5th-year medical student seminar presentation under the supervision of Dr. Thung, a specialist.

1. PARKINSON’S
DISEASE
AUDI R A HMA N A F FA N SYA F IQI

2. PARKINSONIAN DISORDERS
 Parkinsonian syndromes or parkinsonism refer to the group of diseases that
resembles Parkinson’s disease in some part of their clinical features
 Thus, they may have rest tremors, bradykinesia, rigidity, and/or postural instability
Parkinsonism
Primary
(neurodegeneration)
Atypical
Parkinsonism
Parkinson’s
Disease
Secondary

3. AETIOLOGY
The causes of idiopathic PD are still not fully understood. The
relatively uniform worldwide prevalence suggests that a single
environmental agent is not responsible. There may be multiple
interacting risk factors, including genetic susceptibility
I. AGE AND GENDER
II. ENVIRONMENTAL FACTORS
III. GENETIC FACTORS

4. PATHOLOGY

5. CLINICAL FEATURES
MOTOR SYMPTOMS
These develop slowly and insidiously and are often initially attributed to ‘old
age’ by patients. The core motor features of PD are (TRAP) , definite
diagnosis – 3 out of 4 features:
 Tremor
 Rigidity
 Akinesia
 Postural and gait disturbance

6. CLINICAL FEATURES
MOTOR SYMPTOMS
 Resting tremor
 It is often described as pill-rolling
 Fine action tremor
 70 – 80% of cases
T R E M O R
R I G I D I T Y
 Cogwheel type
 Lead pipe stiffness

7.  What distinguishes it from slowness of movement from other causes is a
progressive fatiguing an decrement in amplitude and speed of repetitive
movements, such as opening and closing the hand or finger tapping
 There is difficulty initiating movement
 The upper limb is usually affected first and is almost always unilateral for the
first years
 Rapid dexterous movements are impaired, causing difficulty writing
(micrographia) and doing up buttons and zips, for example
 Facial immobility gives a mask-like semblance of depression
 Frequency of spontaneous blinking diminishes, producing a serpentine stare
A K I N E S I A
CLINICAL FEATURES
MOTOR SYMPTOMS

8. CLINICAL FEATURES
NON - MOTOR SYMPTOMS
SLEEP DISTURBANCES
 Sleep fragmentation
 Sleep apnea
 REM behavioral disorder
 RLS
 Day time sleepiness
AUTONOMIC NS
DYSFUNCTION
 Constipation
 Sexual dysfunction
 Urinary problem
 Sweating
 Orthostatic hypotension (47%)MENTAL CHANGES
 Dementia (40 – 48%)
 Depression (58%)
 Apathy (50%)
 Hallucinations (44%)
SENSORY PHENOMENON
 Pain
 Dysesthesias

9. NATURAL HISTORY OF PARKINSON'S
DISEASE
Ist
Symptoms
Loss of
Nigro-
Striatal
cells
Anosmia
3to 5 yrs
Diagnosis
ONSET
Treatment
HONEYMOON
PERIOD
4 to 6 years
MOTOR
COMPLICATIONS
Surgery/DBS
2 yrs 5 years
Cognitive
Decline
Death
1 year
6 to 7 years
Presymptomatic
stage
Postural instability
Non Motor
complications

10. STAGES OF PD

11. STAGES OF PD
STAGE I STAGE II STAGE III STAGE IV STAGE V
Mild symptoms
Moderate
symptoms with
facial
modifications
Progression of
disease is
occurred
Drastic change is
observed
Advanced stage
with aggressive
symptoms
Tremors on one
side and
postural
changes are
observed
Tremors on both
sides of the
body is
observed
Imbalance of
body and
improper
reflexes are
observed
Personal
assistance is
required even in
simple tasks
Hallucination
and spasm
occurs in this
stage

13. CLINICAL EVALUATION
 Most patients respond well to treatment and there is generally a period of
several years in which symptoms are well controlled with relatively little disability
 Response to dopaminergic drugs is never lost but treatment – related
fluctuations may develop, which can be limiting, especially for patients with early
age at onset
 Eventually, usually by the mid-seventies, late stage, treatment-unresponsive
features, such as cognitive impairment, swallowing difficulty, loss of postural
stability and falls, start to emerge
 The rate of progression is very variable, with a benign form running over several
decades
 Usually, the course is over 10 – 20 years, death resulting from
bronchopneumonia and immobility

14. UNIFIED PARKINSON’S DISEASE
RATING SCALE

15. UNIFIED PARKINSON’S DISEASE
RATING SCALE

16. DIAGNOSIS
 There is no laboratory test; diagnosis is made by recognizing
physical signs and distinguishing idiopathic PD from other
Parkinsonian syndromes
 Patients with suspected PD should be referred to a specialist
without initiation of treatment
 MRI is normal and not necessary in typical cases
 Dopamine transporter (DAT) imaging using SPECT or PET makes
use of a radio-labelled ligand binding to dopaminergic terminals
to assess the extent of nigrostriatal cell loss
 It may occasionally be needed to distinguish PD from other causes
of tremor or from drug–induced parkinsonism, but it cannot
discriminate between PD and other akinetic-rigid syndromes

