Parkinson's disease

• 巴金森 氏症 9606011

1
• 電影「回到未來」美國影星米高福克斯
，前重量級拳王阿里等知名人士罹患巴
金森氏病
• 全美約有 100 萬人罹患此病，巴金森氏
病是一漸進性退化性的神經疾病，好發
於中老年齡的人，但超過 65 歲以後則驟
升，男女之比約為 5:4 。

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巴金森 氏病是身 體的什麼地 方
出了問 題 ?

• 是一種 慢性的中樞 神經系統失 調。

• 它的產 生是因為 腦內基底核 (basal
ganglia) 一種叫 黑核 (Substantia Nigra)
的腦細 胞退化死亡 , 而無法製造足夠
的多巴 胺 (Dopamine) 。
• 腦內需 要多 巴胺來指 揮肌肉 的活動 ；
缺乏足 夠的多巴胺 就產生各種 活動障
礙。
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 巴金森 症的 症狀
• 四肢的 顫抖 ，肌肉僵硬 ，及 動作緩慢
。
• 姿態傴 僂，表情僵 硬，步態拖 曳，行
動時手 臂僵在身體 的一邊，同 時 手指
活動困 難。

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其他症 狀
• 說話 : 小聲 , 缺乏抑揚頓挫 , 較不流利 .
• 平衡 : 變差 , 容易摔跤 .
• 肌肉疼 痛 : 肌肉僵硬導致的酸痛和抽筋
引起的疼痛 .
• 憂鬱症 及焦慮症 : 很常見 .
• 自律神 經系失調 : 便秘 , 排尿障礙 , 性
無能 , 起立性低血壓 , 昏厥等 .
• 失智症 : 有 20~30% 會有智能減退的現
象. 5
6
腦內多巴胺神經的通道
基底核

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 Parkinsonism

• In 1817, Dr. James Parkinson

• "shaking palsy (paralysis)"or "paralysis"
agitant.
• Parkinson's disease, parkinsonism or
parkinson's syndrome.

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 Parkinson's disease
• Involuntary tremulous motion, with
lessened muscular power, in parts not
in action and even when supported ;
• with a propensity to bend the trunk
forward, and to pass from a walking to
a running pace.
• the senses and the intellects being
uninjured.
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 Parkinson's disease
• Early symptoms of parkinsonism frequently
involve only one of three cardinal symptom or
rigidity, bradykinesia and tremor.
• Symptoms often are unilateral and almost
imperceptible at first and slowly progress in
severity
• Spread from one area of involvement such as
one finger, hand or shoulder to the whole
body.
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 Parkinson's disease

• While the concentration of

acetylcholine seems to be unchanged
in parkinsonism, the deficiency of
dopamine disturb this balance, and
cholinergic activity predominates.
• The primary defect in parkinson's
disease appears to be a state of
dopamine deficiency.
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Anticholinergics 是藉由維持 Dopamine
與 Ach 的平衡

• 投與 Anticholinergics 主要用在疾
病初期 , 改善顫抖 .
• Anticholinergics 不能解決
Dopamine 的問題

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The differential diagnosis of parkinsonism

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放大圖

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Clinical criteria for the diagnosis of
Parkinson’s disease (Hughes et al1992)

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巴金森 氏病 是什麼 引起 的 ?

• 遺傳
• 中毒及 自由基
• 感染

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 Etiology of Parkinson's disease
• Primary parkinsonism
Idiopathic parkinsonism
• Secondary parkinsonism
Trauma
Chemicals
Drugs
Post-encephalic parkinsonism
Infection
Tumor
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 Parkinsonism 巴金森症大致分三類

