Movement disorders disease

Baorong Zhang M.D.Baorong Zhang M.D. Professor and ChairProfessor and Chair ZJU Department of NeurologyZJU Department of Neurology and ZJU Brain Center and ZJU Brain Center (email: brzhang@zju.edu.cn)(email: brzhang@zju.edu.cn)

Definition

Movement disorder disease is induced by basal ganglia damage with different kind causes, such as : toxin, degeneration, infalmanntary, infarction , genetics, ect.

It comprise a spectrum of abnormalities that range from the hypokinetic disorders (of which Parkinson's disease is the best-known example) at one extreme to the hyperkinetic disorders (exemplified by Huntington's disease and hemiballismus) at the other.

Major Diseases of the Basal Ganglia

Parkinson’s diseaseHuntington’s diseaseWilson diseaseMultiple system atrophy: SND,OPCA,SDSDystonia Restless Leg SyndromePsychiatric diseases (OCD)

Tremor definition

Tremor: Video. PD.avia rhythmic oscillatory movementbest characterized byits relationship to voluntary motor

activity

Tremor classification

Intension: cerebellar rest : PD(4-6 Hz)..PDbrother 012.mpgaction: Essential and cerebellar postural: metabolism(8-12 Hz)

Chorea and Tic

Chorea: denotes rapid irregular muscle jerks

that occur involuntarily and unpredictably in

different parts of the body(Video:)HD-

chorea.MPG Tic: Sudden,repetitive,stereotyped,purposeless

brief actions,gestures,sounds and words that emerge from a background of

normal motor activity.

Spasticity and Myoclonus

Spasticity: continue clonic contraction,

upper motor neuron( hereditary spastic

paraplegia,HSP) Myoclonus: a single sudden jerk or a short

series occurring in slow : CJD(Creutzfeldt-

Jakob disease(Prion disease), AIDS

dementia complex

Athetosis and Dystonia

Athetosis : in contrast to chorei form movementsthese are slowerwriting,resembling the actions like a worm or snake

Dystonia

Dystoniasustained muscle contractionsoften causing twisting movements or abnormal postures

Parkinson’s diseas

General consideration Causes Pathogenesis Clinical findings Different diagnosis treatment

James Parkinson 1817

“ 帕金森病”的由来 --- 伦敦医生 Parkinson

History of Parkinson´s disease (PD)History of Parkinson´s disease (PD)

First described in 1817 by an English physician, First described in 1817 by an English physician, James Parkinson, in “An Essay on the Shaking James Parkinson, in “An Essay on the Shaking Palsy.”Palsy.”

The famous French neurologist, Charcot, further The famous French neurologist, Charcot, further described the syndrome in the late 1800s.described the syndrome in the late 1800s.

The stone of parkinson’s diseaseJame parkinson’s foundingBiochemistry foundingMPTPMutaion of Gene

帕金森病概况

全球约 400 万帕金森病患者 一般在 55 岁以上的人群中患病率在 1% 以上 65 岁以上的老人中患病率高到 2% 。 近期的一项调查显示中国 65 岁以上人群 PD 患病率

接近 1.7 ％，与西方国家接近 (Zhang ZX etal) 因此在中国大陆至少有约 200 万 PD 患者，远远超

过欧美主要国家 PD 患者人数的总和

Zhang ZX ， Roman GC ， Hong Z ， et a1 ． Parkinson’ S disease in China ：prevalence in Beijing ， Xian ， and Shanghai ． Lancet ， 2005 ， 365 ： 595-597

Epidemiology of PDEpidemiology of PD

The most common movement disorder The most common movement disorder affecting 1-2 % of the general affecting 1-2 % of the general population over the age of 65 years.population over the age of 65 years.

The second most common The second most common neurodegenerative disorder after neurodegenerative disorder after Alzheimer´s disease (AD).Alzheimer´s disease (AD).

Incidence of PD

World Health Organization estimates for incidence

and prevalence follow:

wemen: 4.9/100,000

men: 5.8/100,000

0-19 years: 0.0/100,000

20-64 years: 3.9/100,000

65 years and over: 49.3/100,000

Prevalence of PD

wemen: 6/100,000 wemen: 6/100,000

men: 8/100,000 men: 8/100,000

0-19 years: 0/100,000 0-19 years: 0/100,000

20-64 years: 6/100,000 20-64 years: 6/100,000

65 years and over: 70/100,00065 years and over: 70/100,000

There’s about 200,000 PD patient in China.There’s about 200,000 PD patient in China.

