Treatment of Parkinson Disease in Indonesia :

where we are in Indonesia ?

D.P.G Purwa Samatra

Moving in Harmony with Movement Disorders

 "Moving in Harmony with Movement Disorders"

Out line

Epidemilogi
Treatment saat ini
Future treatment
Pembedahan
 "Moving in Harmony with Movement Disorders"

Introduction
PD is the 2nd most common
neurodegenerative disease after
Alzheimer’s disease with
prevalence of 0.5-1% among
those 65-69 y.o, rising to 1-3%
among person ≥80 y.o
Projected growth rates in number of individuals > 50 with Parkinson disease in
the most populous nations in the world from 2005 - 2030.
 "Moving in Harmony with Movement Disorders"

Prevalence of Parkinson’s disease by age

• In a meta-analysis of worldwide Prevalence of PD by age and geographic location
(per 100,000 people)1
data, the prevalence of PD
Age range (years)
increased with age, from 41 per Location
100,000 people in individuals 50–59 60–69 70–79 80+

40–49 years to 1,903 per South America 228 637 2,180 6,095
100,000 people in individuals
≥801 Europe/
North America/ 113 540 1,602 2,953
• Comparing regions of the world, Australia

Asia had a lower prevalence than Asia 88 376 646 1,418

other areas at all ages studied1

• 1. Pringsheim et al. Movement Dis 2014;29(13):1583–1590 5

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Parkinson’s disease is a widespread public health issue

Cost per case of specific brain disorders in Europe8
• PD is recognised as the second-most common Cost per patient (€)
neurodegenerative disorder1
0 10,000 20,000 30,000 40,000
• Approximately 6 million people are diagnosed with
Tumour
Parkinson’s disease (PD) worldwide2,3
Multiple sclerosis
• In Europe, there are an estimated
Stroke
1.2 million people with PD3
Dementia
• PD affects 1–2 per 1,000 of the population4,5
Psychotic disorder
• PD affects 1% of the population over the age of 60, Parkinson’s disease
but is rare in individuals younger than 50 years4,6
Epilepsy
• The prevalence of PD rises with age, and in the
Affective disorders
oldest age groups, PD reaches a prevalence of
approximately 4%4,7 Trauma
Addiction
Anxiety disorders
Migraine
• 1. Bertram & Tanzi. J Clin Invest 2005;115(6):1449–1457;
2. European Parkinson’s Disease Association website. Accessed Feb 2017;
3. GBD 2015. Lancet 2016;388:1545–602; 4. Tysnes & Storstein. J Neural Transm 2017;124:901–905;
5. von Campenhausen et al. Eur Neuropsychopharmacol 2005;15(4):473–490; 6. de Lau & Breteler. Lancet Neurol 2006;5(6):525–535; 6
7. Zou et al. Eur Rev Med Pharmacol Sci 2014;18(24):3908–3915; 8. Andlin-Sobocki et al. Eur J Neurol 2005;12(Suppl 1):1–27
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The economic burden of Parkinson’s disease

• In a study estimating the economic Breakdown of PD-related costs 1

burden of PD in the USA between Inpatient care

1999–2002:1 Uncompensated
19.9%
Outpatient
• Direct costs: $10,349 per patient care care
7.5%
• Indirect costs: $25,326 per patient 18.8%

• Total cost to the US: $23.0 billion per year Prescription

• Outpatient care and drug costs drugs

4.4%
accounted for a relatively small
proportion of the economic Productivity loss
burden1 49.4%

By far the largest share of the cost (49.4% of

the total) is due to productivity loss1
• 1. Huse et al. Mov Disord 2005;20(11):1449–1454 7
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The increasing economic burden of Parkinson’s disease

Costs of PD over 4 years • An analysis within the Spanish
4.000
Indirect costs health system estimated the
Direct costs costs of PD during 4 years1
3.000
• Direct costs increased by 52%
Costs (€)

from year 1–41

2.000
• Indirect costs increased by
1.000
129%1
Costs increased with the progression
0 and the severity of the disease1
0 1 2 3 4

