movement disorders and extrapyramidal system

Movement Disorders and Extrapyramidal System

Sibel Ertan, MDDept. of Neurology

Definition Neurologic syndromes in which there is either an excess of movement, or a paucity of voluntary and automatic movements unrelated to weakness or

spasticity.

Most movement disorders are associated with pathologic alterations in the

basal ganglia or their connections.

But disorders of the• Cerebellum or its pathways• Cerebral cortex• Thalamus• Brain stem• Spinal cord• Peripheral nerves may also cause several movementdisorders.

PutamenThalamus

STNSNr

GPiGPe

Caudate

SNc

Basal Ganglia

BBasal ganglia subcortical nuclei:caudate, putamen & globus pallidus are named corpus striatum Caudate &putamen are named striatum globus pallidus & putamen are named lentiform nuclei

caudate putame

nglobus pallidus

Definition

The term extrapyramidal system, coined by British neurologist Kinnier Wilson, refers to the basal ganglia and an array of brain stem nuclei (red nucleus, reticular formation etc.)

to which they are connected.

Striatum (caudate+putamen) is the principle receptive structure of the basal

ganglia.

Globus pallidus is the principle output structure of the basal ganglia.

STRİATUM

SEREBRAL KORTEKS

Glu

D1P Mad.

D2ENK.

AK

SS

GABA

Glu

GPi/SNpr

GABA

SNpc

M. SpinalisVe

Beyin Sapına

GABA

Glu

DA

GPe

GABA

GABA

STNGABA

Glu

PPN

VA/VLTALAMUS

Glu

Glu

GABA

Glu

GABA

Glu

Glu

Glu

NORMAL

STRİATUM

SEREBRAL KORTEKS

Glu

D1P Mad.

D2/ENKEFALİNDİNORFİN

AK

SS

GABA

Glu

GPi/SNpr

GABA

SNpc

M. SpinalisVe

Beyin Sapına

GABA

Glu

GPe STNGABA

VA/VLTALAMUS

Glu

GABA

Glu

GABA

GABADA

PARKINSON HASTALIĞI

STRİATUM

SEREBRAL KORTEKS

Glu

D1P Mad.

D2ENK.

AK

SS

GABA

Glu

GPi/SNpr

GABA

SNpc

M. SpinalisVe

Beyin Sapına

GABA

Glu

DA

GPe

GABA

STNGABA

VA/VLTALAMUS

GABA

Glu

Glu

GABA

ERKEN DÖNEM HUNTINGTON HASTALIĞI

• Diseases of the basal ganglia are associated with abnormal involuntary movements that typically occur at rest and disappear in sleep.

• They are generally divided into two categories: Hyperkinetic and hypokinetic

• The hyperkinetic variety is seen in such disorders as chorea, athetosis, ballism, dystonia, tremor, and tics.

• The hypokinetic variety is seen largely in Parkinson’s disease and Parkinson plus syndromes

• Following anatomic loci for pathology are agreed on:- Substantia nigra in Parkinson’s disease- Caudate nucleus in chorea- Subthalamic nucleus in ballism- Caudate or lentiform nucleus (especially putamen) in dystonia

Hypokinetic Disorders

• ParkinsonismSix cardinal features:

1. Tremor at rest2. Rigidity3. Bradykinesia-hypokinesia4. Flexed posture

5. Loss of postural reflexes6. Freezing phenomenon

• Tremor, rigidity, and flexed posture are referred positive phenomena.

• Bradykinesia, loss of postural reflexes, and freezing are negative phenomena.

