PD for LAO doctor - Khon Kaen University for LAO doctor.pdf · Parkinson’s Disease 188 Dr James...

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1 Parkinson’s Disease Associate Professor SOMSAK TIAMKAO Associate Professor SOMSAK TIAMKAO Division of Neurology, Department of Medicine Division of Neurology, Department of Medicine Faculty of Medicine, Faculty of Medicine, Khon Khon Kaen Kaen University University http://epilepsy.kku.ac.th http://epilepsy.kku.ac.th Parkinson’s Disease 188 188 Dr James Parkinson Dr James Parkinson an Essay an Essay on the shaking palsy on the shaking palsy 1817 1817 62 62 An Essay on the shaking palsy An Essay on the shaking palsy 6 6 44 44 basal ganglia basal ganglia dopamine dopamine 34 34 L L- dopa dopa neurodegenerative disease neurodegenerative disease Incidence and Prevalence (tremor) (tremor) 70% 70% rest tremor 3 rest tremor 3- 5 Hz 5 Hz (rigidity (rigidity ) ) cogwheel rigidity cogwheel rigidity ( ( bradykinesia bradykinesia ) ) Postural instability Postural instability Gait difficulty Gait difficulty Clinical manifestations Clinical manifestations Mask Face Stoop posture Micrographia Posture

Transcript of PD for LAO doctor - Khon Kaen University for LAO doctor.pdf · Parkinson’s Disease 188 Dr James...

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Parkinson’s Disease

Associate Professor SOMSAK TIAMKAOAssociate Professor SOMSAK TIAMKAO

Division of Neurology, Department of MedicineDivision of Neurology, Department of Medicine

Faculty of Medicine, Faculty of Medicine, KhonKhon KaenKaen UniversityUniversity

http://epilepsy.kku.ac.thhttp://epilepsy.kku.ac.th

������� Parkinson’s Disease

�� 188 188 ������������ ���������� Dr James Parkinson Dr James Parkinson � � an Essay an Essay

on the shaking palsy on the shaking palsy ������� ���������� ��� 1817 1817 ������������������ 62 62 ����

�� An Essay on the shaking palsy An Essay on the shaking palsy

�� ������������������ 6 6 ��

�� 44 44 ������������ �������� �! �! basal ganglia basal ganglia ���� dopamine dopamine "�"�"�"�

�� 34 34 ������������ #��!� $�#��!� $� L L--dopa dopa ������% ������%

�� #�&�#�&� neurodegenerative disease neurodegenerative disease �!��'�� ��(#)�� �!��'�� ��(#)��

Incidence and Prevalence

�� ����� ����� (tremor)(tremor)

������������ 70% 70%

�� ��� ��� rest tremor 3rest tremor 3--5 Hz5 Hz

�� ��������������(rigidity(rigidity) ) ������������ cogwheel rigiditycogwheel rigidity

�� ������� ���������� ������� ( (bradykinesiabradykinesia) )

�� Postural instabilityPostural instability

��Gait difficulty Gait difficulty

Clinical manifestationsClinical manifestations

Mask Face

Stoop posture

Micrographia

Posture

2

Rest tremor Rest tremor

Action tremorAction tremor Pill rolling

Rest tremor; foot Pulling test

3

Abnormal posture ������ ����� Cogwheel rigidity

����� Cogwheel rigidity Difficulty to standDifficulty to stand

Walking difficultyWalking difficulty Difficulty to turning

4

�� !�"���� ���� #

���������������� 4040--70 70 ����

�� #��!�#�&����#�������#��!�#�&����#�������(60%) (60%)

�����*��#�&�*��'����*��#�&�*��'�

��(���+,,������(���+,,������

�������(�!���������(�!����(70%)(70%)

�����(�����������(�������� LL--dopadopa

Substantia Nigra

������$���� -'� -'� cell cell ./��./�� ��'�� ����'�� ��

�� �"'� �!#�&�'�'���"'� �!#�&�'�'�� #$��#$��

��Oxidative stressOxidative stress

��ExcitotoxicityExcitotoxicity

��Mitochondrial dysfunctionMitochondrial dysfunction

��InflamatoryInflamatory factors factors

��Apoptosis Apoptosis

Aetiology of Parkinson’s disease

Degeneration of the substantia nigra (with Lewy bodies ?)

ParkinsonParkinson’’s diseases disease

PARK-1(αααα-Synuclein)

PARK-2(Parkin) mitochondrial

dysfuction ?

oxidative stress ?genetic susceptibiliesDebrisoquin hydroxylase ?