Years

• 1. Martinez-Martín et al. PLoS One 2015;10(12):e0145310 8

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Parkinson’s disease is a disease

with growing prevalence and
negative effects on quality of life

• Boland & Stacy. Am J Manag Care 2012;18(7 Suppl):S168–175

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Risk factors associated with Parkinson’s disease

Risk factors1,2 Protective factors1,2
• Age • Smoking/tobacco use
• Sex • Caffeine
• Genetics • Urate
• Pesticide exposure • Physical activity
• Dairy • NSAIDsa
• Melanoma • Calcium channel blockers
• Traumatic brain injury

The risk of developing PD is a balance of the effect of positive and negative

factors on the genetic predisposition of an individual2
aStrongest evidence for ibuprofen, for other NSAIDs the evidence is mixed or poor;1,2 NSAID=nonsteroidal anti-inflammatory drug

• 1. Lee & Gilbert. Neurol Clin 2016;34(4):955–965; 10

2. Ascherio & Schwarzschild. Lancet Neurol 2016;15(12):1257–1272
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The burden of non-motor symptoms on the patient

• Neuropsychiatric symptoms, including depression, Correlation between non-motor symptoms
anxiety, apathy, fatigue and psychosis and quality of life scores
(hallucinations and/or delusions) are common in (adapted from Duncan et al., 20142)
patients with PD1

Quality of Life Questionnaire

Worsening score on the PD
• A questionnaire study assayed the effect of non-
motor symptoms on quality of life for patients with
PD2
• Many non-motor symptoms correlated with quality
of life scores:2
• Depression
• Anxiety
• Impaired concentration
Increasing number of
• Memory complaints non-motor symptoms
• Sleep disturbance
There was a significant correlation between the total number of
non-motor symptoms reported and quality of life2
• PDQ=Parkinson’s Disease Quality of Life Questionnaire 11
• 1. Aarsland et al. Mov Disord 2009;24(15):2175-2186; 2. Duncan et al. Mov Disord 2014;29(2):195–202
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Braak Staging of Parkinson’s Disease

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Parkinson’s Disease Treatment: Continuum of Interventions

Disease Severity Mild Moderate Severe

Dyskinesia, Postural
Patient Symptoms Signs of levodopa “On-Off” Instability,
“wearing-off” Motor Freezing, Falls,
Fluctuations Dementia

Treatment Levo COMT inhibitors, DBS

Agonists others
Dopamine
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Strengths and limitations of levodopa

Short half-
life Gold standard, the most
(~1 hour)1 effective symptomatic
therapy in PD4,5

Only a small
percentage of oral
levodopa reaches
the brain1 Acceptable
tolerability
profile5
Early wearing-off
leading to reduced
quality of life2,3
Improvements in
quality of life seen
Motor fluctuations in short term6
and dyskinesia will
develop over long
term treatment3,4
1. Nutt & Fellman. Clin Neuropharmacol 1984;7(1):35–49; 2. Chapuis et al. Mov Disord 2005;20:224–230;
3. Freitas et al. Semin Neurol 2017;37(2):147–157; 4. Hametner et al. J Neurol 2010;257(Suppl 2):S268–S275;
5. Ferreira et al. Eur J Neurol 2013;20(1):5–15; 6. Sethi. Neurologist 2010;16(2):76–83
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OTHER MEDICATIONS USED IN THE TREATMENT OF

PARKINSON’S DISEASE
Dopamine and DAs at the synapse4
Dopamine agonists (DAs)1
DAs mimic the action of dopamine by activating
dopamine receptors
DAs are useful as monotherapy in earlier stages of
PD, and are also useful as adjunctive treatment in
patients experiencing motor fluctuations1,2
DAs can cause/contribute to a variety of side
effects, including nausea, psychosis and ‘impulse
control disorders’ (e.g., hypersexuality, pathological
1. Wolters & Baumann. Parkinson Disease and Other Movement Disorders. 2014
gambling, binge eating, and compulsive buying)1,3 2.
3.
Fox et al. Mov Disord 2018;33(8):1248–1266
Apomorphine. SPC. 2018
4. Lundbeck Institute Campus. https://institute.progress.im/en/image-bank
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OTHER MEDICATIONS USED IN THE TREATMENT OF

