PD is a Multi-system disorder. It A TIP OF ICEBERG WITH MOTOR AND NON-MOTOR FEATURES Not all motor manifestations are DIRECTLY related to nigrostroatal dysfunction. Involvement of Glutamate, NA, A.Ch is documented LC (REM- behavior) PPN (FOG) Glu , Adenosine, Cannabinoid and Opioid systems (LID)

1. HATEM SAMIR M. SHEHATA
PROF OF NEUROLOGY - CAIRO UNIVERSITY
Extra-nigral motor scenarios in
Parkinson Disease
PD DAY - 11 APRIL 2017

2. DISCLOSURE
All confidential patients’ data and videotaping are disclosed after a
written informed consent to share these info with other HCP

3. PD Epidemiology
• PD is the 2nd
most common neurodegenerative disorders,
affecting > 1 % of individuals older than 60 years
• World-wide the prevalence: 60 - 230 / 100.000
• Egypt.
2nd
highest prevalence (557/100,000)
Upper Egypt (1,103/100,000) “highest prevalence
worldwide” (1)
• Tallawy et al. 2013. (2)
- Parkinsonism: 316/100.000
- IPD: 213/100.000
- Vascular parkinsonism: 90/100.000
Background
• PD is the 2nd most common neurodegenerative disorders,
affecting approximately 1% of individuals older than 60 years
• World-wide the prevalence: 57-230/100,000 people
• Egypt is the world's 2nd highest
prevalence of PD (557/100.000)
Rate increases in upper
Egypt (1)
• Tallawy et al. 2013. (2)
- Parkinsonism: 316/100.000
- IPD: 213/100.000
- Vascular parkinsonism: 90/100.000
1. VIARTIS, London, UK , 2003,
2. Tallawy et al. Prevalence of PD and other types of parkinsonism in Al Kharga district, Egypt.
Background
• PD is the 2nd most common neurodegenerative disorders,
affecting approximately 1% of individuals older than 60 yea
• World-wide the prevalence: 57-230/100,000 people
• Egypt is the world's 2nd highest
prevalence of PD (557/100.000)
Rate increases in upper
Egypt (1)
• Tallawy et al. 2013. (2)
- Parkinsonism: 316/100.000
- IPD: 213/100.000
- Vascular parkinsonism: 90/100.000
1. VIARTIS, London, UK , 2003,
2. Tallawy et al. Prevalence of PD and other types of parkinsonism in Al Kharga district, Egypt.
1. VIARTIS, London, UK , 2003
2. Tallawy et al. Prevalence of PD and other types of parkinsonism in Al Kharga district, Egypt

4. Not just motor difficulties
PD can be associated with:
MOTOR DIFFICULTIES
EXECUTIVE
DYSFUNCTION
TREMOR, RIGIDITY,
BRADYKINESIA, POSTURAL
INSTABILITY
MENTAL SHIFTING,
COGNITIVE FLEXIBILITY,
WORKING MEMORY, MOOD
DOPAMINERGIC CELL
LOSS IN ‘SN-C’
DOPAMINERGIC &
NON-DOPAMINERGIC
FRONTO-STRIATALNIGRO-STRIATAL
BOTH PROGRESS AS DISEASE ADVANCES

5. PD IS A TIP OF ICEBERG WITH MOTOR AND NON-MOTOR FEATURES
Pons
Medulla
Amygdala
Peripheral Autonomic
Nervous System
(heart, GIT, bladder)
Olfactory cortex
Hypothalamus
Parkinsonism
Substantia Nigra
Basal forebrain (limbic)
Spinal cord
(intermediolateral column)
Neocortex
Temporal cortex
Multi-system disorder
Long prodromal period
Dual-hit
NMS

6. EXTRA-NIGRAL SCENARIOS
1. Sleep disorders. REM-sleep behavior disorders
2. Motor complications:
• dyskinesia MOTOR
• de-automatization NON-MOTOR
3. Mood: Depression
4. Cognitive
5. Psychosis
6. Fatigue/pain
7. Visual problems
8. GIT/olfaction
9. Autonomic: OSH, urgency, sexual, sweating

