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Parkinson's disease

• 巴金森氏症 9606011

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• 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 gangl

ia) 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 .

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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 body

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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

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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-inf

arct 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 agentsReserpine, Tetrabenazine

• Drugs act by other mechanism • Methyldopa (block dopa decarboxylase) Me

thylepinephrine (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 acet

ylcholine 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

Honeymoon period

Motor Complication period

Cognitive decline period

0 yr

onset

早期剛使用 L-dopa

5 yrs

20 % P't have history

中期 Wearing-off, dyskinesias, Dystonias, On-off

12yrs

15 yrs

晚期 disabling

有 25 ﹪ 病患會有失智症

Death

40-45 % survival

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Advancing PD:Motor Complications in Treated Pts

Wearing offEarly morning offs

Delayed onNo OnRandom 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 DopaminergicFunction 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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Dopamine agonist

Stimulates 132 dopamine receptors

directly,by passing the presynaptic dopaminergic neurons

Selegiline Irreversibly inhibits oxidative deamination of dopamine by monoamine oxidase,typeD,thereby increasing dopamine concentrations.

COMT inhibitor

Inhibit L-dopa metabolism in peripheral neurons.

Mechanisms to Enhance DopaminergicFunction Within the CNS

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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

3-OMD

COMT=cathechol O-methyltransferase DDC= dopa decarboxylase

DOPAC=dihydroxyphenylacetic acid

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

L-dopa

L-Tyrosine

Tyrosine hydroxylase

3-methoxytyramine Dopamine

Dihydroxiphenyl acetaldehyde

HVADOPAC

COMT

MAO

COMT

DDC

COMT

MAO

Other metabolic routes

DDC

Pathways of levodopa and dopamine metabolism in the brain and periphery

Abbreviations: COMT = catechol-O-methyltransferase DDC = dopa decarboxylase DOPAC = dihydroxyphenylacetic acid HVA = homovanillic acid MAO = monoamine oxidase 3-OMD = 3-O-methyldopa

Other metabolic routes

DDC

MAO

Tyrosine hydroxylase

MAOCOMT

COMT

DDC

COMT3-OMD

3-methoxytyramine

L-tyrosine

DOPAC

Dihydroxyphenyl-

HVA

Dopamine

Levodopa

acetaldehyde

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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 DrugsDrug name Trade name Initial dose Dosing

increment

Maximum dose

L-dopa Dopar 500mg-1g 100-750mg 8 g

Carbidopa/ L-dopa25mg/250mg

10mg/100mg 25mg/100rng

Sinemet® 1# tid

or qid

I Qd or

orqd

2g

Benserazide/ L-dopa

25mg/100mg 50mg/200mg

Madopar ® 125mg bid 125mg qw 2 g

Amantadine Symetrel ® 100mg 200-

300mg/d

Bromocriptine Parlodel ® 5-10mg 5-10mg 150mg

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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.

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Dopamine Agonists

• Ergot-derived

– Bromocriptine Mesylate (Parlodel)

– Pergolide Mesylate (Celance)

• Non-ergot-derived

– Ropinirole (Requip)

– Pramipexole (Mirapex)

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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.

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Bromocriptine (Parlodel ®)

• D2 agonist/partial D1 antagonist.• Direct action on dopaminergic receptors in t

he substantia nigra of the midbrain.• Adjunctive treatment with L-dopa or as mo

notherapy.• 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 fluct

uations.• Initia1,0.05mg/d for 2 days, increasing in 0.1-0.15

mg/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 neuro

nal storage sites.• Side effects: slurred speech, ataxia, depression, hy

perexcitability, 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.

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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

Effect of entacapone on disabilityscores in MPTP-treated monkeys

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

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

0

2

4

6

8

10

12

14

0 50 100 150 200

Time (min)

Dis

abili

ty S

core

s

Vehicle

Levodopa 2.5 mg/kg

Levodopa 2.5 mg/kg + Entacapone 12.5 mg/kg

Entacapone - Pharmacokinetics and pharmacodynamics

• Rapidly absorbed: tmax = 45 minutes

• Elimination ~ 1 hour ( -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)

*

0

1

2

3

4

Day 0 Day 1 Day 28

”ON

” t

ime

(h)

*

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.

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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

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Amantadine Dosing guidelines in renal impairmentClcr 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.

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Anticholinergic drugs

• Trihexyphenidyl hydrochloride (Artane ®)• Biperidene (Akineton ®)• Benadryl• Benzhexol• Benztropine (Cogentin)• Orphenadrine• Procyclidine

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Anticholinergics Side Effect

• Blurred Vision • Mild confusion

• Dry mouth • Constipation

• Drowsiness • Urinary retension

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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

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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

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Drug Therapies for Parkinson's Disease

• 2. Anticholinergic drugs

Benzhexol, Benztropine, Biperiden,

Orphenadrine, Procyclidine

• 3. Dopamine agonists

Bromocriptine, Lysuride, Pergolide,

Apomorphine

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Drug Therapies for Parkinson's Disease

• 4 . Monoamine 0xidase type B inhibitor

Selegeline

• 5. Miscellaneous

Amantadine

• 6. COMTI

Entacapone

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Common therapeutic problems in Parkinson’s disease

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Common therapeutic problems in Parkinson’s disease

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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.

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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.

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• 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、而且有益的人生。

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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)

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“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.

87

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.

88

89

90

91

92

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.

93

Questions 1

• 1. What additional problem would one consider in this gentleman's case?

• 2. What therapeutic strategy (if any) would you consider?

94

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).

95

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.

96

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.

97

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?

98

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.

99

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.

100

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.

101

Question 3

• What should be done?

102

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.

103

• A mini-mental state examination to assess cognitive function in more detail would be appropriate.

• Intercurrent infection should also be excluded.

104

• 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

105

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

106

Parkinson’s - Pharmacotherapy

Adjunctive

• Anticholinergics.

• Amantadine.

• Selegiline

• (Rasagiline)

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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.

108

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.

109

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

• Amantadine (Symmetrel) • Anticholinergic Agents: Benztropine (Cogenti

n) Procyclidine (Kemadrin) Trihexyphenidyl (Artane)

• Antihistamines : Diphenhydramine (Benadryl) Orphenadrine (Norflex)

• Dopamine Replacement: Carbidopa/L-dopa (Regular) (Sinemet), Carbidopa/L-dopa (CR) (Sinemet C

R)

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• Dosage Unit • Titration Schedule • Usual Daily Dose • Adverse Effects

111

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