PD for LAO doctor - Khon Kaen University for LAO doctor.pdf · Parkinson’s Disease 188 Dr James...
Transcript of PD for LAO doctor - Khon Kaen University for LAO doctor.pdf · Parkinson’s Disease 188 Dr James...
1
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 ������������ #��!� $�#��!� $� L L--dopa dopa ������% ������%
�� #�&�#�&� neurodegenerative disease neurodegenerative disease �!��'�� ��(#)�� �!��'�� ��(#)��
Incidence and Prevalence
�� ����� ����� (tremor)(tremor)
������������ 70% 70%
�� ��� ��� rest tremor 3rest tremor 3--5 Hz5 Hz
�� ��������������(rigidity(rigidity) ) ������������ cogwheel rigiditycogwheel rigidity
�� ������� ���������� ������� ( (bradykinesiabradykinesia) )
�� Postural instabilityPostural instability
��Gait difficulty Gait difficulty
Clinical manifestationsClinical manifestations
Mask Face
Stoop posture
Micrographia
Posture
3
Abnormal posture ������ ����� Cogwheel rigidity
����� Cogwheel rigidity Difficulty to standDifficulty to stand
Walking difficultyWalking difficulty Difficulty to turning
4
�� !�"���� ���� #
���������������� 4040--70 70 ����
�� #��!�#�&����#�������#��!�#�&����#�������(60%) (60%)
�����*��#�&�*��'����*��#�&�*��'�
��(���+,,������(���+,,������
�������(�!���������(�!����(70%)(70%)
�����(�����������(�������� LL--dopadopa
Substantia Nigra
������$���� -'� -'� 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���
5
%����� "&� 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
��� ��'�(�($�� Parkinsonism ��� #
�� Idiopathic ParkinsonIdiopathic Parkinson’’s disease s disease
�� 80 % 80 % ���(���������(������ LL--dopadopa
�� Secondary parkinsonism Secondary parkinsonism
�� ������ parkinsonism parkinsonism #���$��#���$��
�� drug induced, toxic substance, Wilsondrug induced, toxic substance, Wilson’’s s
disease, progressive disease, progressive supranuclearsupranuclear palsypalsy
�� ������ parkinsonism parkinsonism #�&�(���������#�&�(���������
�� normal pressure hydrocephalus, multiple normal pressure hydrocephalus, multiple
system atrophysystem atrophy
WilsonWilson’’s diseases disease Hoehn and Yahr Staging
�� Stage Stage 11 #�&����#���#�&����#���
�� Stage Stage 22 #�&�(�����#�&�(����� '�����9��'�����9��
�� Stage Stage 33 #�&�(�����#�&�(����� #��!���#��!��� postural instabilitypostural instability
�� Stage Stage 44 #�&����9��#�&����9�� ��������$��#)";���������$��#)";�
�� Stage Stage 55 bed ridden bed ridden )�;�)�;� ��!��1#�=���!��1#�=�
6
Late stage Parkinson’s disease �)*���� # ��� Parkinson’s disease
�������#$;�������#$;��
�� ������ ������
����-"9)����-"9)��
����������
��*��.-#(;!��"�*��.-#(;!��"�
�� !�"���� ����
��#(��#�"�!�9�"�#(��#�"�!�9�"�
��*��$�*��$� *��.-#(;!��"�*��.-#(;!��"�
��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
7
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)
8
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
9
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�������������
10
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