� Early Parkinson’s disease
� Pathophysiology
� Is Parkinson’s a syndrome?
� Therapeutic approaches
� Stages
� The future
� 1000 BC descriptions in Indian and Chinese texts of probable Parkinson’s
� 1680 – rest tremor described (da la Böe)
� 1817 – An essay on the shaking palsy
� 1870s – refinement by Charcot and others
Outlines of Orcytology Parkinsonia dorsetentsis
� “a sympathetic concern, and a tender
interest for the sufferings of others, ought
to characterize all those who engage
themselves in a profession, the object of
which should be to mitigate, or remove,
one great portion of the calamities to
which humanity is subject”
Long before rigidity actually develops,patients have significant difficulty performingordinary activities: this problem relates toanother cause. In some of the various patientsI showed you, you can easily recognize howdifficult it is for them to do things even thoughrigidity or tremor is not the limiting feature.Instead, even a cursory exam demonstratesthat their problem relates more to slowness inexecution of movement rather than to realweakness.
In spite of tremor, a patient is still able to do
most things, but he performs them with
remarkable slowness. Between the thought
and the action there is a considerable time
lapse. One would think neural activity can
only be effected after remarkable effort.
� Rejected the name “paralysis agitans” or
“shaking palsy”
� Differentiated from multiple sclerosis
� Noted two types – tremorous dominant
and the akinetic-rigid form
� There is an aspect of marked mental
hebetude, or at all events an extreme
slowness of expression, so that it is difficult
to elicit answers to questions about his
history… Yet we contrive to get, in
process of time, though the task is
laborious, a fair amount of information
from him. The face wears a peculiarly
stolid expression.
� The movement of the fingers at the
metacarpalphalangeal joints is similar to
that by which Orientals beat their small
drums.
Loss of dopaminergic neurons of the
pars compacta in the substantia
nigra
and other areas
www.urmc.rochester.edu
Lewy bodies
Lewy body
abnormal
accumulation of the
protein alpha-
synuclein bound to
ubiquitin in the
damaged cells.
This insoluble protein accumulates inside
neurones forming inclusions called Lewy
bodies
Frederic Levy 1885-1950
� Neuroleptic agents led to dramatic
improvements of schizophrenic and
other psychotic behaviours
But………
� induced parkinsonism largely
indistinguishable from Parkinson’s disease
itself
Progression of Parkinson Disease Jankovic Arch Neurol. 2005;62:351-352.
Progression
of
Parkinson’s
Disease
Nonlinear Progression of Parkinson Disease as Determined by Serial Positron
Emission Tomographic Imaging of Striatal Fluorodopa F 18 Activity Hilker et al
Arch Neurol. 2005;62(3):378-382.
PD may
become
symptomatic
when
striatonigral
neurons are
30% deplete
mean
preclinical
period of
5.6±3.2 years
Timing of Treatment Initiation in Parkinson’s
Disease: A Need for Reappraisal?
Schapira, Obeso Ann Neurol. 2006 Mar;59(3):559-62
Schapiro-
Obeso
hypothesis
The
compensatory
mechanisms
cause damage,
possibly
through release
of glutamate
which is
neurotoxic
Burn 2017
A 62 yr-old man with occupational pesticide exposure, drinks coffee & never a
regular smoker idiopathic RBD & olfactory loss
no constipation, depression or anxiety & no daytime somnolence
quantitative motor testing in the borderline/low-normal range (no expert
examination available)
•Step 1: Establish prior probability from available table as 1.25%
•Step 2: Calculate total LR = 1.2 (male) x 1.5 (pesticide) x 0.88 (coffee) x 1.25
(non-smoker) x 130 (RBD) x 4.0 (olfaction) x 0.8 (no constipation) x 0.85 (no
depression or anxiety), 0.88 (no somnolence) x 1.0 (borderline motor testing –
result omitted) = 616
•Step 3: Calculate post-test probability, using one of two methods:Make an exact
quantitative probability calculation using calculators. Result = 89%, or
From published table, LR must be 300. Actual LR >300, so patient meets criteria
for probable prodromal PD
Risk Quantification - Example
“One of the major developments in our attitude towards Parkinson’s disease has been the growth of a concept of Parkinsonism as a syndrome - a symptom –complex which may emanate from various causations. The ‘shaking palsy’ of James Parkinson is now looked upon as merely one representative (though still the most important) of a number of clinical events.”
parkinsonismparkinsonism
Idiopathic Parkinson’sIdiopathic Parkinson’s
Multiple system
atrophy
Multiple system
atrophyprogressive
supranuclearpalsy
progressive supranuclear
palsy
dementia with Lewy
bodies
dementia with Lewy
bodiesDrug induced parkinsonismDrug induced parkinsonism
vascular parkinsonism
vascular parkinsonism
“I have seen such patients
everywhere on the streets of
Rome, of Amsterdam, in Spain.
It is always the same picture.
They can be identified from
afar. You do not need a medical
history”
Parkinson advocated:
venesection, specifically advocating
blood letting from the neck, followed by
vesicatories to induce blistering and
inflammation of the skin. Small pieces of
cork to be purposefully inserted into the
blisters to cause a “sufficient quantity” of
purulent discharge
� Ordenstein
(Charcot’s
intern) –
belladonna
alkaloids
� quinquina, a quinine derivative, must be
diluted with syrup made from orange
rind and each dose of silver nitrate must
be impregnated in 9 g of soft bread to
form an ingestible pill.
1910 – Dopamine first
synthesised
1938 – discovery of
dopa decarboxylase
1950s – dopamine
localisation within the
brain (specifically in the
striatum)
1961 – first infusion of
levodopa
� Bed-ridden patients who were unable to sit up, patients who could not stand up when seated, and patients who when standing could not start walking performed all these activities with ease after L-dopa [levodopa]. They walked around with normal associated movements and they could even run and jump. The voiceless, aphonic speech, blurred by pallilalia and unclear articulation, became forceful and clear as in a normal person (Birkmayer and Hornykiewicz 1961).
APOMORPHINE LEVODOPA / CARBIDOPA
INTESTINAL GEL
DEEP BRAIN
STIMULATION
� Roots back to 1960s
� Vascular lesions in some patients
improved parkinsonian symptoms
� Rapid impulses to basal ganglia,
including STN, can markedly reduce
tremors
Worth 2015
Amudha 2015
1.6
years
Other Parkinsonian condition
Progressive Supranuclear Palsy
Dementia with Lewy Bodies
Multiple System Atrophy
Arteriosclerotic
pseudoparkinsonism (Vascular)
Drug Induced parkinsonism
Red flags
Culprit medication
History of strokes
Early falls
Symmetrical
Rapid onset / rapid progression
Poor response to levodopa
Early dementia or hallucinations
Cerebellar signs
Vertical gaze palsy
5.9
years
4.9
years
2.2
years
2.2
years
Stepwise drug reduction – psychosis and hallucinosis (Playfer & Hindle 2nd ed.)
� Adenosine 2a (A2a agonists)
� IPX066 – extended release levodopa
� XP21279 - sustained release L-dopa
� ND0611 - carbidopa subcutaneous
patch
� ?exenatide
� ?Foetal cell transplants
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