• Idiopathic Parkinsonism 原發性 / 典型的巴金森

症
佔 70-80﹪ 的病患 , 是原因不明的退化性腦
病,
依發病年齡 / 遺傳 / 症狀分為五型 :
1. 典型 PD: 約 41 歲後發病 , 佔 80 ﹪
2. 早發型 PD: 發病於 21-40 歲
3. 年青型 PD: 發病 21 歲以前
4. 家族型 PD: 有家族史 , 顯性遺傳
5. 路易體 PD: 退化的黑質腦細胞出現 Lew's 22
 Parkinsonism 巴金森症大致分三類
• Secondary Parkinsonism 次發性巴金森症
有病因 , 其顫抖通常不是典型的靜止性顫抖或
很早就出現癡呆或跌倒
1. 藥物誘發巴金森症 : 降血壓藥 , 抗精 神病的
藥物
2. 腦感染 : 病毒引起的腦炎 , 如 AIDS
3. 腦外傷 : 如拳擊家腦病 boxer's brain
4. 腦缺氧 : 心臟病發作 , 中風 , 休克 , 溺水 , 瓦
斯 (CO)
中毒等
5. 中樞神 經毒物 : 猛 / 汞 / 銅長期暴露 , 氯化物
中
毒 ,SO2 慢性中毒 , 長期酗 酒 23
 Parkinsonism 巴金森症大致分三類

• Symptomatic Parkinsonism
• 其它腦病伴隨的巴金森症狀 :
腦中風 , 腦瘤 , 癡呆症 , 水腦等

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 早發型巴金森氏病
• 臨床表現與典型 PD 有些不同 , 發病年齡較早
• 還包括 :
有家族史比例高
所有病人皆有肌肉僵 硬和動 作緩 慢
靜止性顫抖少見 , 如有顫抖其表現也非典型
可能出現肌緊張症 (dystonia)

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 早發型巴金森氏病
晝夜症狀變化比較明顯 ,
一般經過一夜睡眠 , 症狀會明顯改善
初期症狀往往從下肢開始
初期症狀通常兩側同時出現 , 但是一邊
比較嚴重
感覺症狀可能比運動症狀早出現 , 常抱
怨腿酸痛　
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Common causes of Parkinsonian
syndrome
• Heavy metal poisoning
• Anoxia (CO poisoning)
• Post-traumatic
• Cerebrovascular disease (multi-
infarct dementia)
• Alzheimer's disease

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 Chemical - induced
parkinsonism
• Acute CO
• Chronic exposure to heavy
metals: Lead, Manganese and
Mercury.
• Other chemicals : CS2 , CN － ,
CH3Cl, photographic dyes.

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 Drug produce
parkinsonism
• Dopamine receptor blocking
agents Phenothiazines, Butyrophenone,
Metoclopramide.
• Dopamine-depleting agents
Reserpine, Tetrabenazine
• Drugs act by other mechanism
• Methyldopa (block dopa decarboxylase)
Methylepinephrine (false neurotransmitter)
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Non-neuroleptic drugs associated with
drug-induced parkinsonism

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Drugs which may produce a Parkinson
-like syndrome

• Amitriptyline and other tricyclic antidepressants

• Carbamazepinc
• Chlorpromazine and other phenothiazines
• Chlorprothixene
• Haloperidol and other butyrophenones
• Reserpine
• Thiothixene

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Examples of phenothiazines that
produce extrapyramidal effects
Drug Relative degree
Trifluoroperazine High
Perphenazine High
Fluphenazine High
Prochlorperazine High
Promazine Moderate
Chlorpromazine Moderate
Thioridazine Low
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 巴金森氏症的臨床四大診斷症狀

• Tremor at rest
• Muscle Rigidity
• Bradykinesia
• Akinesia
• Postural instability

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 巴金森氏症之臨床症狀

• 顫抖 (Tremor): 先由一手開始 , 每當坐下

﹑躺下不動時 , 手指會自動抖起來 . 如果
動作一下 , 顫抖會消失。此種顫抖每秒四
至六次 , 相當規律 。
• 僵硬 (Rigidity): 患者的關節僵硬 , 手足被
扳動時 , 關節有如滑過齒輪 , 出現間接性
停頓 , 面部好像帶面具似的 , 缺乏表情及
笑容。
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 巴金森氏症之臨床症狀

• 動作緩慢 (Bradykinesia): 動作緩慢﹑笨

拙 , 尤其是起始動作困難 .
•坐在椅子上不容易站起來 , 扣鈕扣及繫
鞋帶都很困難 .
•字越寫越小 , 而且不清楚 .
•由於走路向前衝 , 步伐小 , 越走越快 , 不
易轉彎容易跌倒。

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 Fig

• Handwriting in Parkinson,s disease.The

size and roundness of the characters
decrease progressively across the page,
because of a breakdown of rapid alternating
movements.