7. SLEEP DISORDERS
REM-SLEEP BEHAVIOR DISORDERS

8. REM-sleep behavior disorders
Motor activity associated with loss
of normal muscle atonia occurs
during REM sleep (REMWA)
50% of patients with idiopathic RBD
have increased risk of developing
PD within 5 years (1)
RBD affects 30–60% of PD patients
Risk factors: old age, long disease
duration, cognitive dysfunction and
psychosis
1- Iranzo A et al., Lancet Neurol. 2006 Jul; 5(7):572-7.
2- Daniel García-Lorenzo et al, Brain; 2013 Jul; 136(7): 2120–2129
PATHOLOGY: SELECTIVE DAMAGE OF LOCUS COREULEUS/SUBCOERULEUS COMPLEX WHICH
CONTAINS CATECHOLAMINERGIC NEURONS THAT CONTAIN NEUROMELANIN IN THE PONTINE
TEGMENTUM DUE TO DEPOSITION OF ALPHA-SYNUCLEIN (2)
Vignette 1

9. Physiological background
✴ Severity criteria
• Mild: RBD < once per month and causes only mild discomfort for the patient or bed-partner.
• Moderate: RBD > once per month but < once per week and is associated with physical
discomfort to the patient or bed-partner.
• Severe: RBD > once per week and is associated with physical injury to the patient or bed-
partner.
✴ Neurotransmitters
• ٍREM is generated by GABA-ergic projection to LC
• LC project through glutamatergic to cortex, basal
forebrain, amygdala
• The PPT and medial medulla are critical for muscle
atonia
• Serotonin, hypocretin, acetylcholine, and dopamine
are implicated in the development of RBD

10. Dopaminergic deficiency is not
responsible for RBD pathogenesis
• RBD or RSWA does not occur in~ 50% of the PD patients
• The use of dopaminergic agents does not improve RBD, and
may increase the tonic EMG activity during REM sleep
• DBS of STN does not ameliorate RBD while provide effective
control of the parkinsonian dopaminergic motor symptoms
• Two conditions that respond to dopaminergic agents, RLS
and PLMD in sleep, are not more common in PD patients with
RBD than without RBD
• RBD is not precipitated by antipsychotic drugs

11. Treatment is challenging
Clonazepam. It is effective in nearly 90% of patients. Dose (0.5 - 2 mg)
Mechanism of action reflects in part its serotonergic properties
Drawbacks. In elderly, it may increase confusion and may worsen OSA
Melatonin. 3-6 mg up to 12 mg/day
It restores RBD-related desynchronization of circadian rhythms
Levodopa may be effective
Other medications, such as T3CAD (it may precipitate RBD), CBZ,
clonidine, and L-tryptophan
THE NEWER GENERATIONS OF ANTIDEPRESSANTS (DES/
VENLAFAXINE AND MIRTAZAPINE) ARE FREQUENT
PRECIPITATORS OR AGGRAVATORS OF RBD

12. MOTOR COMPLICATIONS

13. Motor complications
• For more than 40 years; L-dopa provides a satisfactory and
quick therapeutic benefit, which impresses both patients and
physicians
• With long-term L-dopa treatment, this impressive response is
frequently hampered by MOTOR COMPLICATIONS:
• Once the “honeymoon” period of levodopa has waned, no more love
story an its (belly dancing effect) has emerged
• Other complicated scenario is related to “On-freezers”, when a patient
asks, what can I do when my feet are glued to the floor

14. MCs can hamper PD management
• After 5 years of levodopa
therapy 50%
develop M.C
After 10 years
nearly 100% are affected
• It can be either; hypokinetic
or hyperkinetic phenomena
It can be more disabling than the disease itself
Once established, they are resistant to medical therapy
Thanvi B, Lo T. Long term motor complications of levodopa: clinical features, mechanisms, and management strategies.
Postgrad Med J 2004;80:452–458.