PARK-3, 4, ... ?

toxins ?

Excitatory Inhibitory

A. Normal Motor

Circuit

B. Motor

Circuit in PD

C. Motor Circuit In PD with Levodopa-

induced Dyskinesia

CORTEX CORTEX

PUTAMEN

VL

PPN

GPi

SNr

STN

GPe

SNc

PUTAMEN

VL

PPN

GPi

SNr

STN

GPe

PUTAMEN

VL

PPN

GPi

SNr

STN

GPe

SNc

DA DA

CORTEX

SNc

C W Olanow, J A Obeso et al. TINS Supplement

Diagnosis

�� Diagnosis Diagnosis #�&�#�&� clinical diagnosis clinical diagnosis

�� 0/!������(1������0/!������(1������ 8383%%

�� '����'���� laboratory test laboratory test

�� no serologic, imaging test no serologic, imaging test

�� Definite diagnosis Definite diagnosis #�&�������.5� ��6��� #�&�������.5� ��6���

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%����� "&� Missed Diagnosis

�� HemiparkinsonHemiparkinson �.�.1��1������.5���#�&�����.5���#�&� strokestroke

�� Arm pain Arm pain *����#�&�*����#�&� cervical cervical

spondylosisspondylosis

�� Normal pressure Normal pressure

hydrocephalus hydrocephalus 1������.5���1������.5���#�&�#�&� Parkinson Parkinson’’s disease s disease

�� Low back pain Low back pain

�� Rheumatoid arthritisRheumatoid arthritis

��� ��'�(�($�� Parkinsonism ��� #

�� Idiopathic ParkinsonIdiopathic Parkinson’’s disease s disease

�� 80 % 80 % ���(���������(������ LL--dopadopa

�� Secondary parkinsonism Secondary parkinsonism

�� ������ parkinsonism parkinsonism #���$��#���$��

�� drug induced, toxic substance, Wilsondrug induced, toxic substance, Wilson’’s s

disease, progressive disease, progressive supranuclearsupranuclear palsypalsy

�� ������ parkinsonism parkinsonism #�&�(���������#�&�(���������

�� normal pressure hydrocephalus, multiple normal pressure hydrocephalus, multiple

system atrophysystem atrophy

WilsonWilson’’s diseases disease Hoehn and Yahr Staging

�� Stage Stage 11 #�&����#���#�&����#���

�� Stage Stage 22 #�&�(�����#�&�(����� '�����9��'�����9��

�� Stage Stage 33 #�&�(�����#�&�(����� #��!���#��!��� postural instabilitypostural instability

�� Stage Stage 44 #�&����9��#�&����9�� ��������$��#)";���������$��#)";�

�� Stage Stage 55 bed ridden bed ridden )�;�)�;� ��!��1#�=���!��1#�=�

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Late stage Parkinson’s disease �)*���� # ��� Parkinson’s disease

�������#$;�������#$;��

�� ������ ������

����-"9)����-"9)��

����������

��*��.-#(;!��"�*��.-#(;!��"�

�� !�"���� ����

��#(��#�"�!�9�"�#(��#�"�!�9�"�

��*��$�*��$� *��.-#(;!��"�*��.-#(;!��"�

��Depression Depression ����������

�� ������ ������ �������� �>�������� �>

Drug-induced parkinsonism

� Dopaminergic antagonist drug(neuroleptic, antipsychotic)� Haloperidol

� Perphenazine

� Phenothiazine

� Dopaminergic depletors� Reserpine

� Tetrabenazine

� Alpha-methyldopa

� Calcium channel blockers

� Flunarizine

� Cinnarizine

� Other

� Phenyltoin

� Lithium

� Amiodarone

� Bethanecal

� Lovastatin

Oral dyskinesia

Comparison of Drug-induced Parkinsonism and PD

May be pronounceUsually mild to moderate

Anticholinergic drug response

Remittance within weeks to months

Symptom and sign slowly progress

Withdrawal of suspected drug

Bilateral., symmetrical postural or rest tremor

Unilateral or asymmetrical rest tremor

Tremor type

Acute, subacuteInsidious, chronicCourse

Bilateral, symmetrical

Unilateral or asymmetrical

Symptom onset

Drug-induced parkinsonism

Parkinson’s diseaseFeature

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Long-term complications of treatment

� Motor complications

� Motor fluctuations

- Wearing off

- Delay ON / No ON

- ON/ OFF

� Dyskinesias

- End of dose

- Peak dose

� Non-motor complications� Neuropsychiatric complications

� Depression / Dementia

� Hallucination / psychosis

� Sleep abnormality

� Freezing

� Autonomic complications

� etc.,

“Wearing-Off” Fluctuation

� Increasingly shortened benefit period following each dose of levodopa

� Regular and predictable occurs 2-4 hours after levodopa dose

� Presenting with motor, sensory, psychiatric, autonomic fluctuation

On-Off Fluctuations

� Sudden, unpredictable shifts between undertreated and overtreated states.