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Hoehn & Yahr Staging

• Stage 1: Unilateral disease

• Stage 2: Mild bilateral disease; good balance.
• Stage 3: Mild/moderate bilateral; some postural
instability; still independent.
• Stage 4: Severe disability; Unable to function
independently.
• Stage 5: Wheel chair bound w/o assistance.

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巴金 森氏病 有那 些治療 方法
?

• 1. 藥物治療
• 2. 外科手術治療
• 3. 其他輔助性治療

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A summary of anatomical targets for the
treatment of Parkinson’s disease

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 Principles of drug therapy
• Reducing the functional excess of
acetylcholine with anticholinergic
agents.
• Alleviating the pathological deficiency
of dopamine with drug, that act on the
dopaminergic system.
• Augmenting the synthesis of brain
dopamin: Levodopa, madopar,
Sinement
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 Principles of drug therapy
• Directly stimulating dopamine receptor :
Bromocriptine, Apomorphine, other ergot
alkaloids.
• Stimulating endogenous dopamine release
and reducing the reuptake of dopamine by
presynaptic site : Amantadine
• Reducing dopamine catabolism : Deprenyl
[Selegiline (l-deprenyl, Eldepryl® or Anipryl ®]
•

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 PD 是一 個持續 、 進 行性病 程發 展 , 臨床 多著
重於 中期的 療效 與併發 症的 處理
中期
Wearing-off, 晚期 disabling
早期 dyskinesias, 有 25 ﹪ 病患
剛使用 L- Dystonias, On-off 會有失智症
dopa

Honeymoon Motor Cognitive decline period

period Complication
period
15 yrs
0 yr 5 yrs
onset 12yrs
20 % P't
Death
have history
40-45 % survival

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Advancing PD:
Motor Complications in Treated Pts

Wearing off
Early morning offs
Delayed on
No On
Random On-Offs
Freezing
L-dopa peak dose dyskinesia
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 Drug Treatment of Parkinsonism
• (1)
L-dopa
• (2)
Dopamine agonists: Bromocriptine
• (3)
MAO inhibitor
• (4)
COMT (Catechol-O-methyl
transferase) inhibitors
• (5) Amantadine
• (6) Anticholinergics

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 藥物的發展歷史
• 1867 Ordenstenin 首次用 belladonna 治巴金森
病
• 1929 Kleeman 用顛茄素 , 或稱 Atropine
• 1943 Corbin 使用抗乙醯膽鹼藥物 , Artane ®
• 1967 Cotzias 等人用大量口服 Dopamine 獲得良
好效果
• 1967 Birkmayer 和 Hornykiewecz 以左多巴
+DDC 抑制劑 , 使多巴劑量減低 , 減少多巴副作
用
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 藥物的發展歷史
• 1969 Schwab 用抗病毒藥 , Amantadine
• 1974 Calne 用多巴胺受體刺激劑 , Parlodel ®
• 1975 Birkmayer 和 Rieder 用 MAO-I, Deprenyl ;
MAOB-I, Selegiline. 同時 , 神經保護療法研究
熱潮開始
• 1998 COMT 抑制劑成功上市 , Comtan
• 外科處理方式目前仍不成熟

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 Mechanisms to Enhance Dopaminergic
Function Within the CNS

Drug Mechanism

Anticholinergic Decrease cholinergic function, thereby

increasing relative activity of
remaining dopamine

Amantadine Enhances dopamine synthesis and release

from presynaptic storage granules,and
decreases presynaptic re-uptake of
dopamine.
Levodopa Replaces dopamine,via conversion by dopa
decarboxylase within presynaptic
dopaminergic neurons
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 Mechanisms to Enhance
Dopaminergic
Function Within the CNS
Dopamine Stimulates 132 dopamine receptors
agonist directly,by passing the presynaptic
dopaminergic neurons
Selegiline Irreversibly inhibits oxidative
deamination of dopamine by
monoamine oxidase,typeD,thereby
increasing dopamine
concentrations.
COMT Inhibit L-dopa metabolism in peripheral
inhibitor neurons.