15. DYSKINESIAS FREEZING
Indirect pathway inhibits thalamocortical projection
I I
II
E E
E
Mal-adaptive neuroplasticity
The core component of LID is
overactivity of the direct striato-
nigral pathway resulting in
activated cortex
Non-dopaminergic systems: Glu,
Adenosine, Cannabinoid play roles
A de-automatization disorder
Automaticity:
unconscious effortless
procedural control
(regulate by B.G)
Controlled cognitive
process:
when confronted by
conflicting stimuli (cortex)

16. L-dopa-Induced Dyskinesia (LID)
L-dopa

17. DYSKINESIAS. Clinical scenarios
Risk factors:
• Younger age (50% in < 60y vs. 16% in elderly)
• Longer disease duration
• Severe disease
• Higher levodopa dosage (longer
duration of pulsatile dopaminergic
treatment (typically, levodopa)
ELLDOPA *: L-dopa dose is a major factor in
development of dyskinesias, which can develop
as early as 5–6 months after treatment initiation
depending on doses
Patients receiving 600 mg/day had significantly
more dyskinesia than patients on placebo, 150 or 300 mg/day (p < 0.001)
* The Early versus Late L-DOPA (ELLDOPA). Fahn S et al. Levodopa and the progression of PD. N Engl J Med 2004;351:2498-508
excessive dopaminergic stimulation
low dopaminergic activity
Relationship between onset of LID
and the dopaminergic response

18. Dyskinesia.
Loss Of Pre-Synaptic Homeostasis
• In early PD, LD-derived dopamine is packaged into
synaptic vesicles by vesicular monoamine transporter
2 (VMAT-2)
• DA is stored, and released (both in tonic and phasic
bursts) in response to impulses [physiological
transmission]
• With disease progression: dopaminergic striatal loss
Nigrostriatal post-synaptic and presynaptic changes
• These response modifications in receptors for
dopamine or other neurotransmitters
SENSITIZATION OVERACTIVITY OF DIRECT
PATHWAY
Inactivation rate
Synthesis
Denervation Super-sensitivity
PRIMING
EACH DOSE ADMINISTRATION MODIFIES THE RESPONSE TO THE SUB-SEQUENT DOPAMINERGIC DOSE

19. Priming.
Molecular mechanisms
sensitization with
subsequent response
modification - lower level of
DAT expression
over-expression of signal
transduction machinery
components
gene expression
permanently affects striatal
medium spiny neurons
Non-dopaminergic systems.
Glu , Adenosine,
Cannabinoid and Opioid
systems play roles

20. Denervation of
nigrostriatal
dopaminergic pathway
Requisites for LID
Chronic exposure of
denervated SNc to pulsatile
dopaminergic stimulation

21. Denervation of
nigrostriatal
dopaminergic pathway
Chronic exposure of
denervated SNc to pulsatile
dopaminergic stimulation
PRIMING to compensate
for progressively lower DA
level
Propensity for dyskinesia is higher
with LD than DA (directly stimulate
D2 ‘except apomorphine’ )
Requisites for LID
L-dopa has a unique kinetic and
dynamic aspects of levodopa are
crucial (short t½, erratic absorption, peaks/
trough fluctuation and pulsatility mode)
REDUCED synthesis and release of
DOPAMINE
Loss of buffering capacity

22. Denervation of
nigrostriatal
dopaminergic pathway
Chronic exposure of
denervated SNc to pulsatile
dopaminergic stimulation
PRIMING to compensate
for progressively lower DA
level
Propensity for dyskinesia is higher
with LD than DA (directly stimulate
D2 ‘except apomorphine’ )
Synthesis/metabolism/
RE-UPTAKE of DA from
non-DA neurones
LD response is dominated
by its “bioavailability,
kinetic, dynamic
aspects” [pulsatility]
Potentiation of
GLUTAMATE
receptors
Requisites for LID

23. Denervation of
nigrostriatal
dopaminergic pathway
Chronic exposure of
denervated SNc to pulsatile
dopaminergic stimulation
PRIMING to compensate
for progressively lower DA
level
Propensity for dyskinesia is higher
with LD than DA (directly stimulate
D2 ‘except apomorphine’ )
Synthesis/metabolism/
RE-UPTAKE of DA from
non-DA neurones
LD response is dominated
by its “bioavailability,
kinetic, dynamic
aspects” [pulsatility]
Potentiation of
GLUTAMATE
receptors
Requisites for LID