May be less prevalent in China and other Asian countries, and in African-Americans.

Prevalence rates in men are slightly higher than in women; reason unknown, though a role for estrogen has been debated.

Causes

GeneticsAgeSexEnvironmental Toxin Injury InfectionVascular

Primary PD(75%):idiopathic Parkinson's disease

1.5 men/women ratio

Main risk factor : age

Young onset: before 50 y.o.

Rare familiar forms: genetic clues

Idiopathic causes:

Genes involved in familial PD

PARK 1-81. Park1: alpha-synuclein dominant: mutation

2. Park2: Parkin, mainly recessive;

3. Park3 (Chr 2p13 dominant) [1998]4. Park4: alpha-synuclein dominant: gene duplication5. Park5: UCHL1, possibly dominant) 6. Park6: PINK1, recessive7. Park7 (Chr 1p33-p34; recessive)8. Park8: LRKK2-dardarin

More genes?

Case-control study of pesticides in Taiwan*

Exposure variable

Years used

Cases Controls

OR+

Herbicides/pesticides

01-19>20

741432

1992120

1.01.54.5

Paraquat

01-19>20

89724

218139

1.01.26.4

+ Odds ratio, adjusted for age, gender, smoking

*Liou HH, et al. Neurology 1997;48:1583-8

Second Parkinson’s disease causes

Secondary PD (25%):

Vascular disease

Infectious and postinfectious

Postencephalitic

Neurosyphilis

AIDS

Secondary causes

Toxins:Manganese ,Cyanide

Methanol ,Carbon ,monoxide MPTP,Pesticides Medications:Neuroleptics

, Dopamine-depleting agentsCalcium-channel blockers Valproic acidFluoxetine

Rare causes

Hypoparathyroidism with basal Hypoparathyroidism with basal

ganglia calcification , ganglia calcification ,

Hypothyroidism and hyperthyroidismHypothyroidism and hyperthyroidism

Miscellaneous:Miscellaneous:

Repeat trauma (notably from boxing)Repeat trauma (notably from boxing)

Structural lesions: Structural lesions:

Tumors ,Infarctions ,HydrocephalusTumors ,Infarctions ,Hydrocephalus

Neuropathology of PDNeuropathology of PD

Eosinophilic, round intracytoplasmic inclusions Eosinophilic, round intracytoplasmic inclusions called lewy bodies and Lewy neurites.called lewy bodies and Lewy neurites.

First described in 1912 by a German First described in 1912 by a German neuropathologist - Friedrich Lewy.neuropathologist - Friedrich Lewy.

Inclusions particularly numerous in the substantia Inclusions particularly numerous in the substantia

nigra pars compactanigra pars compacta..

Functional neuroanatomy of PDFunctional neuroanatomy of PD

Substantia nigra: The major origin of the dopaminergic Substantia nigra: The major origin of the dopaminergic innervation of the striatum.innervation of the striatum.

Part of extrapyramidal system which processes Part of extrapyramidal system which processes information coming from the cortex to the striatum, information coming from the cortex to the striatum, returning it back to the cortex through the thalamus.returning it back to the cortex through the thalamus.

One major function of the striatum is the regulation of One major function of the striatum is the regulation of posture and muscle tone.posture and muscle tone.

Neuropathology of PD: Lewy bodiesNeuropathology of PD: Lewy bodies

Not limited to substantia nigra only; Not limited to substantia nigra only; also found in the motor nucleus of the vagus nerve,also found in the motor nucleus of the vagus nerve,

the hypothalamus, the nucleus basalis of Meynertthe hypothalamus, the nucleus basalis of Meynert

the cerebral cortex, the olfactory bulb and the autonomic the cerebral cortex, the olfactory bulb and the autonomic nervous system.nervous system.

Confined largely to neurons; glial cells only rarely affected.Confined largely to neurons; glial cells only rarely affected.