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 Dopamine 的合成與代謝途徑 ,
其中 Levodopa 變成 Dopamine 是速率決定步驟
L-Tyrosine
Tyrosine hydroxylase
COMT
3-OMD Other metabolic
L-dopa
routes
DDC DDC
Dihydroxiphenyl
MAO
3-methoxytyramine
Dopamine acetaldehyde
COMT
MAO HVA COMT
DOPAC
COMT=cathechol O-methyltransferase DDC= dopa decarboxylase
DOPAC=dihydroxyphenylacetic acid

HVA=homovanillic acid MAO=monoamine oxidase 3-OMD=3-O-methyldopa

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 Pathways of levodopa and dopamine
metabolism in the brain and periphery
L-tyrosine

Tyrosine hydroxylase

COMT
3-OMD Levodopa Other metabolic routes

DDC DDC

COMT MAO Dihydroxyphenyl-

3-methoxytyramine Dopamine
acetaldehyde

DOPAC

MAO COMT

HVA

Abbreviations: COMT = catechol-O-methyltransferase DDC = dopa decarboxylase

DOPAC = dihydroxyphenylacetic acid HVA = homovanillic acid
MAO = monoamine oxidase 3-OMD = 3-O-methyldopa
補充 Dopamine 的策 略 , 是目前 治療的
Gold standard

• L-dopa/DDC-I 依舊為 PD 的標準治療物

L-dopa 是 dopamine 的 precursor
L-dopa +DDC-I, 使多巴劑量減低 , 減
少多巴的副作用 .
但是 , 病患仍然容易漸漸失去對 L-dopa
的
反應 .
L-dopa 長期使用 , 會加速殘存細胞死亡
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補充 Dopamine 的策 略 , 是目前 治療的
Gold standard

• Polypharmacy to delay L-dopa or maximize L-

dopa effects
-Dopamine Agonists
-MAO-B inhibitors ( 減少 ? 代謝 )
-COMT inhibitors ( 減少 ? 在週邊的代謝 )
-Anticholinergics ( 維持 ? 與 ? 的平衡 )
-Amantadine ( 可能是促進 ? 釋放 / 回收 )

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L-dopa side effects
• Gastrointestinal: Nausea,Vomiting, Anorexia
• Cardiovascular: Cardiac arrhythmia, Sinus
tachycardia, Premature
ventricular contraction
• Central Nervous system:
Hallucination, depression, agitation
paranoia,delusion, loss of judgment

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 Dopa-decarboxylase inhibitors
• Carbidopa + L-dopa = Sinemet®
1 : 10 25mg/250mg
10mg/100mg
1 : 4 25mg/100mg
• Benserazide + L-dopa = Madopar®
1 : 4 25mg/100mg
50mg/200mg

Benserazide
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Dopaminergic Drugs
Drug name Trade name Initial dose Dosing Maximum
dose
increment
L-dopa Dopar 500mg-1g 100-750mg 8g

Carbidopa/ 1# tid I Qd or 2g
L-dopa Sinemet®
25mg/250mg or qid orqd
10mg/100mg
25mg/100rng
Benserazide/
Madopar ® 125mg bid 125mg qw 2g
L-dopa
25mg/100mg
50mg/200mg