24. How to quantify clinimetrically !!
• Several rating scales have been used in clinical practice since the
1970s for the assessment of dyskinesia in PD
• In KA-MDU we use the (UDysRS) which have excellent clinimetric
properties
The two most recent scales
(PDYS-26 and UDysRS) with
excellent clinimetric properties
Core Assessment Protocol for Intracerebral Transplantation
Abnormal Involuntary Movement Scale
Clinical Dyskinesia Rating Scale
The Parkinson Disease Dyskinesia Scale

25. Targeting management (1)
• Altering dopaminergic dosing
and timing can abate dyskinesias,
but usually impact the control of
parkinsonism
• Putative therapies could focus on
the glutamatergic, GABAergic,
α2adrenergic, serotonergic
(5HT1A, 5HT2A), opioid agonists,
adenosine A2A antagonists (2), and
cannabinoid CB1 receptors
antagonists
FIRST TRIAL. BEFORE ADDING
OTHER DRUGS TO INCREASE
ABSORPTION
INCREASE BIOAVAILABILITY OF LEVODOPA
BY 20-25%, INCREASE ITS T½ BY 25-75%,
REDUCE PEAK-TROUGH VARIATIONS AND
INCREASE THE AUC FOR THE ANTI-
PARKINSONIAN RESPONSE
DUODOPA AQUEOUS GEL INFUSION
REDUCES OFF TIME AND REDUCES
DYSKINESIA
(LCE)
1. Thanvi B, Lo T., (2004)
2. Adenosine A2A receptors are abundantly expressed in BG and can
modify abnormal striatal signaling in advanced PD. istradefylline
NOURIAST 20 mg and preladenant, Tozadent