PARKINSON’S DISEASE
Monoamine oxidase type B (MAO-B) inhibitors1,2 MAO-B inhibitor mechanism of action at the synapse3
MAO breaks down dopamine
MAO-B inhibitors have shown efficacy in
patients with PD as monotherapy or as adjunct
therapy

MAO-B = monoamine oxidase type B

1. Wolters & Baumann. Parkinson Disease and Other Movement Disorders. 2014
2. Fox et al. Mov Disord 2018;33(8):1248–1266
3. Lundbeck Institute Campus. https://institute.progress.im/en/image-bank 16
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OTHER MEDICATIONS USED IN THE TREATMENT OF

PARKINSON’S DISEASE
Catechol-O-methyltransferase (COMT) inhibitors1
COMT breaks down levodopa
To increase the amount of levodopa that gets to the
brain, COMT inhibitors are used to decrease the
metabolism of levodopa
COMT inhibitors increase the half-life of levodopa by
up to about 50%
In some countries, a COMT inhibitor is available with
levodopa/decarboxylase inhibitor as a combination
tablet, easing the patient’s pill burden COMT = catechol-O-methyltransferase
1. Wolters & Baumann. Parkinson Disease and Other Movement Disorders. 2014
2. Lundbeck Institute Campus. https://institute.progress.im/en/image-bank
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 "Moving in Harmony with Movement Disorders"

The future of treatment for Parkinson’s disease

What does the ideal
The current treatment paradigm1,2
future hold?
When symptomatic therapy is indicated, patients can be initiated on
levodopa, a dopamine agonist, or an MAO-B inhibitor Individuals with genetic
As the disease advances, symptomatic monotherapy can be PD receive gene therapy
augmented with the use of combination therapy, e.g., levodopa to restore the correct
combined with a dopamine agonist and/or an MAO-B inhibitor genes and prevent the
Some patients with more advanced PD can benefit significantly from
onset of PD
device-aided therapies, such as deep brain stimulation, or continuous
infusions of dopaminergic agents Individuals who would go
Non-motor symptoms should be treated as they emerge, with on to develop PD are
symptomatic therapies identified early and
In addition to medical treatments, there should be an emphasis on treated with drugs that
non-pharmacological therapies, e.g., physical exercise and speech
prevent the onset of
therapy
motor symptoms
 "Moving in Harmony with Movement Disorders"

Treatment principles in the advanced stages of Parkinson’s disease

❑The oral delivery of drugs may be
After long-term levodopa therapy, some problematic in patients with PD;
specifically, the involvement of the
patients develop motor complications, gastrointestinal system complicates the
which comprise ON–OFF motor intestinal absorption of drugs3
fluctuations and dyskinesia1 ❑Improved levodopa delivery strategies
being explored:2
In the advanced stages, numerous ❑Transdermal – through the skin,
non-motor symptoms will emerge which e.g., a patch
are more troublesome to the patient and ❑Pulmonary – breathed into the
lungs,
respond only partially, if at all, to drugs2 e.g., an inhaler
❑Percutaneous – directly into the
intestine, e.g., intestinal infusion