Amantadine ® 100mg 200-

Symetrel 300mg/d
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Bromocriptine ® 5-10mg 5-10mg 150mg
Drug Holiday ( 藥物 假期 )
• 方法：↓住院 , 暫服原來劑量之 L-dopa
↓ 開始減半量 , 使用幾天
　　　　↓完全停藥 , ５－７天
　　　　↓恢復原本一半劑量
　　　　↓視需要緩慢增加劑量
　假期過後約三分之二的病人，只需要原來一半
藥量即有良好改善 .
　　　　
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Drug Holiday ( 藥物 假期 )
• 停藥期間 , 症狀轉為明顯 , 有的病人甚至
臥床動彈不得 . 皮下注射低劑量的
Heparin 可防止肺栓塞之危險 . 特別注意
其它 : 感染、褥瘡 , 吸入性肺炎
• 適用範圍：效果減弱 , on-off 現象 , 嚴重
的精神症狀出現時均可適用

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On-off Effect
• The treatment of the on-off effect :
more frequent administration of L-dopa,
the use of the L-dopa/carbidopa and the
substitution of a direct-acting dopamine
agonist : bromocriptine.

58
Dopamine Agonists

• Ergot-derived
– Bromocriptine Mesylate (Parlodel)
– Pergolide Mesylate (Celance)
• Non-ergot-derived
– Ropinirole (Requip)
– Pramipexole (Mirapex)

59
 ®
Bromocriptine (Parlodel )
• Bromocriptine (Parlodel) -a direct-acting
dopamine agonist
• Indications: amenorrhea/galactorrhea associated
with hyperprolactinemia, parkinsonism
• While L-dopa requires conversion in the brain to
its active form doapmine, bromocriptine acts
directly to stimulate intact postsynaptic receptors.

60
 ®
Bromocriptine (Parlodel )
• D2 agonist/partial D1 antagonist.
• Direct action on dopaminergic receptors in
the substantia nigra of the midbrain.
• Adjunctive treatment with L-dopa or as
monotherapy.
• Initial 1.25mg bid, increasing in 2.5mg/day
increments q2w to a usual dosage of 10-
40mg/day in 3 divided doses.
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 ®
Pergolide Mesylate (Celance )
• DI & D2 agonist
• Adjunct therapy with L-dopa.
• Long-term parkinsonian patients with clinical
fluctuations.
• Initia1,0.05mg/d for 2 days, increasing in 0.1-
0.15mg/d increment q3day for 12 days; then in
0.25mg/day increments q3day to a usual dosage of
1-4mg/day in 3 divided doses. Max dose:
5mg/day.
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 ®
Ropinirole (Requip )

• Selective D2 agonist
• Early Parkinson's disease: monotherapy and
in delaying the need for L-dopa therapy.
• Advanced parkinson's disease: controlling
motor fluctuations; having, a L-dopa
sparing effect.

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L-deprenyl

• L-deprenyl is a potent, well tolerated,

and safe inhibitor of MAO-B.
• 10 mg Qd.

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Amantadine
• The mechanism of action may inhibit the reuptake
of dopamine and other catecholamines from
neuronal storage sites.
• Side effects: slurred speech, ataxia, depression,
hyperexcitability, insomnia, dizziness, libido
reticularis and in extremely large dose,
convulsions and hallucinations.
• The usual dose is 100mg/day with breakfast for
the first week and then 100mg with breakfast and
lunch thereafter.

65
Catechol-O-Methyltransferase Inhibitors

• Tolcapone
100-200mg tds
May induce liver dysfunction
Monitor liver function closely
withdrawn already from marketing
• Entacapone (Comtan®)
200mg with each dose of L-dopa to max
200mg/day
66
 Effect of entacapone on disability
scores in MPTP-treated monkeys
14
Vehicle
12
Levodopa 2.5 mg/kg
Disability Scores

10 Levodopa 2.5 mg/kg +

Entacapone 12.5 mg/kg
8
6

4
Pretreatment with carbidopa 12.5 mg/kg p.o.
n=4
2

0
0 50 100 150 200
Time (min)

Smith et al. Mov Dis 1997; 12: 935-45.