� Indirect result of the alteration of presynaptic dopamine terminals resulting from fluctuating transmitter levels.

Dyskinesia Dyskinesia

� Drug- and disease-related.

� Choreiform/choreodystonia dyskinesias invariably are related to long-term levodopa therapy.

� “On” dyskinesias: chorea, myoclonus and dystoniamovements.

� Diphasic dyskinesias:stereotyped, repetitive movement of lower limbs

� “Off”dyskinesias :dystonic postures (feet)

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Treatment of Motor Complications of PD

� Reduce each dose of levodopaDopamine agonistAnticholinergic drug

Peak-dose dyskinesia/dystonia

� DomperidoneCisaprideDrug-failure response

� Controlled-release levodopaDopamine agonistCOMT inhibitorDietary management

“Off”- period dystonia

� Liquid levodopaDopamine agonistClozapine

“On-off” fluctuation

� More frequent dosing of levodopaCOMT inhibitorDopamine agonistControlled release levodopa

“Wearing-off” fluctuation

Activa® Parkinson’s Control SystemActivaActiva®® ParkinsonParkinson’’s Control Systems Control System

Activa® System

Implanted ComponentsImplanted ComponentsImplanted Components

Activa® System

Instruments

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T2W FSEaxial coronal

STN

Basal gangliaBasal ganglia

THE DOPAMINERGIC SYNAPSE OF THE THE DOPAMINERGIC SYNAPSE OF THE THE DOPAMINERGIC SYNAPSE OF THE THE DOPAMINERGIC SYNAPSE OF THE

NIGROSTRIATAL TRACT IN THE STRIATUMNIGROSTRIATAL TRACT IN THE STRIATUMNIGROSTRIATAL TRACT IN THE STRIATUMNIGROSTRIATAL TRACT IN THE STRIATUM

LevodopaLevodopaLevodopa

MAO-BI

Tyrosine L-dopa Dopamine

DAmetabolite

DA

DA

DA

DA

MAO-B

Dopamine

receptorsreceptors

Presynaptic neuronPresynaptic neuron

PostsynapticneuronPostsynapticneuronneuron

metaboliteCOMTCOMT

reuptakereuptakeAmantadine

COMTI

Apomorphine or Apomorphine or

DADA

Dopaminergic Treatment

���������������� ����

1. ������������������������

2. ������������� ����!"� L-dopa �� * ��� !� +��,���-��� !�

3. �������/0�������������

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Early-onset Parkinson�s disease (<50 yr)

1. Mono-therapy with DA-agonist

2. Early combination of DA-agonist and low-dose of L-dopa

3. Anti-cholinergic for tremor

Parkinson�s disease (50-70 yr)

1. Mono-therapy with DA-agonist

2. Low-dose L-dopa mono-therapy

3. Combination of L-dopy and DA-agonist

Parkinson�s disease (> 70 yr)

1. L-dopa mono-therapy

2. Combination of L-dopa and DA-agonist

, �����"�E����1. ������* �� L-dopa ��FG

2. ������* �� L-dopa ,��� HE

3. I�"������������������������

4. I�"/���/�!E+������������ �����+-"���!�

Marketed preparations of L-dopa

L-dopa + benserazied :

�Madopar 125 mg dispersible tablets

�Madopar 250 mg tablets

�Madopar HBS 125 mg tablets

Marketed preparations of L-dopa

L-dopa + carbidopa:

�Sinemet 25/100 mg tablets

�Sinemet 25/250 mg tablets

�Sinemet CR 50/200 mg tablets

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Marketed preparation � DA : Bromogon 2.5 mg

Celance 0.05 mg, Parlodel 2.5, 5 mg

� MAO B inhibitor : Seline 5, 10 mg

� COMT inhibitor : comtan 200 mg

Thank you for your attention