1. Wolters & Baumann. Parkinson Disease and Other Movement Disorders. 2014;
2. Jenner. Transl Neurodegener 2015;4:3;
3. Chaudhuri et al. Parkinsonism Relat Disord 2016;33(Suppl 1):S2–S8
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Properti farmakologis
Golongan alkaloid aporphine, formula: C17H17NO2, bersifat lipofilik, afinitas terhadap reseptor dopamine
spektrum luas : D1 dan D2-like receptor (D1, D2S, D2L, D3, D4, D5), sementara agonis dopamine seperti
pramipexole dan ropinirole hanya pada D2 dan D3, serta memiliki pula moieitas piperidine.
Bioavailabilitas oral sangat terbatas (<4%), karena metabolism hepatik tingkat 1 hampir komplit.
Saat ini yang telah berlisensi: sediaan parenteral injeksi subkutan atau infus, bioavailabilitas 100%, distribusi
volume, waktu paruh dan klirens plasma antara kedua sediaan berimbang.
Faktor yang mepengaruhi injeksi subkutan: lokasi injeksi, kondisi kulit, volume dan kedalaman injeksi, dan
adanya nodul subkutan.
Konsentrasi puncak pada darah (Cmax) 10 menit, konsentrasi maksimal dalam LCS setelah 30 menit, waktu
paruh sekitar 33 menit, onset respons klinis umumnya dalam 7-10 menit.
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Apomoíphine Pump

• Reduce 'off time'

• Improve QOL

• Major AE 'nodule formation'

AE, adverse event; LEDD, L-dopa equivalent daily dose; QOL, quality of life.
a. Katzenschlager R, et al. Lancet Neurol. 2018;17:749-759; b. Drapier S, et al. J Neurol. 2016;263:1111-9.
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Efikasi
Hasil berbagai studi open label : memperbaiki kondisi sudden “off” pada PP
stadium lanjut walaupun terapi oral optimal.
Penurunan waktu “off”
Penurunan keparahan dyskinesia (hasil masih inkonsisten)
Studi perbandingan apomorphine dan levodopa → skala efek yang ekuivalen
Perbandingan efikasi apomorphine dan levodopa:

Keluaran Apomorphine Levodopa

Rerata durasi efek 56 menit (30- 211 menit (145-
motorik 80) 315)
Onset 3-14 menit 19-75 menit
(7,9) (35,4)
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LEVODOPA
INTESTINAL GEL
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DUOGLOBE Duopa Sľudy

▪ 195 patients, 15 centers
▪ Off time and dyskinesia improve
▪ AEs most common: tube placement
▪ AEs most common in first 2 weeks
▪ Most common AE was abdominal pain
▪ 10% discontinue per year
▪ 30% by 5 years need a tube replaced

Photo: David Standaert, WPC.

Standaert DG, et al. Mov Disord Clin Pract. 2021;8:1061-1074
These materials are provided to you solely as an educational resource for your personal use. Any commercial use or distribution of these materials or any portion thereof is strictly prohibited.
 "Moving in Harmony with Movement Disorders"

Gene therapy
• There are many potential risks of gene
therapy:1
Gene therapy is the use of genetic material (DNA or RNA) as an o Uncontrolled overproduction of the
agent to alter cellular/biological function and treat disease – targeted protein, resulting in adverse
either to correct a genetic flaw or to introduce new genes1 effects
This can be done in two different ways:1 o ‘Insertional mutagenesis’, where the
Ex vivo – where the manipulation is performed outside of introduced gene inserts into the host
the body, in cell culture genome at a site promoting cancer
In vivo – where the manipulation is performed within the o Induction of an autoimmune and
body inflammatory response
There are many potential candidates for gene therapy, including • The serious risk of insertional mutagenesis can
the LRRK2 gene, the Parkin gene and the SCNA gene1 be controlled by the use of ex vivo methods,
and the careful selection of the method of
insertion within the genome1