Entacapone - Pharmacokinetics and
pharmacodynamics

• Rapidly absorbed: tmax = 45 minutes

• Elimination ~ 1 hour ( β-phase)

• Reversible COMT inhibition

• Selectively inhibits peripheral COMT

• 40% to 65% COMT inhibition in erythrocytes for 2

hours following 200 mg dose
Entacapone - Effect on
levodopa pharmacokinetics
• Increases levodopa t½ up to 75%

• Increases levodopa AUC up to 48%

• Cmax = unchanged

• tmax = unchanged
Entacapone - Efficacy with standard
levodopa preparations (1)
4
*
*

3
”ON” time (h)

0
Day 0 Day 1 Day 28

Mean (SE) “ON” time in parkinsonian patients receiving levodopa + dopa decarboxylase
inhibitor alone (day 0), after the first 200 mg dose of entacapone (day 1), and after 4 weeks
(day 28) of adjunctive treatment with entacapone (levodopa test) * p = 0.05

Ruottinen and Rinne. Clin Neuropharmacol 1996; 19: 222-33.

COMT-I
可以大大降低 L-dopa 在周邊被代謝掉 ,

使腦中 L-dopa 量增加 2-3 倍

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Comtan 的益處 ®

• 改善 L-dopa/DDCI 的巴金森病患 motor fluctuation 問

題
減少約 50% 的 L-dopa 血中濃度 peak-to-trough 波
動
增加“ ON” 時間 1.2 小時
減少“ OFF” 1.2 小時
• 改善 total motor function 整體運動功能﹑ QOL 生活品
質﹑ freezing 冰凍感
• 減少每日 L-dopa/DDCI 劑量約 25-30 %
• 改善病患的 compliance
• 服用簡單﹑方便﹑安全 72
Amantadine Dosing guidelines in renal
impairment
Clcr ml/min/1.73m2 Suggested
maintenance regimen
>80 100mg BID

60 200mg/100mg alternate days

50 100mg/day

40 100mg/day

30 200mg twice weekly

20 I 00mg thrice weekly

<10 200mg/100mg alternating Q7 days

a. Loading dose of 200mg recommended on the first day for Clcr<30ml/min

b. Includes patients maintained on thrice-weekly hemodialysis.

73
 Anticholinergic drugs

• Trihexyphenidyl hydrochloride
(Artane ®)
• Biperidene (Akineton ®)
• Benadryl
• Benzhexol
• Benztropine (Cogentin)
• Orphenadrine
• Procyclidine 74
 Anticholinergics Side Effect

• Blurred Vision • Mild

confusion
• Dry mouth •
Constipation
• Drowsiness • Urinary
retension

75
Drug therapies for parkinson's disease

• 1 . L-dopa preparations
(with peripherally acting DDCI)
A. L-dopa with benserazide(Madopar)
Ratio benserazide : L-dopa Madopar
12.5/50 62.5
25/100 125
50/200 250
Slow release 25/100 125

76
Drug therapies for parkinson's disease
B. L-dopa with carbidopa (Sinemet)
Ratio carbidopa: L-dopa Sinemet
10/100 110
25/250 275
12.5/50 Sinemet LS
25/100 Sinemet Plus
Slow release 50/200 Sinemet CR

77
Drug Therapies for Parkinson's Disease

• 2. Anticholinergic drugs
Benzhexol, Benztropine, Biperiden,
Orphenadrine, Procyclidine

• 3. Dopamine agonists
Bromocriptine, Lysuride, Pergolide,
Apomorphine

78
Drug Therapies for Parkinson's Disease

• 4 . Monoamine 0xidase type B inhibitor

Selegeline
• 5. Miscellaneous
Amantadine
• 6. COMTI
Entacapone

79
Common therapeutic problems
in Parkinson’s disease

80
Common therapeutic problems
in Parkinson’s disease

81
Parkinson therapy conclusion
• The parkinsonism patient must be
closely monitoring achieves
maximum benefit from drug
therapy.
• The complex combination of drugs
often used in these patient must
be frequent adjusted because they
have a high potential for adverse
reactions, drug-drug interactions. 82
Parkinson therapy
conclusion
• With proper therapy, the sign
and symptoms of parkinsonism
may be controlled for many
years and the life span of these
patients may approach that of
the general population.

