice se inlocuiesc treptat adaugand

nar: AGONIST DOPAMINERGIC in doze crescatoare
rstnic: LEVODOPA in doze mici crescatoare

era sub agonist dopaminergic si simptomatologia se agraveaza:

creste initial doza de agonist respectand dozele maxime/ toleranta
ca simptomatologia se inrautateste dar toleranta e buna se adauga doze mici de
EVODOPA

era sub LEVODOPA:

creste treptat doza de LEVODOPA (de preferinta <600 mg/zi) / spatiere doze
se adauga un inhibitor de COMT la fiecare doza de LEVODOPA
daca raspunsul terapeutic este unul bun si stabil se poate initia STALEVO
poate adauga un agonist dopaminergic daca acesta nu era asociat cu titrare len
permitand scaderea dozelor de LEVODOPA
iere de AMANTADINA
 EVIDENCE BASED MEDICINE

TRATAMENTUL BOLII
PARKINSON
STADIILE AVANSATE ALE BOLII PARKINSON
ei pacienti aflati in tratament cu doze mari de LEVODOPA + AGONIST
INERGIC
at un IMAO-B
ata AMANTADINA pentru diskineziile LEVODOPA induse

mentul fluctuatiilor motorii -

ul in care raspunsul scade brusc in ciuda unei scheme de tratament core

ala
MORFINA s.c. pentru o perioada de tranzitie
talarea raspunsului la tratamentul initial ??

DOPA/LEVODOPA GEL (DUODOPA):

at in formele cu fluctuatii motorii severe/diskinezii
tii de tratament chirurgical
STN (tanar, fara dementa, fluctuatii motorii severe)
mentul fenomenelor non-motorii:
Treatment of Non-Motor Symptoms in
Parkinsons Disease Autonomic
Dysfunction
Treatment option
Oxybutinin
Bladder urgency Tolterodine
Amitriptyline (if concomitant depression)
Sildenafil
Erectile dysfunction
Apomorphine
Simple measures: chewing gum, sucking sweets
Sialorrhoea Anticholinergic drugs (glycopyrrolate)
Botulinum toxin for refractory cases
Consider dopamine agonists
Constipation Adequate fluid intake, exercise
Aperients: psyllium fibre, lactulose, polyethylene glycol
Adjust dopamine agonist dose if needed
Orthostatic hypotension Fludrocortisone
Midodrine
Stocchi F. In: Principles of Treatment in Parkinsons Disease; 2005.
Raffaele R, et al. Eur Urol 2002;41:382-6.
O'Sullivan JD. J Neurol Neurosurg Psychiatry 2002;72:681.
Tetrud JW. In: Parkinsons Disease; 2005. 163
Goldstein DS. Lancet Neurol 2003;2:669-76.
Treatment of Non-Motor Symptoms in
Parkinsons Disease Sleep Disturbances

Treatment option
Non-pharmacological: sleep hygiene
Insomnia
Pharmacological: melatonin, benzodiazepines(clonazepam),
zopiclone, zolpidem
RBD Benzodiazepine (clonazepam)
Dopamine agonists
RLS Levodopa
Opiates
Caffeine
Modafinil
EDS
Reduce dopaminergic drug dose
Switch from one dopamine agonist to another

Abbreviations: RBD, rapid eye movement (REM) sleep behaviour disorder; RLS, restless legs
syndrome; EDS, excessive daytime sleepiness
Adler CH, Thorpy MJ. Neurology 2005;64(12 Suppl 3):S12-20.
Stocchi F. In: Principles of Treatment in Parkinsons Disease; 2005.
Barone P, et al. Neurology 2004;63(8 Suppl 3):S35-8.
Phillips B. Neurology 2004;62(5 Suppl 2):S9-16.
 TRATAMENTUL DEMENTEI ASOCIATE BP
ELIMINAREA FACTORILOR AGRAVANTI:
ANTICOLINERGICE
ANTIDEPRESIVE
BENZODIAZEPINE
OXYBUTININA

ADAUGARE DE INHIBITOR DE COLINESTERAZA

RIVASTIGMINA RECOMANDAT DE CATRTE GHIDURI
DONEPEZIL/GALANTAMINA IN UNELE CAZURI/ FARA DOVEZI DE EFICACITATE

TRATAMENTUL PSIHOZEI DIN BP

CONTROLUL FACTORILOR DECLANSATORI:
infectii, tulburari metabolice, dezechilibre hidroelectrolitice, parasomnii
REDUCEREA POLIPRAGMAZIEI:
reducerea/oprirea anticolinergice/antidepresive/anxiolitice/sedative
REDUCEREA TRATAMENTULUI ANTIPARKINSONIAN
STOP ANTICOLINERGICE/AMANTADINA
REDUCEREA/STOP AGONISTILOR DOPAMINERGIC/ IMAO-B SI ICOMT
ANTIPSIHOTICE ATIPICE: CLOZAPINA
INHIBITORI DE COLINESTERAZA
 BOALA
CEREBROVASCULARA
DZ

SOMN
GENITOURINAR
DISAUTONOMIC
TREMOR

NMF
BRADIKINEZIE RIGIDITATE ICD/ DDS/
HTA
DAWS

BOALA PARKINSON -MOTOR

NEUROPSIHIATRIC SENZITIV

GASTROINTESTINAL BOALA
ULCEROASA
Adaptat dupa
Chaudhuri, Todorova, 2014
OSTEOPOROZA
VA MULTUMESC !