BOLILE GANGLIONILOR BAZALI

- SINDROAMELE HIPOKINETICE -

- BOALA PARKINSON -

Dr. MIHAI VASILE, SUUB - NEUROLOGIE

 MOTILITY ORGANISATION OF MOTOR PATHWAYS

Many (more than 6) parts of the nervous system are engaged primarily in the
control of movement:

2 subcortical systems:
the basal ganglia (striatum, pallidum, and related structures, including
the substantia nigra and subthalamic nucleus)
the cerebellum

Each system plays an important role in the control of muscle tone, posture,
and coordination of movement by virtue of its connections, via
thalamocortical fibers, with the corticospinal system and other descending
cortical pathways.
MOTOR PATHWAYS
 SIMILARITIES BETWEEN THE BASAL GANGLIA AND CEREBELLUM

COMPONENTS OF MOTOR SYSTEM

INFLUENCE THE CEREBRAL CORTICAL ACTIVITY VIA THE THALAMUS

LINKED WITH THE CEREBRAL CORTEX VIA RECURRENT LOOPS

HAVE INTERNAL CIRCUITRY THAT MODULATES LOOPS ACTIVITY

RECEIVE MODULATING INPUTS THAT INFLUENCE THEIR ACTIVITY:

CLIMBING FIBERS FOR CEREBELLUM

DOPAMINE INPUTS FOR BASAL GANGLIA

 ROLE OF BASAL GANGLIA

Denny-Brown and Yanagisawa, concluded that the basal ganglia function as a kind of
clearinghouse where, during an intended or projected movement:
one set of activities is facilitated
all other unnecessary ones are suppressed

they used the analogy of the basal ganglia as a brake or switch:

the tonic inhibitory (brake) action of the basal ganglia preventing target
structures from generating unwanted motor activity

the switch function referring to the capacity of the basal ganglia to select
which of many available motor programs will be active at any given time.
 MOTOR FUNCTIONS OF BASAL GANGLIA
CONTROL:

VOLUNTARY MOVEMENT (INITIATION AND SELECTION):

SELECT AND MAINTAIN PURPOSEFUL MOTOR ACTIVITY WHILE

SUPPRESS USELESS OR UNWANTED PATTERNS OF MOVEMENT

MUSCULAR TONE:

REGULATE THE BALANCE BETWEEN EXCITATORY AND

INHIBITORY TO NEURONS INNERVATING SKELETAL MUSCLES

BODY 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 telencephalon as striatum

 NEOCORTICAL- STRIATAL THALAMIC LOOPS

SEGREGATED CIRCUITS OF BASAL GANGLIA

Alexander et al. were the first to describe the basic closed-loop component of
neocortical connections with the basal ganglia and related thalamic nuclei

The projections of these loops, as they pass sequentially through the basal ganglia
nuclei are:
parallel
largely segregated

N.B. - there is evidence for interactions between the main projection lines both
within the basal ganglia and between external structures
Basal ganglia loops motor
Basal ganglia loops non-motor
Prefrontal loop
(Associative) Limbic loop
CORTICAL AND SUBCORTICAL LOOPS OF BASAL GANGLIA

RED - EXCITATORY
BLUE - INHIBITORY
NON-MOTOR OUTPUT FOR BASAL GANGLIA
 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
INDIRECT PATHWAY SNr
NC. LUYS 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 patterns
 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
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

faimosul director al Spitalului Salpetriere - Jean-Martin Charcot
 BOALA PARKINSON PERSPECTIVE ISTORICE

James Parkinson, 1817

Shaking Palsy 1970 introducerea tratamentului
Jean-Martin Charcot, 1867 cu Levodopa

Clasificare clinica si diagnostic diferential 1980 descrierea complicatiilor motorii

Propune titulatura de boala Parkinson ale tratamentului cu Levodopa
Primul tratament alcaloizi de beladona
Friedrich Heinrich Levy, 1912 1990 studii genetice si imagistice,
cautarea markerilor biologici
Incluziuni intracitoplasmatice corpi Levy tratamentul chirurgical
Constantin Trtiakoff, 1919
Degenerarea celulara in substanta neagra
Herbert Ehringer and Oleh Hornykiewicz, 1960
Deficitul dopaminergic in striat