Rest Tremor• 4-5 Hz• Present in the extremities, almost always distally• Classic “pill-rolling” tremor involves the thumb

and the forefinger• Rest tremor disappears with action but

reemerges as the limb maintain a posture.• Rest tremor is also common in the lips, chin, and

tongue• Rest tremor of the hands increases with walking• Stress worsens the tremor

Rest tremor

Erken evre - klinikHastalığın premotor belirtileri:RBDAğrıDepresyonKoku duyumunda azalmaKonstipasyonErken dönemde başka hastalıklar ile karışabilen semptomlar:<40 yaş distoni + bradikineziAlt ekstremite bradikinezisiDistoni, rijidite, ağrı

Rigidity

• Increased resistance (muscle tone) to passive movement elicited when the examiner moves the patient’s limbs, neck or trunk

• Equal in all directions• The underlying tremor may cause

“cogwheeling”

Flexed posture

• Commonly begins in the arms and spreads to involve the entire body

• Striatal hand• Striatal toe• Lateral tilting of the trunk is common

Posture

Bradykinesia

• Slowness of movement, difficulty in initiating a movement, and loss of automatic movement

• Hypokinesia is the reduction in amplitude of movement

Bradykinesia

Loss of postural reflexes

• Pulltest is positive• With progress of the disease frequent fallings• The patient collapses into the chair on

attempting to sit down (sitting en bloc)

Freezing

• Inability to perform active movements (motor block)

• Often involves the legs when walking but can also involve eyelid opening,speaking and writing.

Freezing

The many causes of parkinsonism are

divided into four categories:

1.Idiopathic (%77.7)

2. Parkinson-plus syndromes (%12.2)

3. Symptomatic (secondary) (%8.2)

4. Heredodegenerative diseases (%0.6)

1.Idiopathic (%77.7)- %10 genetic- %90 unknown

2. Parkinson-plus syndromes (%12.2)- Multisiystem atrophy- Alzheimer’s disease- Lewy body dementia- Progressive supranuclear palsy- Lytigo-bodig (ALS-dementia-Parkinsonism

3. Symptomatic (secondary) (%8.2)- Toxic- Metabolic- Drug induced- Lesions- Infections

4. Heredodegenerative diseases (%0.6)

The core biochemical pathology in parkinsonism is decreased dopaminergic neurotransmission in the basal ganglia.

• Degeneration of the nigrostriatal dopamine system• Degeneration of the striatum with loss of dopamine

receptors• Drug induced parkinsonism as the result of blockade of

dopamine receptors.

Parkinson’s Disease

Parkinson-plus Syndromes

Drug-induced Parkinsonizm

Nigral Dopaminergic Neuron Terminals and

Striatal Receptors

Parkinson’s disease – HistoryParkinson’s disease – History

1817: James Parkinson “Shaking Palsy” 1960: Dopaminergic neuronal loss in substantia nigra1960: Levodopa1982: MPTP (ABD, California) (toxic substance in synthetic heroin)After 1982: Experimental models2005: Etiopathogenesis ?

Parkinson’s disease (primary parkinsonism)Parkinson’s disease (primary parkinsonism)• Degeneration of the neuromelanin-containing

neurons in the brain stem, especially in substantia nigra pars compacta and in the locus ceruleus.

• Many of the surviving neurons contain eosinophilic cytoplasmic inclusions known as Lewy bodies.

• By the time symptoms appear, the substantia nigra already has lost about 60% of dopaminergic neurons and the dopamine content in the striatum is about 80% less than normal.

Parkinson’s disease (primary parkinsonism)Parkinson’s disease (primary parkinsonism)

• PD makes up approximately 80% of cases of parkinsonism.

• Mean age at onset in both sexes is 55 years (range:20-80).• Over 60 yrs of age risk of Parkinson’s disease is %1• Male/female = 3/2.• Prevalence 160/100.000 and incidence 20/100.000/yr.• The cause of PD is unknown.