Diagnosis of PD Diagnosis of PD

Clinical examination Clinical examination No disease-specific biological marker No disease-specific biological marker

available available Positron Emission Tomography (PET) or Positron Emission Tomography (PET) or

Single-photon Emission Computed Single-photon Emission Computed Tomography (SPECT) with dopaminergic Tomography (SPECT) with dopaminergic radioligands radioligands

Exclusion of several causes of secondary Exclusion of several causes of secondary ParkinsonismParkinsonism

Parkinson’s disease clinical findings

Primary symptoms:

Resting tremorRigidityBradykinesiaGait disturbance

Chronic, progressive neurodegenerative disease

Illustration of Parkinson's disease

Main signs for PD

Motor signs

Non-motor signs

Motor signs

TremorAkinesiaRigiditylose of postural reflexesReduced arm swing

Motor signs

Masked facesStrooped Posture / Shuffling GaitLow Speech Volume (Hypomimia)Micrographia(Small Handwriting)Postural Instabilty(Ususally Late)

Non-motor signs

Orthostatic HypotensionHyposomiaUrinary IncontinenceSleep Behaviour DisorderDementia (Late)- In 40-80% at some

stage of PD

Non-motor signs

depressionconstipation PainDementiaSlowed ThinkungAnxiety / Pain attacksRBD

Classification of motor complicationDyskinesiaDYSKINEIA1.MPG

Peak dyskinesia

Biphasic dyskinesia

dystonia

Motor-fluctuation

Wearing off phenomina

On-off phynomena

0n-delay

Two type-Dyskinesia-Video

Motor dyskineia(confortable)peak dyskinesia2.MPG

PD-Motor and non-motor.avi(unconfortable)

Motor fluctuation

Completely off: Severe PD-OFF 031.avi

ON time decreased

OFF time increase: 翁采琴 129.avi

On delay

EEvaluated by interview and clinical assessment in the following categories:valuated by interview and clinical assessment in the following categories:

Mentation, behavior, and mood Mentation, behavior, and mood

Activities of daily living Activities of daily living

Motor Motor

Complications of therapy Complications of therapy

Hoehn-Yahr Stage Hoehn-Yahr Stage

Schwab and England Activities of Daily Living ScaleSchwab and England Activities of Daily Living Scale

The Unified Parkinson's Disease Rating Scale The Unified Parkinson's Disease Rating Scale

(UPDRS)(UPDRS)

鉴别诊断

为了鉴别血管源性帕金森综合征（ Vascular Parkinsonism,VP ）

尚无统一的诊断标准，曾经命名：arteriosclerotic parkinsonism, arteriosclerotic pseudo-parkinsonism lower-body parkinsonism

在 100 例临床诊断 PD 中，病理证实 3 例系腔隙性脑梗引发的 VP, 无路易小体（ Hughes, 1992 ）

VP 的临床特点： 下肢受累为主（步态不稳、易跌倒） 容易合并痴呆 常为对称性强直 震颤少见 多数多巴制剂等治疗效果不显著 MR: 基底节区慢性缺血灶。急性缺血引发的 VP 罕见

鉴别诊断 经典的神经阻滞剂

氟哌啶醇

奋乃静、维思通等动眼危象 .wmv

氯丙嗪

舒必利

钙离子拮抗剂：西比灵

利血平

… …

起病前过去的 6 个月内使用过下列药物

鉴别诊断 - 脑炎

流行性甲型脑炎（昏睡性脑炎， Encephalitis lethargica ）

因为舌蝇传播的一种昏睡性脑炎， 1915-1926 年大流行

临床表现为：高热、咽喉红肿、头痛、昏睡、眼球运动障碍、帕金森症候群。

鉴别诊断 - 多系统萎缩（ MSA ）

以帕金森症候群为主要表现的称为 MSA-P（占 80% ）以小脑症状为主要表现的称为 MSA-C （占20% ）

鉴别诊断

  进行性核上性麻痹 原发性帕金森病

临床表现对称性 对称 起病不对称步态障碍 ,跌倒 病程早期即出现 病程早期极少出现眼球上、下视 不能 能姿位反射 早期出现损害 正常躯干姿位 呈伸展位 行走时呈屈曲位行走时摆臂动作 可有 病程早期行走时即无面容 惊恐面容 面部表情减少眨眼 3-5 次 /分钟 10-14 次 /分钟静止性震颤 不常见 常见肌张力障碍和强直的部位 更多出现在躯干 更多出现在肢体手部变形 无 有特征性的手部变形对左旋多巴的反应 无或差 好左旋多巴诱导的异动症 极少 经常“剂末”、“开关”现象 不常见 常见