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 level
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

Early it was assumed that LBs cause neuronal cell death,

but now LB represent a cytoprotective mechanism; can
Images courtesy of JJ Hauw,
Department of Neuropathology occur in other disorders: Alzheimer,
Hpital de la Piti-Salptrire, postencephalitis etc
Paris, France.
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 the

motor symptoms, reflect the fact that the neurodegenerative process is not 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 coeruleussubcoeruleus 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 conned 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 rst order sensory association areas of the
neocortex and premotor areas, occasionally mild changes in primary sensory areas
and the primary motor eld.
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 sporadic and autosomal dominant PD forms
due to mutations in SCNA and LRRK2

Corti O et al - Physiol Rev 2011; 91: 11611218

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

EPIDEMIOLOGIE:

BP este una din cele mai frecvente boli neurodegenerative (1% peste 60 ani)

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/BW

ALTE MANIFESTARI NON-MOTORII LA DEBUT :

HIPOTENSIUNE ARTERIALA ORTOSTATICA

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

Specificitate de 82%

Pasul 1: Diagnosticul de parkinsonism:

Bradikinezie (obligatorie)

+ cel putin unul din :

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

istoric de AVC repetate cu parkinsonism progresiv

istoric de traumatisme craniene repetate
istoric de encefalita
istoric de crize oculogire
tratament neuroleptic la debut simptome
expunere la MPTP
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 autonomice precoce
dementa precoce si apraxie
semn Babinski
tumora cerebeloasa/ hidrocefalie pe CT
Pasul 3: Criterii predictive pozitive (cel putin 3 necesare):

debut unilateral
tremor de repaus
evolutie pregresiva
persisenta asimetrie
raspuns bun la medicatia dopaminergica (levodopa)
diskinezii severe levodopa induse
raspuns bun levodopa > 5 ani
durata bolii > 10 ani
 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
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
 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

induced) and repetitive behaviour hypotension

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:
Sensory Symptoms:
(overlap with autonomic symptoms)
Drooling Pain
Paraesthesia
Ageusia Olfactory disturbance
Dysphagia and choking
Other symptoms:
Reflux, vomiting
Fatigue
Nausea Diplopia
Blurred vision
Constipation
Seborrhoea
Unsatisfactory voiding of bowel Weight loss
Weight gain (possibly drug-
Faecal incontinence induced)

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

 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
SPECT may be helpful to distinguish PD from essential
tremor (ET)
Tolosa E, et al. Lancet Neurol 2006;5:75-86.
Samii A, et al. Lancet 2004;363:1783-94.
Others 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 Drug-induced
Post-traumatic DA-receptor blockers
Antipsychotics
Vascular Anti-emetics
CA-channel blockers
Hydrocephalus Anticonvulsants
Space-occupying lesion Phenytoin
Valproic acid
Toxic Antiarrhythmics
Manganese Amiodarone
MPTP Others
Lithium
Carbon monoxide
Cyanide
Carbon disulfide
Parkinsonism and Intracellular Proteins

Synucleinopathies Tauopathies
Parkinson's disease Progressive supranuclear
Genetic palsy
-synuclein mutation
Parkin mutations Corticobasal degeneration
UCH-L1 mutation PDC Guam
Others
Multifactorial
Post-encephalitic
Multiple system atrophy FTDP 17
Diffuse Lewy body Post-traumatic
disease
ATYPICAL PARKINSONISM
EVOLUTION AND PROGNOSIS
OF
PARKINSONS DISEASE
 Parkinsons Disease Scales and Scores
Hoehn and Yahr Staging of Parkinsons
Disease
Stage One
1. Signs and symptoms on one side only Stage Four
2. Symptoms mild 1. Severe symptoms
3. Symptoms inconvenient but not 2. Can still walk to a limited extent
disabling 3. Rigidity and bradykinesia
4. Usually presents with tremor of one limb 4. No longer able to live alone
5. Friends have noticed changes in posture,
5. Tremor may be less than earlier
locomotion and facial expression
stages
Stage Two
1. Symptoms are bilateral Stage Five
2. Minimal disability 1. Cachectic stage
3. Posture and gait affected 2. Invalidism complete
Stage Three 3. Cannot stand or walk
1. Significant slowing of body movements 4. Requires constant nursing care
2. Early impairment of equilibrium on
walking or standing
3. Generalised dysfunction that is
moderately severe
Hoehn MM, Yahr MD. Neurology 1967;17:427-42.
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
Drug Therapy Symptomatic treatment of motor Symptoms
Dopaminergic agents
Levodopa
Non-dopaminergic agents
Levodopa + carbidopa
Levodopa + benserazide
Anticholinergic agents:
COMT inhibitors* (entacapone,
tolcapone) Trihexyphenidyl
Dopamine agonists
Non-ergot Benztropine
Pramipexole
Ropinirole NMDA antagonists