Parkinson’s DiseaseParkinson’s Disease Unilateral onset Frequent initial sympton: unilateral

upper ektremity tremor Bilateral involvement All over the course of the disease

asymmetric involvement

Clinical Staging of PH According Clinical Staging of PH According to Hoehn-Yahr Scaleto Hoehn-Yahr Scale

0- Asymptomatic1- Unilateral involvement2- Bilateral involvement3- Involvement of postural reflexes, imbalance and falls Mild-moderate morbidity4- Needs continious support5- Bedridden

Parkinson’s Disease - SymptomatologyParkinson’s Disease - Symptomatology Tremor: Static postural, 3-7 Hz, (hand, arm, foot, leg, tongue, chin, lip) Bradykinesia - Hypomimia - Micrography Rijidity Disarthria (hipophoni, palilali) Gait disorder (short steps) Motor blocks (freezing) Loss of associated movements of the arms Flexed posture

Disphagia Loss of postural reflexes, falls Pain, sensory complaints Autonomic findings: Constipation, postural

hypotension, sweeting, urinary incontinans, empotans

Depression: ~% 50 of cases Dementia: Mild, % 20-40 of cases

Parkinson’s Disease - SymptomatologyParkinson’s Disease - Symptomatology

Diagnosis of PDDiagnosis of PD

Based on clinical findings and signs

No radiologic “marker” No laboratory “marker”

Parkinson’s disease (primary parkinsonism)Parkinson’s disease (primary parkinsonism)TreatmentTreatment

• Treatment is aimed at controlling symptoms because no drug or surgicl approach unequivocally prevents progression of PD.

• Treatment is lifelong.• Treatment includes pharmacotherapy, physiotherapy

and surgery.

Motor semptomların semptomatik tedavisi• Dopaminerjik ajanlar

– Levodopa• Levodopa + karbidopa• Levodopa + benserazid• COMT inhibitörleri* (entakapon,

tolkapon) – Dopamin agonistleri

• Non-ergo† – Pramipeksol– Ropinirol– Rotigotin– Piribedil– Apomorfin

• Ergot deriveleri– Bromokriptin– Pergolid– Kabergolin– Dihidroergokriptin– Lisurid

– Selektif MAO-B‡ inhibitörleri• Selejilin• Rasajilin

• Non-dopaminerjik ajanlar– Antikolinerjik ajanlar:

• Triheksifenidil• Benztropin

– NMDA§ antagonistleri• Amantadin

* Katekol-O- metil transferaz inhibitörleri ; her zaman L-dopa ile birlikte kullanılırlar

† Apomorfinin subkutan enjeksiyon formları var ve L-dopa ile ilişkili motor fluktuasyonlarda kullanılır

‡ Monoamin oksidaz tip B§ N-metil-D-aspartat

Schapira AHV, Olanow CW. In: Principles of Treatment in Parkinson’s Disease; 2005.

PH Tedavisinde Kanıta Dayalı EtkinlikKategori Levodopa COMT

inhibitörleriMAO-B

inhibitörleriAntikolinerjikler

& amantadinDopamin agonistleri

Erken Evre Monoterapi √ √ ± √ (pramipeksol, ropinirol, pergolid)

İleri Evrede L-Dopa ile kombine √(MF) ? ±

√ (pramipeksol, bromokriptin, kabergolin, pergolid)

Motor komplikasyonların tedavisi - √(MF) ? √ (D; amantadin)

- (MF)√ (pramipeksol, ropinirol, pergolid)

Motor komplikasyonların önlenmesi - ? - (D)

? (MF) ? √ (pramipeksol, ropinirol, kabergolin)

Görüntülemede dopaminerjik nöron kaybında yavaşlama

-(?) ? ? ? √ (pramipeksol, ropinirol)

√ etkin (maksimum kanıt)± olası etkinlik- Etkili değil? Yetersiz kanıt0 çalışma yok

D diskinezilerMF motor fluktuasyonlarCOMT “catechol-O-methyltransferase”MAO-B monoamin oksidaz BDAs dopamin agonistleri

Rascol O, et al. Lancet 2002;359:1589-98.Goetz CG, et al. Mov Disord 2005;20:523-39.Fahn S, et al. N Engl J Med 2004;351:2498-508.