17. PROGNOSIS
 Variable and depends partly on the age of onset
 If symptoms start in middle life, the disease is usually slowly
progressive and likely to shorten lifespan because of the
complications of immobility and tendency to fall
 Onset after 70 is unlikely to shorten life or become severe

18. MANAGEMENT
AIMS
 Providing symptomatic relief with minimal side
effects
 Reduce functional disability
 Reduce or delay long term complications of drug
therapy:
i. Motor fluctuations
ii. Dyskinesias
 Slow disease progression “neuroprotection”
 Treat “non motor complications”

19. MANAGEMENT
S i t e s o f a c t i o n o f a n t i – P D d r u g s

20. MANAGEMENT
(Schapira 07)
M a n a g e m e n t o f e a r l y d i s e a s e

21. MANAGEMENT
M a n a g e m e n t o f a d v a n c e d d i s e a s e o n L e v o d o p a

22. MANAGEMENT
C o m m o n d r u g s u s e d i n P D

23. MANAGEMENT
C o m m o n d r u g s u s e d i n P D

24. MANAGEMENT
C o m m o n d r u g s u s e d i n P D

25. MANAGEMENT
C U R R E N T P H A R M A C O LO G I C A L T H E R A P I E S – S Y M P TO M AT I C T R E AT M E N T
 Levodopa remains the most effective form of treatment and all
patients with PD will eventually need it
 It is combined with a dopa decarboxylase inhibitor –
benserazide (co-beneldopa) or carbidopa (co-careldopa) – to
reduce the peripheral adverse effects (e.g. nausea and
hypotension)
 50mg of levodopa three times daily, increasing after 1 week to
100mg three times daily, is a typical starting dose
 The response is often dramatic
LEVODOPA

26. MANAGEMENT
W hy L e v o d o p a b e c o m e s l e s s e f fe c t i v e o v e r t i m e ?

27. MANAGEMENT
C o m p l i c a t i o n s o f l o n g t e r m L e v o d o p a
MOTOR FLUCTUATIONS : due to pulsatile stimulation
Loss of response
to medication
before next dose
Delay in
response after
dose of L dopa
End of dose
wearing off
Delayed On Dyskinesias Unpredictable
on & offs
D/t loss of
presynaptic dopa
neurons
Delay in
absorption &
crossing of BBB
Fluctuating levels of
dopamine sensitize
DOPA receptors
Competition bet L-
dopa with dietary
proteins BBB
Delayed gastric
emptying
Changes in neuronal
firing in STN/GP

28. MANAGEMENT
E n d o f d o s e “ w e a r i n g o f f ” – f i rs t sy m p t o m t o a p p e a r

29. MANAGEMENT
W h e n d o e s w e a r i n g o f f o c c u r ?
 In the ELLDOPA study, patients initiated with conventional
levodopa (150 – 600 mg/day) experienced motor complications:
LEVODOPA (%) PLACEBO
(%)150 mg 300 mg 600 mg
DYSKINESIA 3.3 2.3 16.5 3.3
WEARING –
OFF
16.3 18.2 29.7 13.3
 The time of onset for these complications was as early as 5 – 6
months after initiation of conventional levodopa therapy
 Higher the levodopa dose more are motor compications

30. MANAGEMENT
N a r ro w i n g o f ‘ t h e ra p e u t i c w i n d o w ’ o v e r t i m e

31. MANAGEMENT
C U R R E N T P H A R M A C O LO G I C A L T H E R A P I E S – S Y M P TO M AT I C T R E AT M E N T
DOPAMINE AGONISTS (DAs)
 It may be used in combination with levodopa or as initial
monotherapy in younger patients (below 65 – 70) with mild to
moderate impairment
 Although less efficacious in symptom control than levodopa and
generally less well tolerates, DAs are associated with fewer motor
complications over a 5 year period
 Non – ergot DAs (pramipexole and ropinirole or rotigotine via
transdermal patch) are used in preference to ergot-derived drugs,
which may be associated with fibrotic reactions, including cardiac
valvular fibrosis
 Domperidone is used as an antiemetic when initiating DAs therapy
(other antiemetics should not be used, as they may worsen
symptoms by blocking central dopamine receptors)

32. MANAGEMENT
 Selegiline
i. 5 – 10mg once daily (a monoamine oxidase (MAO)-B inhibitor)
reduces catabolism of dopamine in brain
ii. It has a mild symptomatic effect
iii. Rasagiline is another MAO-B inhibitor
 Amantadine
i. A modest anti-parkinsonian effect but is used mainly to improve
dyskinesias in advanced disease
OTHER DRUGS IN PD