Rotigotine
Amantadine
Piribedil
Ergot
Bromocriptine
* catechol-O-methyltransferase inhibitors;
Pergolide always used in conjunction with levodopa
Cabergoline apomorphine is available for subcutaneous
injections and may be useful in patients with
Dihydroergocryptine levodopa-related motor fluctuations
monoamine oxidase type-B
Lisuride
Selective MAO-B inhibitors
N-methyl-D-aspartate

Selegiline
Rasagiline
Schapira AHV, Olanow CW. In: Principles of Treatment in Parkinsons Disease; 2005.
 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 action
oxidase B; COMT, catechol-O-methyltransferase; DBS, deep being only part of the drug's effect
only drugs commonly used are listed
brain stimulation
experimental
Rascol O, et al. Lancet 2002;359:1589-98. 94
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 barrier
Is utilised from 1960 in PD
always utilised with inhibitors of dopa- decarboxylase (benserazide/ carbidopa)
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 presynaptic
nigrostriatal terminals
Finally, dopamine is metabolised via auto-oxidation by MAO-B and by catechol-O-methyltransferase
 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 up into vesicles will
therefore be metabolized to DOPAC.
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 paradoxical and excessive
movements (dyskinesias) with each dose.
 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

or a similar dose of the 25/250-mg combination

 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)

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 complications, such as motor
fluctuations, on/ off phenomena, and dyskinesias appear
ON STATE :
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 slowing)
inner restlessness, and inner tremulousness
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
Complications related to dopaminergic therapy

Motor and nonmotor fluctuations

Dyskinesia
Neuropsychiatric problems
hallucinosis and behavioural disorders
(e.g. dopaminergic dysregulation, punding, hypersexuality)
Excessive daytime sleepiness
Leg 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 state

Frequency (%)
fluctuation (%)
Anxiety 66 88
Drenching sweats 64 59
Slowness of thinking 58 83
Fatigue 56 75
Akathisia 54 63
Irritability 52 88
Hallucinations 49 25
Witjas et al. 2002
Witjas et al. 2002
 A newer class of catechol-O-methyltransferase (COMT) inhibitors,
typified by entacapone/ tolcapone

extends the plasma half-life and the duration of L-dopa effect by preventing its breakdown
ENTACAPONE: 200 mg with every dose of LEVODOPA
Tolcapone - hepatotoxicity
Gordin et al. 2003
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 diphasic dyskinesias
 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, ropinirole)

Poewe W. In: Principles of Treatment in Parkinsons Disease; 2005.

 Clinical Pharmacology of Dopamine Agonists

Dopamine receptor Interaction with other

Drug Half-life (h)
interaction receptors
NA 5-HTP
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 D3/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 such as pramipexole3,4

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,
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 frequencies at the expense of
exacerbating motor fluctuations and dyskinesias)
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 on mitochondrial membrane, anti-apoptotic effect and reduction of oxidative
stress with potential neuroprotective properties

Cersosimo MG, et al. In: Principles of Treatment in Parkinsons Disease; 2005.