原发性帕金森病与进行性核上性麻痹的鉴别

鉴别诊断PSP 临床诊断 ..psp2.MPG 标准 (NINDS-SPSP)

鉴别诊断 - 皮层底节变性

临床特点 皮层症状：失用、皮层感觉缺失、异己手等 锥体外系症状：不自主运动、帕金森综合征、肌张力障碍等

影像特点（磁共振 FLAIR相） 非对称性皮质萎缩，中央区皮质下白质高信号 非对称性大脑脚萎缩，中脑被盖萎缩

Case 女 , 62Y, Feeling change and no

emotion one yearSpeeche slowCognitive declineMMSE 为 17 分（ Parimary school

education ）Modopar test ：After UPDRS motor score is the same

as before 40

Video 1 2 3

The Challenge of PD Treatment

Early treatment:Hypotentionnause,vomitingHallucinationPrecaution:individual dosage,little

by little

The challenge of PD treatment: Late stage

Dyskinesias Motor fluctuation Depression Insomia Pain Dementia Constipation

Treatment

Parkinson's disease is a chronic disorder that requires broad-based management including patient and family education,

support group services general wellness maintenance

physiotherapy, exercise, and nutrition.

Medications or surgery can just provide relief from the symptoms.

I. increase dopamine synthesis capacityII. direct activate post-synaptic receptorsIII. inhibit dopamine metabolismIV. alter the interaction/balance with other

neurotransmitters V. dopamine releasersVI. L-DOPA peripheral metabolism inhibitors

What is the desired goal of pharmacological What is the desired goal of pharmacological therapies for Parkinson’s disease?therapies for Parkinson’s disease?

- Produce more output from the striatal dopamine neurons

DRUG THERAPYReview

• Main Line Agents:• L-DOPA plus carbidopa (Sinemet®)• dopamine receptor agonists (ropinirole, pramipexole )• MAO B Inhibitors (rasagiline , selegiline)

•Lower Efficacy/Second Line or Adjuvant Agents:

anticholinergics (benztropine, trihexyphenidol)• DA reuptake Inhibitor (amantadine)• COMT Inhibitor (entacapone)

The dopamine-agonists bromocriptine, pergolide, pramipexole, ropinirole , cabergoline, apomorphine, and lisuride, are moderately effective.

Dopamine agonists initially act by stimulating some of the dopamine receptors.

Dopamine agonists can be useful for patients experiencing on-off fluctuations and dyskinesias as a result of high doses of L-dopa.

Dopamine Agonists

多巴胺受体的相关名称

D1 家族

受体亚型D1 D5

D2 家族

受体亚型D2 D3 D4

D1, D2 subcorticalD3, D4, D5 cortical

1st generation agonists (ergot derivatives*)

bromocriptine (D2 agonist)

pergolide (D2/D3 agonist)

2nd generation agonists: (non-ergot)

ropinirole (D2/D3 agonist)

pramipexole (D2 agonist)rotigotine (D3/D2/D1 agonist)

Other Dopamine Agonists

short-acting non-ergoline agonist

apomorphine( D1 and D2 receptors )

Other Dopamine Agonists

short-acting non-ergoline agonist

apomorphine( D1 and D2 receptors )

MAO-B inhibitor: SelegilineRasagilineCOMT inhibitor:entacapone

Amantadine block DA reuptake,glutamate receptors

A2A antiagonist: clinical trial

总 结

帕金森病运动并发症是帕金森病重要症状，应该早期诊断、早期治疗

早期帕金森病起始治疗推荐使用非麦角类多巴胺受体激动剂，以推迟左旋多巴使用，延迟运动并发症的发生

Historical Aspects

1872: Meigs and Mason Academy of Medicine adult-onset progression tendency to insanity and

suicide inheritance pattern. Hereditary Chorea.

George Huntington

• “I have drawn your attention to this form of chorea gentlemen, not that I considered it of any great practical importance to you, but merely as a medical curiosity, and as such it may have some interest.”

Huntington Disease: Historical Aspects

“ Over fifty years ago, in riding with my father on his professional rounds, I saw my first cases of ‘that disorder’, which was the way in which the natives always referred to the dreaded disease….we suddenly came upon two women, mother and daughter, both tall, thin, almost cadaverous, both bowing, twisting, grimacing…my medical education had its inception. From this point on my interest in the disease has never wholly ceased.”