Horstink M, et al. Eur J Neurol 2006;13:1170-85.Horstink M, et al. Eur J Neurol 2006;13:1186-202. 50

Erken Dönem PH’da Algoritma

1. Kognitif yıkımı, özgeçmişde psikotik özellikleri veya kişilik patolojileri olan hastalarda DA’leri önerilmiyor. L-Dopa daha emniyetli.

2. İleri yaşda (>70) tedaviye L-Dopa ile başlanmalı.

3. Yavaş ancak yeterli doz titrasyonu.4. Hastanın tolere edebildiği ve maksimum

yanıtın alındığı doza dek DA titrasyonu.5. Optimum motor kontrol için zaman

içerisinde L-Dopa’nın tedaviye eklenmesi

Schapira AHV, Olanow CW. In: Principles of Treatment in Parkinson’s Disease; 2005:127. © 2005

Tanı

Tedavi kararı

EVET

Özürlülüğün belirlenmesi

Orta şiddette motor özürlülük, kognitif yıkım yok

DA başla

Tolere edilebilir maksimum yanıta dek DA dozu arttır

MAO-B inhibitörü eklenebilir

Ek tedavi gerektiren özürlülük

HAYIR

Gözden geçir

Hafif motor özürlülük

DA veya MAO-B inhibitörü başla

Ek semptomatik etki gerekli

Henüz başlanmamışsa DA başla

Ek tedavi gerektiren özürlülük

L-Dopa başla

1, 2,3

1,2

3

4

5* Monoamin oksidaz B

Tolere edilebilir maksimum yanıta dek DA dozu arttır

4


Therapeutic choices for Parkinson’s diseaseMedications

Dopamine precursor: levodopa (LD)±carbidopa or benserazide Dopamine agonists: bromocriptine, pergolide, pramipexole, ropinirole, apomorphine, cabergoline, pribedil. Catecholamine-O-methyl transferase inhibitors:tolcapone and entacapone. Dopamine releaser, NMDA receptor antagonist: Amantadine. Monoamine oxidase type B inhibitor: selegiline. rasagiline Anticholinergics:trihexyphenidyl, benztropine, biperidene... Antihistaminics:diphenhydramine, orphenadrine, phenindamine


Therapeutic choices for Parkinson’s disease

Surgery

Ablative surgery:Thalamotomy, pallidotomy. Restorative surgery:Embryonic dopaminergic tissue transplantation Deep brain stimulation:Thalamic stimulation, pallidal stimulation, subthalamic stimulation, PPN


• LD is the most effective drug, BUT 75% of patients have serious complications after 5 years of LD therapy.

• Younger patients, in particular, are more likely to show response fluctuations.

• DOPA-SPARING STRATEGY:Other antiparkinsonian drugs should be used first to delay the introduction of LD.

• Selegiline delays the need for LD therapy by an average of 9 months.

Adverse events and side Adverse events and side effects of L-Dopaeffects of L-Dopa

Noisea, vomiting Postural hypotension Psychosis: Hallucinations delusions

Late Complications of L-DopaLate Complications of L-Dopa

Motor Complications1. “wearing-off” End of dose

phenomenon (predictable)2. “On-off” fluctuations

(unpredictable)3. Dyskinesias: - Chorea (“on” period) - Dystonia (“on” or “of” period)

PD- Motor Complication

L-Dopa induced motor complications “on” period

HoneymoonPeriod

Motor Complication

s

Treatment

Symptoms unresponsiveto treatment

PD Dementi

a

3-5 yrs

8-10 yrs

15-20 yrs

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L-Dopa response at early stageL-Dopa response at early stage

B R Thanvi & T C N Lo

Postgrad. Med. J. 2004;80:452-458.

L-Dopa response at mid-stageL-Dopa response at mid-stage

B R Thanvi & T C N Lo Postgrad. Med. J. 2004;80:452-458.