26. What do guidelines tell ?
emergence of dyskinesias. Although selegiline is pharma-
cologically similar to rasagiline, there are insufficient data from
adequately controlled, randomized trials to recommend its use as
an adjunct in the management of levodopa-related motor
fluctuations.
C42 For patients with PD with motor fluctuations the available
evidence suggests: Entacapone and rasagiline should be
offered to reduce off time. AAN Level A
Dopamine agonists such as pramipexole, ropinirole and
bromocriptine have been shown in clinical trials to reduce off
time by approximately 15%. In a single study, bromocriptine was
found to have similar efficacy to pramipexole. Pramipexole and
ropinirole have never been studied head to head. It is important
to note that dopamine agonists can potentially cause significant
side effects including drowsiness, sudden onset of sleep and
impulse control disorders. It is recommended to carefully screen
patients for pre-existing drowsiness and tendencies toward
compulsive disorders such as gambling prior to prescribing
dopamine agonists, as well as to monitor them for such potential
problems throughout the course of treatment. Impulse control
disorders are estimated to occur in more than 15% patients treated
with dopamine agonists.6,7
Note that bromocriptine is another
dopamine agonist that has been available in Canada for treating
motor fluctuations for more than three decades. However, in
addition to monitoring for all the usual side effects of
dopaminergic therapy, physicians must warn patients about and
remain observant for possible ergot toxicity, including
erythromelalgia and fibrosis of serosal membranes. Cabergoline
is another ergot derived dopamine agonist that is available, but
the
(PEG
Cana
likel
C44
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and
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C45
3C.
T
adva
faile
and/
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indu
have
ew years the duration of benefit from each
progressively shorter. This phenomenon is
of dose deterioration” or “wearing-off”.
s may experience more unpredictable
g: on-off responses and freezing as well as
nts broadly referred to as dyskinesias. These
y have a significant impact on quality of life.
e to identify a universal first-choice adjuvant
or people with later PD. The choice of
rst prescribed should take into account:
lifestyle characteristics
erence, after the patient has been informed
- and long-term benefits and drawbacks of
sses. NICE Level D (GPP)
rioration” or “wearing-off” can be defined as
levodopa within four hours of the last dose.
dose or frequency of levodopa can be a first
ally the emergence of dyskinesias will
apone, a COMT inhibitor and rasagiline, a
ave both been shown in clinical trials to
approximately 1.5 waking hours per day.
lly well tolerated but might exacerbate peak
which case, it is recommended to lower the
by 20%. Tolcapone, the original COMT
has limited availability due to its associated
iline is also well tolerated but can lead to the
inesias. Although selegiline is pharma-
o rasagiline, there are insufficient data from
d, randomized trials to recommend its use as
management of levodopa-related motor
not approved for the treatment of Parkinson’s disease in Canada.
Apomorphine can be administered by a variety of routes either
intermittently, to treat sudden “off” periods unresponsive to
adjustment of other medications, or by continuous infusion.
However, its use in Canada is restricted to emergency release.
Transdermally administered dopamine agonists such as
rotigotine (“the patch”) are not currently available in Canada. The
side effect profile and efficacy are in general similar to those of
other dopamine agonists.
C43 Pramipexole and ropinirole should be considered to reduce
off time. Pergolide is not available in Canada secondary to
its association with valvular fibrosis. AAN Level B
Studies comparing immediate and modified-release
preparations of levodopa have many methodological short-
comings but most have shown benefit in the management of
“wearing off”. It is important to remember that the overall amount
of levodopa absorbed is roughly 25% less in the modified-release
preparations of levodopa and this must be taken into account
when switching between preparations. The side-effect profile is
similar in both drugs. There is however a significant reduction in
the number of doses per day with modified-release levodopa. In
later PD, modified-release levodopa may be erratically absorbed,
resulting in delayed-on or no-on responses. Modified release
levodopa remains most useful in addressing overnight wearing-
off. A variety of approaches have been used to provide levodopa
by continuous enteral infusion, the most practical of which is in
the form of a gel administered through a percutaneous enteral
(PEG) tube. Although approved with conditions by Health
Canada, this treatment is not available in Canada and the cost is
likely to prohibit widespread use.
dose or frequency of levodopa can be a first
ually the emergence of dyskinesias will
apone, a COMT inhibitor and rasagiline, a
have both been shown in clinical trials to
approximately 1.5 waking hours per day.
ally well tolerated but might exacerbate peak
which case, it is recommended to lower the
by 20%. Tolcapone, the original COMT
has limited availability due to its associated
giline is also well tolerated but can lead to the
kinesias. Although selegiline is pharma-
o rasagiline, there are insufficient data from
d, randomized trials to recommend its use as
management of levodopa-related motor
th PD with motor fluctuations the available
ests: Entacapone and rasagiline should be
ce off time. AAN Level A
ists such as pramipexole, ropinirole and
been shown in clinical trials to reduce off
ly 15%. In a single study, bromocriptine was
ar efficacy to pramipexole. Pramipexole and
r been studied head to head. It is important
ne agonists can potentially cause significant
ng drowsiness, sudden onset of sleep and
rders. It is recommended to carefully screen
isting drowsiness and tendencies toward
rs such as gambling prior to prescribing
as well as to monitor them for such potential
t the course of treatment. Impulse control
of levodopa absorbed is roughly 25% less in the modified-release
preparations of levodopa and this must be taken into account
when switching between preparations. The side-effect profile is
similar in both drugs. There is however a significant reduction in
the number of doses per day with modified-release levodopa. In
