Movement Disorders and

Extrapyramidal System
Sibel Ertan, MD
Dept. 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 movement
disorders.

Basal Ganglia
Caudate

Putamen GPe GPi

Thalamus

STN
SNr
SNc

Basal ganglia
subcortical
nuclei:

caudat
e
putame
n
globus
pallidus

caudate,
putamen &
globus pallidus
are named
corpus
striatum
Caudate
&putamen are
named
striatum
globus pallidus
& putamen are
named

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.

NORMAL

SEREBRAL KORTEKS
Glu

Glu

STRATUM

D1
P Mad.
DA
GABA Glu

Glu

D2
ENK.

AK

Glu

GABA
SS

Glu

VA/VL
TALAMUS

GABA
Glu

SNpc

GPe
GABA

GABA

GABA

STN

GABA
Glu

Glu

GPi/SNpr
M. Spinalis
Ve
Beyin Sapna

GABA
Glu

PPN

PARKINSON HASTALII

SEREBRAL KORTEKS
Glu

Glu

STRATUM

D1
P Mad.

DA

GABA

D2/ENKEFALN
DNORFN

AK

Glu

GABA
SS

VA/VL
TALAMUS

GABA

SNpc

GPe

GABA

STN

GABA

Glu

GABA

Glu

GPi/SNpr
M. Spinalis
Ve
Beyin Sapna

GABA

ERKEN DNEM HUNTINGTON HASTALII

SEREBRAL KORTEKS
Glu

Glu

STRATUM

D1
P Mad.

D2
ENK.

AK

Glu

GABA
SS

VA/VL
TALAMUS

DA
GABA
GABA

Glu

SNpc

GPe

GABA

Glu

GABA

GPi/SNpr
M. Spinalis
Ve
Beyin Sapna

STN

GABA

GABA

 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 Parkinsons
disease and Parkinson plus syndromes
Following anatomic loci for pathology are agreed on:
- Substantia nigra in Parkinsons disease
- Caudate nucleus in chorea
- Subthalamic nucleus in ballism
- Caudate or lentiform nucleus (especially putamen)
in dystonia

Hypokinetic Disorders

 Parkinsonism
Six cardinal features:

1. Tremor at rest
2. Rigidity
3. Bradykinesia-hypokinesia
4. Flexed posture

5. Loss of postural reflexes

6. 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 - klinik

Hastaln premotor
belirtileri:
RBD
Ar
Depresyon
Koku duyumunda azalma
Konstipasyon
Erken dnemde baka
hastalklar ile
karabilen semptomlar:
<40 ya distoni +
bradikinezi
Alt ekstremite
bradikinezisi
Distoni, rijidite, ar

Rigidity
Increased resistance (muscle tone) to
passive movement elicited when the
examiner moves the patients 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

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
- Alzheimers 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.

Nigral Dopaminergic Neuron Terminals

and
Striatal Receptors
Parkinson
s Disease

Parkinsonplus
Syndromes

Drug-induced
Parkinsonizm

Parkinsons disease History

1817: James Parkinson
Shaking Palsy
1960: Dopaminergic neuronal
loss in substantia nigra
1960: Levodopa
1982: MPTP (ABD, California)
(toxic substance in
synthetic heroin)
After 1982: Experimental
models
2005: Etiopathogenesis ?

Parkinsons 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.

Parkinsons 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 Parkinsons disease is %1
Male/female = 3/2.
Prevalence 160/100.000 and incidence 20/100.000/yr.
The cause of PD is unknown.

Parkinsons 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

to Hoehn-Yahr Scale
0- Asymptomatic
1- Unilateral involvement
2- Bilateral involvement
3- Involvement of postural reflexes,
imbalance and falls
Mild-moderate morbidity
4- Needs continious support
5- Bedridden

Parkinsons 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

Parkinsons Disease - Symptomatology

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

Diagnosis of PD
Based on clinical findings and
signs
No radiologic marker
No laboratory marker

Parkinsons disease (primary parkinsonism)