L-Dopa response at late stageL-Dopa response at late stage

B R Thanvi & T C N Lo Postgrad. Med. J. 2004;80:452-458.

Clinical Features ExcludingIdiopathic PD

••Stepwise progression Stepwise progression of of parkinsonian parkinsonian symptoms and historysymptoms and historyof of recurrent strokerecurrent stroke

••History History of of recurrent head traumarecurrent head trauma••History History of of encephalitisencephalitis••Oculogyric crisisOculogyric crisis••Neuroleptic useNeuroleptic use••Sustained remissionSustained remission••Unilateral involvement after Unilateral involvement after 3 3 years years of of symptomsymptom--onset onset

••Supranuclear gaze palsySupranuclear gaze palsy

Clinical Features ExcludingIdiopathicPD

••CerebellarCerebellarfindingsfindings••Early Early severe severe autonomic symptomsautonomic symptoms••Early Early severe severe dementiadementia••BabinskiBabinskisignsign••Communicating hydrocephalus and Communicating hydrocephalus and basal ganglionic lesionsbasal ganglionic lesions

••NegativeNegativeresponseresponsetotoLL--DopaDopa••MPTP MPTP intoxicationintoxication

MMuultisltisyystem Atrostem Atrophyphy Degenerative, sDegenerative, sporadiporadic,c, rapid progressiverapid progressive Falls at early stages, severe dysarthriaFalls at early stages, severe dysarthria Significant symmetrySignificant symmetry Mild or absent tremorMild or absent tremor Age at onset of the disease Age at onset of the disease 30 years 30 years

CombinationCombination ParkinsonizmParkinsonizm: : L-Dopa response is poor/absentL-Dopa response is poor/absent CCerebellarerebellar symptoms symptoms PyPyramidal ramidal symptomssymptoms Autonomic dysfunctionAutonomic dysfunction

MSA - P

MSA•MRI (sensitivity%88-%60, specifisity%93-%100)–Putaminalhypointensity–In the outer border of putamenhyperintensity–Atrophy of the cerebellum, middle cerebellar peduncles, midbrain –Increased signal intensity in pons(hot crossbun)Orta hat “raphe” ve transverspontinliflerde sinyal artışı, tegmentum, piramidal traktusve superiorserebellarpedinkületkilenmiyor

MSA – MRI findings

• A- Axial T2 weightedimaging showing“putaminal hiperintens rim”(Spesifisite?, sensitivite?)

• B- Axial T2 weightedimaging showing“Hot cross bun sign”

MSA – C MRI bulguları

Progressive supranuclear palsy (PSP)

PSP

Normal PSP

Secondary Parkinsonism - CO Intoxication

Lower body parkinsonism

Hyperkinetic Disorders

– Tremor

* Involuntary oscillations of a body part produced by alternating or synchronous contractions of reciprocally innervated muscles.

* Physiological tremor These tremors are very small amplitude and are

demonstrable only by means of accelerometer. Enhanced physiological tremor: medical conditions, drugs, anxiety, fear…

* Essential tremor ET Typically a postural tremor (4-12 Hz) but may be

accentuated by goal-directed movements. The site of involvement in most cases is the hands and it is frequently asymmetric initially.

* Parkinsonian tremor Tremor at rest, at a frequency of 4-5 Hz, is the

most characteristic and the most prominent type of tremor in PD, but postural and kinetic tremor are also frequently seen. Onset of the tremor is usually in one of the hands; rarely, it may begin in the legs.

* Intention tremor Rhythmic involuntary oscillations that undergo

exacerbation as the hand or foot approaches the target of a voluntary movement. It indicates involvement of the cerebellum or its connections.

Essential tremor

Goal directed tremor

– Chorea (“dance”)

Characterized by sudden, frequent involuntary, arrhythmic, purposeless, and quick jerks of the trunk, extremities, and head associated with facial grimaces. They are usually distal and of low amplitude. Causes of chorea are hereditary, autoimmune, vascular, metabolic, toxic, inflammatory or drug induced.