* monoamine oxidase B Horstink M, et al. Eur J Neurol 2006;13:1170-85.
 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 patients with prostate hypertrophy, closed-angle glaucoma,
tachycardia, gastrointestinal obstruction, megacolon
Cersosimo 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;13:1170-85.
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 an adjunct

Ameliorate dyskinesias l-DOPA induced

Potential cognitive side effects also limit its use

Cersosimo 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.
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 Levodopa
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 adrenoreceptors.

provides rapid, effective relief of off episodes iv 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:
dislocation,obstruction and breakage of the duodenal catheter.
PEG related side effects - peritonitis and local stoma inflammation.
 DUODOPA

pompa duodenala cu eliberare controlata de Levodopa

invaziva
montarea endoscopica a unei jejunostome transgastric pe care se administreaza
LEVODOPA/CARBIDOPA gel cu eliberare controlata de o pompa
perioada de testare a efectelor terapeutice sonda nasogastrica cateva saptamani
titrare doza optima : 1 saptamana
indicatii:
forme severe cu fluctuatii motorii/diskinezii
contraindicatii: dementa severa
efecte terapeutice:
stimulare dopaminergica continua
control bun simptomatic
efecte predictibile
nu mai depinde de timpul de golire gastrica
nu da wearing-off
monoterapie
putine diskinezii
probleme tehnice:
stoma (infundare/scurgeri/peritonita)
mobilizare 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 subtalamic

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 severe Fluctuatii motorii severe Fluctuatii motorii
severe
Diskinezii Diskinezii Diskinezii
Akinezie nocturna Akinezie nocturna Tremor sever
CONTRAINDICATII Dementa severa Dementa severa Varsta>70 ani
Tendinta la halucinatii Contraindicatii chirurgie Dementa
abdominala
Necomplianta/ Necomplianta/ Depresie/anxietate
Fara suport Fara suport Contraindicatii
chirurgie cerebrala
NU SUNT Depresia Depresia/anxietatea
CONTRAINDICATII Varsta Halucinatiile
Dementa Varsta Halucinatiile
usoara/moderata Dementa
usoara/moderata
PACIENTUL IDEAL TANAR, FARA DEMENTA SI CU FLUCTUATII MOTORII SEVERE
 EVIDENCE BASED MEDICINE

TRATAMENTUL BOLII PARKINSON

STADIUL INITIAL AL BOLII PARKINSON

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

neuroprotector/ educatie pentru sanatate

pacient tanar (< 65 ani):

simptomatologie usoara
IMAO-B sau
AMANTADINA sau
ANTICOLINERGIC (pentru tremor)

simptomatologie moderata:
AGONIST DOPAMINERGIC SELECTIV SI NONERGOLINIC
in cazul in care se doreste o ameliorare rapida motorie (profesional): LEVODOPA doze mici
in cazul in care nu raspund/ reactii adverse dopaminergice severe: LEVODOPA doze mici

pentru tremor:
doze mici de AGONIST DOPAMINERGIC (ROPINIROL/PRAMIPEXOL)
PROPRANOLOL 40-120 mg/zi
 EVIDENCE BASED MEDICINE STADIIILE MODERATE ALE BOLII
PARKINSON
TRATAMENTUL BOLII PARKINSON

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

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

tanar: AGONIST DOPAMINERGIC in doze crescatoare
varstnic: LEVODOPA in doze mici crescatoare

daca era sub agonist dopaminergic si simptomatologia se agraveaza:

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

daca era sub LEVODOPA:

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

TRATAMENTUL BOLII PARKINSON

STADIILE AVANSATE ALE BOLII PARKINSON

de obicei pacienti aflati in tratament cu doze mari de LEVODOPA + AGONIST
DOPAMINERGIC
asociat un IMAO-B
asociata AMANTADINA pentru diskineziile LEVODOPA induse

tratamentul fluctuatiilor motorii -

in cazul in care raspunsul scade brusc in ciuda unei scheme de tratament corecta si
maximala
APOMORFINA s.c. pentru o perioada de tranzitie
reinstalarea raspunsului la tratamentul initial ??

CARBIDOPA/LEVODOPA GEL (DUODOPA):

indicat in formele cu fluctuatii motorii severe/diskinezii
indicatii de tratament chirurgical
DBS STN (tanar, fara dementa, fluctuatii motorii severe)
tratamentul 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. 145
Goldstein DS. Lancet Neurol 2003;2:669-76.
 Treatment of Non-Motor Symptoms in Parkinsons
Disease Sleep Disturbances

Treatment option
Insomnia Non-pharmacological: sleep hygiene
Pharmacological: benzodiazepines, 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
DONEPEZIL/GALANTAMINA

TRATAMENTUL PSIHOZEI DIN BP

CONTROLUL FACTORILOR TRIGGER:
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