83
•巴金 森症的 原因 到目前 尚未 確定， 而且 也
沒有治 癒的 方法。
•不過 ，過去 二、 三十年 在 藥品研 究上 有長
足的進 步， 目前有 許多 種藥物 可以 減輕症
狀。
•因為 每一位 患者 的症狀 和對藥物 的反 應不
盡相同 ，需 要神經 專科 醫生試 驗調 配最適
當的藥 品組 合來使 用。
•同 時，每 天適 當的運 動和 用藥同 樣地 重要。
大部分 的患 者如果 用藥 和運動 配合 恰當，
應當可 以享 受長期 、快 樂、而 且有 益的人 84
 藥物反應的相關詞彙
• 左多巴反應 (L-dopa Responsiveness)
• 劑末失效 (end-dose deterioration or
wearing off)
• 運動機能波動症 (Motor Fluctuations)
• 來電 (On)
• 斷電 (Off)
• 異動症 (Dyskinesia)
• 肌張力不全 (Dystonia)
• 神經心理副作用 (Neuropsychiatric Side
Effect) 85
“On-Off”
• Unpredictable transitions from “on” state to “off”
state.
• May last minutes to hours.
• Difficult to manage.
• Adjust Sinemet®, redistribute dietary proteins.
• Usually need help of experienced neurologist
or movement disorder specialist to tailor
therapy.
86
Freezing
• Unpredictable; can be frequent in advanced
disease.
• Not necessarily related to medications.
• May last minutes to hours.
• “My feet are stuck to the floor.”
• Management: Visual and physical cues.
Place line strips on kitchen floor.
Visualize a line in front to “step over.”
Laser pointer.
Caregiver assistance.
87
88
89
90
91
 case 1

• A 70-year-old man,Mr. X.,was diagnosed as

having mild Parkinson’s disease 6 months
ago.This did not require any treatment. He
returns with his wife starting that he is
“terrible” and cannot do what he wants to
do. Examination continues to confirm only
mild motor impairment.

92
 Questions 1

• 1. What additional problem would one

consider in this gentleman's case?
• 2. What therapeutic strategy (if any)
would you consider?

93
 Answers 1
• 1. Given the disparity between Mr. X.'s
reported disability and the observed
impairment, coexisting depression must be a
possibility.
• This is a major. and often unrecognized.
determinant of quality of life in Parkinson's
disease. Talking to his wife might clarify the
issue. supported by the administration to the
patient of a validated depression
questionnaire (e.g. the hospital anxiety and
depression scale or 15 item geriatric
depression scale). 94
 Answers 1
• 2. A simple explanation and/or referral to a
Parkinson's disease nurse specialist may
suffice.
• Alternatively. it might be necessary to
prescribe an antidepressant. A selective
serotonin re-uptake inhibitor (e.g. paroxetine
20 mg daily) would be a reasonable choice
for Mr X.

95
 Case 2

A 53-yr-old lady, Mrs Y., is referred by her

GP because of suspected Parkinson's
disease. This is bilateral and tremor-
dominant. She has a long history of
dyspepsia and reflux. Her father may
have had Parkinson's disease, and she
is worried that she has the same
disease.
96
 Questions 2

• 1.Which question might give

additional diagnostic help in this
lady's social history?
• 2.What features should one
look for in the drug history?

97
 Answers 2
• 1. A history of tremor that is alcohol-
responsive. coupled with a possible positive
family history, should always raise the
possibility of essential tremor as the correct
diagnosis,rather than Parkinson's disease.
In fact, Mrs Y.'s tremor was not alcohol-
responsive, and she had bradykinesia on
neurological examination.