later PD, modified-release levodopa may be erratically absorbed,
resulting in delayed-on or no-on responses. Modified release
levodopa remains most useful in addressing overnight wearing-
off. A variety of approaches have been used to provide levodopa
by continuous enteral infusion, the most practical of which is in
the form of a gel administered through a percutaneous enteral
(PEG) tube. Although approved with conditions by Health
Canada, this treatment is not available in Canada and the cost is
likely to prohibit widespread use.
C44 Modified-release levodopa preparations may be used to
reduce motor fluctuations in people with later PD but should
not be drugs of first choice. NICE Level B
With advancing disease, dyskinesias become more frequent
and more severe resulting in a considerable source of disability to
many patients. The therapeutic window of levodopa becomes
narrower so that small increases in dose to improve clinical effect
result in dyskinesias. To date, only amantadine has been shown in
clinical studies to improve dyskinesia without worsening
parkinsonism. It is important to be aware of important cognitive
side-effects that may arise as well as edema necessitating
discontinuation of the drug.
C45 Amantadine may be considered for patients with PD with
motor fluctuations in reducing dyskinesias. AAN Level C
iline is also well tolerated but can lead to the
inesias. Although selegiline is pharma-
rasagiline, there are insufficient data from
, randomized trials to recommend its use as
management of levodopa-related motor
h PD with motor fluctuations the available
sts: Entacapone and rasagiline should be
e off time. AAN Level A
sts such as pramipexole, ropinirole and
been shown in clinical trials to reduce off
y 15%. In a single study, bromocriptine was
efficacy to pramipexole. Pramipexole and
been studied head to head. It is important
e agonists can potentially cause significant
g drowsiness, sudden onset of sleep and
ders. It is recommended to carefully screen
sting drowsiness and tendencies toward
s such as gambling prior to prescribing
s well as to monitor them for such potential
the course of treatment. Impulse control
d to occur in more than 15% patients treated
ists.6,7
Note that bromocriptine is another
t has been available in Canada for treating
or more than three decades. However, in
ring for all the usual side effects of
y, physicians must warn patients about and
for possible ergot toxicity, including
fibrosis of serosal membranes. Cabergoline
ved dopamine agonist that is available, but
by continuous enteral infusion, the most practical of which is in
the form of a gel administered through a percutaneous enteral
(PEG) tube. Although approved with conditions by Health
Canada, this treatment is not available in Canada and the cost is
likely to prohibit widespread use.
C44 Modified-release levodopa preparations may be used to
reduce motor fluctuations in people with later PD but should
not be drugs of first choice. NICE Level B
With advancing disease, dyskinesias become more frequent
and more severe resulting in a considerable source of disability to
many patients. The therapeutic window of levodopa becomes
narrower so that small increases in dose to improve clinical effect
result in dyskinesias. To date, only amantadine has been shown in
clinical studies to improve dyskinesia without worsening
parkinsonism. It is important to be aware of important cognitive
side-effects that may arise as well as edema necessitating
discontinuation of the drug.
C45 Amantadine may be considered for patients with PD with
motor fluctuations in reducing dyskinesias. AAN Level C
3C. Treatment - Surgery
The surgical treatment for PD is currently considered in
advanced patients when the optimized medical treatment has
failed in treating motor symptoms (such as motor fluctuations
and/or dyskinesia). Surgical lesions of the basal ganglia such as
thalamotomy for treating tremor and pallidotomy for levodopa-
induced dyskinesias were initially employed. However, lesions
have been associated with a high risk of permanent side effects.
infections (6.1%), migration or misplacement of the leads (5.1%),
lead fractures (5%), intracranial hemorrhage (3%), and skin
erosion (1.3%).9 Several factors contribute to the DBS outcome,
such as indications and patient selection, accuracy in surgical
targeting, stimulation programming and medication management.
The most reported complications possibly related to the
stimulation (especially STN DBS) and persistent in the long-term
follow-up include: eyelid opening apraxia (1.8-30%),
dysarthria/hypophonia (4-17%), gait disturbances (14%), postural
instability (12.5%) weight gain (8.4%) and verbal fluency
decline.10
In 2006 the AAN Subcommittee has found insufficient
evidence to support or refute the efficacy of GPi or Vim DBS in
improving off periods, dyskinesia or improving motor function.
However, two large randomized multicenter studies comparing
bilateral STN surgery to the best medical treatment have been
recently published.11,12 Both these studies have shown that there
was a significant improvement of motor function, dyskinesia and
quality of life at six months in the DBS groups rather than in the
medical groups, although the total number of adverse events was
higher in the non-surgical groups. These results add more
evidence that not only STN stimulation is superior to medical
treatment in improving motor signs, but that DBS is also more
effective in improving quality of life measures.
C46 DBS of the STN may be considered as a treatment option in
PD patients to improve motor function and to reduce motor
fluctuations, dyskinesia, and medication usage. Patients
need to be counselled regarding the risks and benefits of this
procedure. AAN Level C
Criteria of selection of patients’ candidate for GPi DBS are
similar to those for STN DBS. The issue as to whether STN is
Rec
DBS i
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loss of
one ye
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with s
STN
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related
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C49 T
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L
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Insufficient evidence to support
or refute the efficacy of clozapine
in reducing dyskinesia (Level U)
Insufficient evidence to make any
recommendations about effectiveness
of DBS of the GPi or VIM nucleus of
the thalamus (Level U)
Predictors for DBS. Pre-operative
response to levodopa (Level B), age
(younger), short disease duration
(Level C)