– Athetosis (“without position”)

Slow, writhing, continuous, wormlike movements of the distal parts of the extremities, chiefly the fingers, which show bizarre posturing.

Generalized chorea

Huntington disease

• Progressive hereditary disorder that usually appears during adult life• Characterized by movement disorder (usually chorea), dementia, personality

disorder• Caudate nucleus and putamen are severly involved • GABAergic efferents projecting to lateral globus pallidus are lost chorea• Later striatal efferents to medial pallidum are lost parkinsonism, dystonia• Prevalence 4-8/100.000• 4p16.3, CAG-repeat disorder (N:11-34) (HD:37-86)• Huntingtin protein• Trinucleotide repeat is unstable in gametes• More juvenil cases of HD when an individual inherits the gene from father• Onset 35-40 yr (5-70)• Movement disorder, personality disorder, mental deterioration (course over a

period of 15 yr)

– Ballism (“jump or throw”)Sudden, quick, continuous, unusually violent, and

flinging in nature.Usually confined to the contralateral vascular lesion

in the subthalamic nucleus.

– Dystonia (“bad tone”)Twisting, slow, contorting, involuntary movement,

that is somewhat sustained and often repetitive. Dystonia can involve any part of the body. Dystonia is classified as (1) focal, (2) segmental (cranial

muscles (Meige syndrome), cranio-cervical dystonia, (3) multifocal (2 or more noncontiguous parts), (4) hemidystonia, (5) generalized (segmental crural + an other part of the body)

Classification of Torsion Dystonia• By age of onset

– Childhood onset, 0-12 yr– Adolescent onset, 13-20 yr– Adult onset, >20 yr

• By distribution– Focal– Segmental– Generalized– Hemidystonia

• By etiology– Primary (familial, sporadic)– Dystonia-plus – Secondary dystonia– Heredodegenerative diseases

Primary Dystonias• Pure dystonia except tremor• Familial and nonfamilial sporadic types• Most primary dystonias are sporadic, adult onset focal or segmental

dystonias• DYT 1 (Oppenheim dystonia)

– Onset 12.5±8.2– In %95 of patients symptoms begin in an arm or leg and the disorder spreads

to the neck or larynx– AD, 9q34.1, Torsin A protein– Penetrance rate 30%, 40%

Dystonic storm

Lingual dystonia

Generalized dystonia, chorea, spasmodic dysphonia (adductor)

Dystonic tremor

Generalized dystonia, myoclonus

Wilson disease Wilson disease (Hepatolenticular degeneration)(Hepatolenticular degeneration)

• Autosomal recessive disorder with the gene being located on the long arm of chromosome 13.

• The gene encodes a copper transporting P-type ATPase that is expressed in liver and kidney

• Two fundamental defects: 1.reduced biliary transport of copper, 2.impaired formation of plasma ceruloplasmin• Free Cu in serum is increased• Overflow of copper from the liver produces accumulation

in other organs, mainly in brain, kidney, and cornea .


• In cornea, copper is deposited close to the endothelial surface of the Descement membrane (Kayser-Fleischer ring; most important diagnostic feature)

• Symptoms begin between the ages of 11 and 25 years• Wilson disease is a disorder of motor function; there are

no sensory symptoms and reflex alterations.• Symptoms of basal ganglia damage usually predominate

but cerebellar symptoms may occasionally be in the foreground.

• Tremors and rigidity are the most common early signs.• Seizures can occur at any stage of the disease.


TreatmentTreatment• Initial phase of the treatment (toxic copper levels are

brought under control)PenicillamineAmmonium tetrathiomolybdateTriethylene tetramine dihydrohloride (trientine)

• Maintenance therapyZinc acetateTrientine + Zinc acetate

movement disorders and extrapyramidal system

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