33. MANAGEMENT
OTHER DRUGS IN PD
 Antimuscarinics
i. e.g. orphenadrine, procyclidine, trihexyphenidyl
ii. May help tremor but are rarely used in PD except in younger
patients
iii. They have a high propensity to cause confusion and cognitive
impairment in older patients
 Apomorphine
i. A potent, short – acting DA administered subcutaneously by an
autoinjector pen as intermittent ‘rescue’ injection for off periods or
by continuous infusion pump
ii. It is used in advanced PD

34. MANAGEMENT
LONG – TERM RESPONSE TO TREATMENT
 As the disease progresses, medical therapy for PD becomes more
difficult as higher doses of dopamine replacement therapy are
required and response becomes more unpredictable with the
development of motor fluctuations and dyskinesias; response to
dopaminergic drugs is never lost, however
 Approximately 10% of patients per year develop motor
complications in the form of “wearing off” , dyskinesias, and
eventually “on/off” phenomena
 Eventually, patients may alternate between the ‘on’ state with
dopamine – induced dyskinesias and periods of complete
immobility (“off”)

35. MANAGEMENT
LONG – TERM RESPONSE TO TREATMENT
 Management of the motor complications of treatment represents
one of the greatest challenges in the management of PD.
Strategies include:
i. Dose fractionation of levodopa – increasing dose frequency
ii. Addition of the catechol–O–methyl transferase (COMT)
inhibitor entacapone (200mg with each levodopa dose) to
prolong duration of action
iii. Slow release levodopa
iv. Avoidance of protein – rich meals and taking doses at least 40
minutes prior to meals
v. Apomorphine continues subcutaneous infusion
vi. Deep brain stimulation and levodopa intestinal gel

36. MANAGEMENT
DEEP BRAIN STIMULATION (DBS)
 Stereotactic insertion of electrodes into the brain has proved to
be a major therapeutic advance in selected patients (usually under
age 70) with disabling dyskinesias and motor fluctuations not
adequately controlled with medical therapy. Targets include:
i. The subthalamic nucleus – response similar to levodopa with
reduction in dyskinesia
ii. The globus pallidus – improves dyskinesia but levodopa is still
required for motor symptoms
iii. The thalamus – for tremor only
 Dopaminergic drugs can be reduced after deep brain stimulation
 There is a trend towards earlier use of DBS before motor
complications become severe

37. MANAGEMENT
L EVODOPA I NT EST I NAL GEL I NF USI ON
 Continuous infusion of this gel into the small intestine via a jejunostomy using a patient-
operated pump is effective for selected patients with severe motor complications
 At present, it is used only where apomorphine and DBS are contraindicated, partly
because of high costs
T I SSUE T RANSPL ANTATI ON
 Transplantation of embryonic mesencephalic dopaminergic cells directly into the
putamen has produced mixed results but is potentially promising; research is ongoing to
refine the technique
 Stem cells and gene therapy approaches are in development
PHYSI OT HERAPY,OCCUPATI ONAL T HERAPY AND PHYSI CAL AI DS
 Physiotherapy, occupational therapy and speech therapy all have a role to play in
managing PD and reducing disability, speech and swallowing problems, and falls
 Walking aids are often a hindrance early on, but later a frame or a tripod may help
 A variety of external cueing techniques may help with freezing

38. REFERENCES
 Kumar, P. J., & Clark, M. L. (2017). Kumar & Clarks clinical medicine. Edinburgh: Elsevier.
 Srivanitchapoom P, Pitakpatapee Y, Suengtaworn A. Parkinsonian syndromes: A review.
Neurol India [serial online] 2018 [cited 2018 Nov 19];66, Suppl S1:15-25. Available
from: http://www.neurologyindia.com/text.asp?2018/66/7/15/226459
 Braak H, Ghebremehin E, Rub U, Bratzke H, Del Tredici K.
Stages in the development of Parkinson’s disease-related pathology. Cell Tissue
Res 2004; 318: 121–34.
 Hindle, John. (2010). Ageing, neurodegeneration and Parkinson's disease. Age and ageing. 39.
156-61. 10.1093/ageing/afp223.
 Parkinson Disease: Practice Essentials, Background, Anatomy. (2018). Retrieved from
https://emedicine.medscape.com/article/1831191-overview
 ELLDOPA=Earlier versus Later LevoDOPA therapy in Parkinson disease
Parkinson’s Study Group. N Engl J Med 2004;351(24):2498.
 Management of Motor Complications in Parkinson’s Disease ‘s slide by Dr Sanihah Abdul
Halim, USM (courtesy from Dr Thung)
 Unified Parkinson’s Disease Rating Scale