A successful gene therapy would slow or halt the

progression of PD1,2

DNA=deoxyribonucleic acid; RNA=ribonucleic acid; SCNA=synuclein alpha gene

1. Allen & Feigin. Neurotherapeutics 2014;11(1):60–67; 2. Coune et al. Cold Spring Harb Perspect Med 2012;2(4):a009431

The potential of stem cell therapies
The potential power of stem cells is that
they can come from the patient, and can
become many different types of cell
depending on the stimulation to which they
are exposed1,2
However, along with the ethical concerns
connected with certain stem cells, when
tested in clinical trials, stem cell therapies
have shown a large variation in efficacy for
relieving the symptoms of PD1
1. Zhu et al. Int J Neurosci 2016;126(11):955–962; 2. Barker et al. Nat Rev Neurol 2015;11(9):492–503
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There are several types of stem cells that are being researched for
their potential in the treatment of PD:2
• Embryonic stem cells – cells derived from the inner cell mass of
early-stage embryos
• Induced pluripotent stem cells – adult cells that are taken and
‘reprogrammed’; they can potentially become any cell type of the
body
• Mesenchymal stem cells – ‘multipotent’ cells derived from the
bone marrow; they can be ‘reprogrammed’ to become neurons
• Expanded neural precursor cells – precursor cells from the brain
can be used to generate dopamine neurons for transplantation
• Induced neurons – these are neurons that are produced by
‘reprogramming’ standard cells,
such as the cells of the extracellular matrix and connective tissue
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Holistic medicine and the multi-disciplinary

approach
Management by medication alone cannot fully address the The multi-disciplinary
symptoms of PD1 approach1
The guidelines for the treatment of PD outline a variety of non-
pharmacological approaches which can be usefully employed:2
Physiotherapy – to improve gait, balance, aerobic capacity,
flexibility, and fitness
Occupational therapy – to help maintain functioning, and
work, family, and other social roles
Speech and language therapy – teaching strategies to
optimise clarity of speech, and improve safety of
swallowing
Integrated models of multi- and inter-disciplinary patient care
are needed to ensure good quality healthcare delivery1

1. Prizer & Browner. J Parkinsons Dis 2012;2(2):79–86; 2. NICE guideline CG35, 2006
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Exercise and Parkinson’s disease

• Non-pharmacological treatment options are a valid part of the treatment paradigm of PD1,2
• Exercise programs and physiotherapy have been extensively studied in patients with PD1,2
• Rehabilitation through physical therapy has a variety of goals and methods that generally promote
benefits in mobility, posture, and balance in individuals with PD1
• Example interventions include treadmill, resistance, and balance training, and dance therapy1
• One meta-analysis compared physiotherapy with no intervention in patients with PD:3
• Walking speed was significantly improved in the physiotherapy group (p<0.001)
• UPDRS Motor score improved with physiotherapy (p<0.001)
• Exercise can modify long-term motor symptoms and physical functioning in patients with PD, potentially
increasing the efficacy of pharmacological treatment and delaying disease progression4

UPDRS=Unified Parkinson’s Disease Rating Scale

1. Borrione et al. World J Methodol 2014;4(3):133–143; 2. Oliveira de Carvalho et al. Clin Pract Epidmiol Ment Health 2018;14:89–98;
3. Tomlinson et al. BMJ 2012;345:e5004; 4. Mak et al. Nat Rev Neurol 2017;13(11):689–703
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Surgical Treatments for Parkinson’s Disease

• Ablative
• Thalamotomy
• Pallidotomy
• Electrical stimulation
• VIM thalamus, globus pallidus internus, sub-thalamic nucleus
• Transplant
• Autologus adrenal, human fetal, xenotransplants, genetically engineered
transplants
 "Moving in Harmony with Movement Disorders"

Surgical ways to treat Parkinson's include:

• Deep brain stimulation
• Focused ultrasound
• Pallidotomy
• Thalamotomy
"Moving in Harmony with Movement Disorders"
"Moving in Harmony with Movement Disorders"
 "Moving in Harmony with Movement Disorders"

Deep Brain Stimulation

Electrode Implantation for DBS

Electrode

Plane of section

Stimulation of globus Stimulation of

pallidus (internal segment) subthalamic nucleus Lead

Lead Lead

Pulse generator
Electrode Electrode
Globus Subthalamic
pallidus nucleus

DBS, deep brain stimulation.

Okun MS. N Engl J Med. 2012;367:1529-38.
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“ON” Time
Without
Dyskinesias
Improves from
27% to 74% of a
Patient’s Waking
19%
Day 27%
7%
49%

74%
23%

Before Surgery 6 Months After Surgery Bilateral

(n=96) STN Implant
(n=91)
“ON” with Dyskinesia “ON” without Dyskinesia “OFF”
TERIMA KASIH