98
 Answers 2
• 2. Given this patient's history of reflux and
dyspepsia. the use of dopamine receptor
blocking agents. such as metoclopramide,
might be relevant.
• Mrs Y. had been taking this drug for nearly
12 months. Drug-induced parkinsonism was
therefore suspected, and when reviewed 3
months after stopping the metoclopramide,
her symptoms and signs had resolved.
99
 Case 3
• Mr Z. has a 6-yr history of Parkinson‘s
disease. He is 75 yrs old. His motor
symptoms are well controlled on a
combination of one tablet of co-careldopa
(25/100), three times a day and selegiline 10
mg daily. His wife comes to clinic with him
and reports that he has recently been
confused at night. Furthermore, he has been
hallucinating, seeing gnomes 小鬼 at the
bottom of the garden. She is very frightened.

100
 Question 3

• What should be done?

101
 Answer 3

• The problem here is to what extent the

features of Mr Z.'s psychosis relate to
his drugs, or to the underlying disease
process.
• Dementia associated with Parkinson's
disease is more common in the older
patient with longstanding disease.

102
• A mini-mental state examination to
assess cognitive function in more detail
would be appropriate.
• Intercurrent infection should also be
excluded.

103
• Selegiline is best avoided in cases like
this and should be discontinued. This
may lead to an improvement in Mr Z.'s
psychotic features, without any other
action being necessary. The use of an
antipsychotic agent in Mr Z. is
absolutely contraindicated. as it will only
serve to worsen his Parkinson,s disease
104
Therapy: What is the Chief Complaint?

• Predominant Symptom Clinical Options

• No functional impairment Watch and wait; Neuroprotection
(?)
• Mild symptoms Amantadine, MAO-B inhibitor
• Mild-moderate sxs Dopamine agonist, levodopa
• Discrete symptoms Tremor—antimuscarinic
Dyskinesias – amantadine
• Motor fluctuations Entacapone, apomorphine

105
Parkinson’s - Pharmacotherapy

Adjunctive
• Anticholinergics.
• Amantadine.
• Selegiline
• (Rasagiline)

106
Levodopa-induced Dyskinesias
• Dyskinesias: abnormal, involuntary writhing
movements (arms, legs, trunk, neck, mouth).
• Associated with peak L-dopa levels.
• Occurs about 60-90 minutes after dose (at “peak”
CNS levels).
• Indication that Sinemet® dosage needs to be
lowered.
• Usually mild but can progress over time to be
very severe and disabling: Younger pts at > risk.

107
Management of Peak-dose
Dyskinesias

• Eliminate adjunctive dopamimetic agents

-(e.g. selegiline)
• Reduce individual L-dopa dose.
-May need supplemental dopamine agonist.
• Add amantadine.
• Beware switch to controlled-release levodopa
• Surgery.

108
 Medications Used for the
Treatment of Parkinson's
Disease Table 53-3

• Amantadine (Symmetrel)
• Anticholinergic Agents: Benztropine
(Cogentin) Procyclidine (Kemadrin)
Trihexyphenidyl (Artane)
• Antihistamines : Diphenhydramine (Benadryl)
Orphenadrine (Norflex)
• Dopamine Replacement: Carbidopa/L-dopa
(Regular) (Sinemet), Carbidopa/L-dopa (CR)
(Sinemet CR)
109
•Dosage Unit
•Titration Schedule
•Usual Daily Dose
•Adverse Effects

110
 Service Organizations for
Patients with Parkinson's Disease
Table 53-1

• American Parkinson Disease Association, Inc. 1250 H\ Ian Boulevard.

Suite 4B Staten Island. NY 10305 1-800-223-2732
• http://www.apdaparkinson.com
• National Parkinson Foundation. Inc.
• 1501 NW Ninth Avenue NW. Bob Hope Road Miami. FL 33136-1494
• 1-800-327-4545 http://www.parkinson.org
• The Parkinson's Disease Foundation William Black Medical Building
710 West 158 Street New York, NY 10032 1-800-457-6676
http://www.pdf.org
• Parkinson's Action Network 300 North Lee Street Alexandria. VA
22314 1-800-850-4726 http://www.parkinsonaction.org
• WE MOVE 204 West 84th Street New York. NY 10024 1-800-437-
6682 http://www.wernove.org

111