27. Vignette 2
55 y. She has PD since 2007; she is otherwise healthy. She started levodopa since 2008.
First assessment: March 2012:
UPDRS III score was 63/124 (off) and 21 (on). Mod. HYS was 3
She has had motor fluctuations and dyskinesia since 2011
Dyskinetic movements (choreiform, jerky and dysrhythmic involving
trunk, limbs and orofacial regions) increase upon activation procedures,
but also appear spontaneously.
The AIMS : 37
Altering dopaminergic dosing and timing (+) Amantadine (+)
clozapine … The dyskinesia was abated, but this can impact the
control of parkinsonism. “On the expense of parkinsonian
symptoms” …. Tailoring is the key

28. 61 y. PD since 2009. He started levodopa since 2009. In early 2014 he had ‘on-dyskinesia’ [jerking, twisting when
his medicine was working]. First: slight (<25% of on-time), then moderate (51-75%). It affects speech, eating tasks,
dressing, walking and balance.
First assessment: June 2015:
UPDRS III score was 85/124 (off) and 31 (on)
BEFORE dose adjustment AFTER dose adjustment
UDysRS: 20UDysRS: 32
Vignette 3

29. GAIT FREEZING ‘MOTOR BLOCKS’

30. “Motor blocks” a sudden and brief absence or marked reduction of
forward progression of the feet despite the intention to walk (Nutt et al,
2011)
FOG episodes are related to: (1) motor-based events (advanced PD),
(2) cognitive aspects (loss of automaticity and dual task conditions), and
(3) limbic activation_ affective status (depression, anxiety)
Clinical Subtypes *
turninghesitation
runway
gaps
target
start
STRONG PREDICTOR OF FALLING
* Shine JM, et al. Parkinsonism Relat Disord. 2012 Jan;18(1):25-9
30% OF PD PATIENTS HAVE FOG
WITHIN 5 Y, AND 60% AFTER 10 Y
Gait freezing. Multi-system:
motor/cognitive/emotional

31. Gait initiation
The commonest scenario
PLANNING PROBLEMS PROGRAMMING PROBLEMS
GAIT AKINESIA
Inability to run already-formed
gait initiation program
(delayed execution)
Inability to make up the
initiation the program from
submovements (subroutines)
• Gait initiation is a phase between motionless standing and steady-state
locomotion: (i) movement preparation period, (ii) movement execution
period
• Gait initiation is moderated by pedunculopontine tegmental nucleus (PPN)
(mesencephalic locomotor center), which is located in caudal mesencephalic
tegmentum, and it is one of the main component of RAS

32. PLANNING PROBLEMS PROGRAMMING PROBLEMS
GAIT AKINESIA
Inability to run already-formed
gait initiation program
(delayed execution)
Inability to make up the
initiation the program from
submovements (subroutines)
• Gait initiation is a phase between motionless standing and steady-state
locomotion: (i) movement preparation period, (ii) movement execution
period
• Gait initiation is moderated by pedunculopontine tegmental nucleus (PPN)
(mesencephalic locomotor center), which is located in caudal mesencephalic
tegmentum, and it is one of the main component of RAS
Studies of gait problems in PD accused
planning problems primarily for faulty calling
up the preserved program
Planning is the problem

33. Mesencephalic Locomotor Center
• PPN + cuneiform + subcuneiform
nuclei
• Bordered laterally by medial lemniscus
and anteriorly by SN
• Two divisions,
(i) cholinergic: for the steady-state
locomotion
(ii) glutamategic: initiation of
programmed movement
• It receives input from cerebral cortex and is “heavily” and
“reciprocally” connected with basal ganglia
• It gives ascending projections to thalamus and connected
to other motor nuclei in the brainstem and spinal cord
PPN SCP
PM line
PPN

34. FOG = de-automatization
Morphometric studies. Atrophy of DLPF, and inferior frontal gyrus in PD-
FOG patients. (share with executive deficits)
Cognitive resources are
insufficient to handle
Unconscious, effortless,
automatic procedural learning

35. FOG = impaired dual task
When patients are asked to perform a secondary task while walking (dual tasking), the risk for FOG increases (Giladi
and Hausdorff 2006; Rahman et al. 2008).