First described by George Huntington in 1872 in families in East Hampton, Long Island

Huntington Chorea

Huntington disease,HD ： is transmitted as autosomal

dominant trait With complete penetrance.Both

sexes are equally affected.

VIEDO- HDfamily1.avi1 HD2.MPG

Genetics characteristics ：Gusella etal (cell,1993) identified the

gene_IT15,

IT15 with exon 67:

IT15 gene code:PloyQ(Huntingtin, Htt ） :

HD in Venezuela 1972-Centennial

Ramon Avila-Giron El Mal de San Vito 165 families

studied in 4 towns Of the 1352

people, 28 had HD 203 people in

those families had died with HD

A sailor (A.D.) involved in dividivi trade with Germany probably introduced HD in this region between 1860 and 1870

Juvenile-onset HD

Dystonia and parkinsonism predominate

Seizures Typically paternal inheritance due to

anticipation; expansion of CAG repeat Faster progression (duration 5-15

years)

Venezuela Collaborative Huntington’s Disease Project

1979- First American expedition to Maracaibo led by Dr. Nancy Wexler

1981- First of annual trips to the region

1983- Discovery of the HD gene marker on chromosome 4

1993- Identification of IT-15

Psychiatric•Depression•Anxiety•OCD•Psychosis

Motor•Eye movements•Chorea•Dystonia•Gait and balance•Dysarthria and dysphagia•ParkinsonismCognitive

•Frontal-Executive•Attention•Planning

•Memory•Visuospatial

Effective Targets for Therapy Based on Mouse Preclinical Studies

ExcitotoxicityMitochondrial

dysfunction

Aggregatetoxicity

Transcriptional dysregulation

Proteasomal andlysosomal

dysfunction

Caspase-mediated cell death

Remacemide,Riluzole

CoQ10, Creatine, BN 82451

Ethyl-EPA, lipoic acid

HDAC Inhibitors: SAHA, sodium butyrate

TransglutaminaseInhibitors: CystaminePolyQ aggregation inh:

Congo red

Caspase Inhibition: Minocycline

GeneticsIntrabodies,

siRNA

Heptaolenticular degeneration,or Wilson disease

Wilson (1912) describe: is a degeneration induced by Cu metabolism disorder with liver cirrhosis and basal ganglia dysfunction

Autosomal genetics Genetics mapping 13q14-21Ceruloplasmin decreasedPathology: deposit in Brain ,liver,

kidney and corneal,

Clinical manifestation

Age; 4-50 YBasal ganglia symptomsPsychological symptoms: no

motivation, intelligence decline personality change

Liver dysfunctionK-F ringKidney function failureSkin color changeBone degeneration: fracture

Diagnosis

1.Ceruloplasmin reduced (200mg/L)2.K-F ring3.MRI4.X ray in Bone5.Blood cu decrease and urine cu

increase in 24h

Treatment

Principle:

lower cu food, lessen cu absorbed

increased cu export

symtomatic treatment

Zinc sulfate:50-150mg/d,tid or qid

D-penicillamine ： 1-1.5g/d 20mg/d for childTraditional Chinese medicineLiver transplantation

治疗

原则：低铜饮食、减少铜吸收、增加铜排出和症状治疗

饮食：避免高铜饮食：豆类；坚果类（花生、胡桃；蔬菜（菠菜、茄子、葱）；瓜果类如南瓜；薯类（芋头、山药）；蕈类（香菇及其他菇类）、软体动物（乌贼、鱿鱼、牡蛎）、贝类（蛤蜊、蛏子、淡菜、河蚌）、螺类、虾蟹类、腊肉、动物的肝和血、巧克力、可可、咖啡、蜜糖、中药的龙骨、牡蛎、蜈蚣、全蝎等。此外，含铜量较高的食物还有牛肉、各种干果等。勿用铜制的食具及用具。

适宜日常摄食的含铜量低的食物：如精白米、精面、鸡蛋、鱼、猪肉、瘦鸡鸭、小白菜、藕、芹菜、橘子、苹果、桃子、牛奶等。

（ 3 ）高氨基酸或高蛋白饮食，有利于铜的排泄 3 。阻止肠道铜的吸收 锌剂 : 50-150mg/d,tid or qid

青霉安： 1-1.5g/d 20mg/d for child

Thank for

your attention ！