36. Difficulties and assessments
• FOG is of 3 types: (1) “on”, (2) “off”, (3) “random”
• Treatment of ‘off-time FOG’ is straight forward, but “on-
freezing” is difficult to treat (A multidisciplinary team approach)
• Dopaminergic treatments modulate all the key steps in DA
transmission except the presynaptic DaT (being the most powerful
determinant of extracellular dopamine concentrations)
• 5-HT facilitation (junctional and non-junctional target sites), MPH
(blocks DaT and NA transporter in striatum and prefrontal
cortex), PT and DBS can help
DOPA-RESISTANT GAIT DISORDER

37. Assessment of FOG is complex due to (1) its episodic nature, and (2)
the influence of environmental and mental factors
FOGQ-SF “valid and reliable”, however, long-term objective gait
measure (24h-ambulatory gait assessment) can help in properly
defining the problem
Difficulties and assessments

38. Difficulties and assessments
• FOG is of 3 types: (1) “on”, (2) “off”, (3) “random”
• The treatment of 'off' time FOG is relatively straight forward,
but “on-freezing” is difficult to treat. (A multidisciplinary team
approach)
• Several reports proposed role of 5-HT facilitation (junctional and
non-junctional target sites), MPH (blocks DaT and NA
transporter in striatum and prefrontal cortex), PT and DBS
MAX SCORE. 24
FOGQ-SF

39. Management hardships
A 66-year-old male: Slowness of
activities and falls, insidious onset and
had been gradually progressive over
the last 2 years
No tremor, forgetfulness, hallucinations,
postural dizziness, or urinary
incontinence
No FH. O/E vertical gaze palsy and
axial rigidity, ‘probable PSP’
TURNING AND START HESITATION
(DURING ON)
TWO ATTACKS “1ST
: 24 SEC, 2ND
: 11 SEC”
Vignette 4

40. 62 y. PD diagnosis (2009); HTN, IHD. Started levodopa since the diagnosis onset.
Rapidly he became ‘on-freezer’ His motor blocks were start hesitation ‘up to gait initiation
failure’ and turning blocks. His UPDRS (65 “off”, 28 “on”), FOG-Q (20)
Pre-treatment Post-treatment
Vignette 5

41. 67 y. PD diagnosis (2006); otherwise healthy
Started levodopa since the diagnosis onset
In late 2011: he experienced motor blocks, first they were rarely encountered and lately they started to be
frequent (initiation, turning)
Associated with frequent falls.
His UPDRS (85 “off”, 34 “on”), FOG-Q (22)
Post-treatments. FOG-Q (14)Pre-treatments. FOG-Q (22)
Notice. Cadence, and stride length improved
Vignette 6

42. 59 y. PD diagnosis (2007); otherwise healthy
Started levodopa since diagnosis onset
He experienced motor blocks (2011), first rare and short episodes; lately, more frequent and
longer (initiation, runway and turning)
His UPDRS (63 “off”, 20 “on”),, FOG-Q (20)
Post-treatments. FOG-Q (12)Pre-treatments. FOG-Q (20)
Vignette 7

43. TO RECAP
•PD is characterized by a substantial loss of dopaminergic cells
in the SNc
•There is an important contribution of non-dopaminergic
degeneration
•PD can be associated with severe motor difficulties (tremor,
rigidity, postural instability, and bradykinesia; due to
dopaminergic deficits), however, some motor difficulties are
not relate to dopamine
•Not all Extra-nigral symptoms are non-motor

44. THANK YOU
Should you need any further data,
kindly contact samirhatem@hotmail.com