Treatment

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 semptomlarn semptomatik

tedavisi
Dopaminerjik ajanlar

Levodopa
Levodopa + karbidopa
Levodopa + benserazid
COMT inhibitrleri* (entakapon,
tolkapon)
Dopamin agonistleri
Non-ergo
Pramipeksol
Ropinirol
Rotigotin
Piribedil
Apomorfin
Ergot deriveleri
Bromokriptin
Pergolid
Kabergolin
Dihidroergokriptin
Lisurid
Selektif MAO-B inhibitrleri
Selejilin
Rasajilin

Non-dopaminerjik ajanlar

Antikolinerjik ajanlar:
Triheksifenidil
Benztropin
NMDA antagonistleri
Amantadin

* Katekol-O- metil transferaz inhibitrleri ;

her zaman L-dopa ile birlikte kullanlrlar

Apomorfinin subkutan enjeksiyon

formlar var ve L-dopa ile ilikili motor
fluktuasyonlarda kullanlr

Monoamin oksidaz tip B

N-metil-D-aspartat

Schapira AHV, Olanow CW. In: Principles of Treatment in Parkinsons Disease; 2005.

Kategori

PH Tedavisinde Kanta Dayal

Etkinlik

Erken Evre Monoterapi

Levodopa

COMT
inhibitrleri

leri Evrede L-Dopa ile

kombine

MAO-B
inhibitrleri

Antikolinerjikler
& amantadin

(pramipeksol,
ropinirol, pergolid)
(pramipeksol,
bromokriptin,
kabergolin, pergolid)

(MF)

Dopamin agonistleri

Motor komplikasyonlarn
tedavisi

(MF)

(D; amantadin)
- (MF)

Motor komplikasyonlarn
nlenmesi

- (D)
? (MF)

(pramipeksol,
ropinirol, kabergolin)

-(?)

(pramipeksol,
ropinirol)

Grntlemede
dopaminerjik nron
kaybnda yavalama

?
0

etkin (maksimum kant)

olas etkinlik
Etkili deil
Yetersiz kant
alma yok

(pramipeksol,
ropinirol, pergolid)

D
diskineziler
MF
motor fluktuasyonlar
COMT catechol-Omethyltransferase
MAO-B monoamin oksidaz B
DAs
dopamin agonistleri

Rascol O, et al. Lancet 2002;359:1589-98.

Goetz CG, et al. Mov Disord 2005;20:523-39.
Horstink M, et al. Eur J Neurol 2006;13:1170-85.
Fahn S, et al. N Engl J Med 2004;351:2498-508. Horstink M, et al. Eur J Neurol 2006;13:1186-202.

50

Erken Dnem PHda Algoritma

1. Kognitif ykm, zgemide
psikotik zellikleri veya
kiilik patolojileri olan
hastalarda DAleri
nerilmiyor. L-Dopa daha
emniyetli.
2. leri yada (>70) tedaviye LDopa ile balanmal.
3. Yava ancak yeterli doz
titrasyonu.
4. Hastann tolere edebildii ve
maksimum yantn alnd doza
dek DA titrasyonu.
5. Optimum motor kontrol iin
zaman ierisinde L-Dopann
tedaviye eklenmesi

Schapira AHV, Olanow CW. In: Principles of Treatment

in Parkinsons Disease; 2005:127. 2005

Tan
Tedavi karar

HAYIR

EVET

Gzden geir

zrlln belirlenmesi

Hafif motor zrllk

1,2
Orta iddette motor zrllk,
kognitif ykm yok

DA veya MAO-B inhibitr bala

1, 2,3
DA bala

Ek semptomatik etki gerekli

4
Tolere edilebilir maksimum
yanta dek DA dozu arttr

3
Henz balanmamsa DA bala

4
MAO-B inhibitr eklenebilir

Tolere edilebilir maksimum

yanta dek DA dozu arttr

Ek tedavi gerektiren zrllk

Ek tedavi gerektiren zrllk

* Monoamin oksidaz B

L-Dopa bala

Parkinsons disease (primary parkinsonism)

Treatment
Therapeutic choices for Parkinsons disease
Medications
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

Parkinsons disease (primary parkinsonism)

Treatment
Therapeutic choices for Parkinsons disease

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

Parkinsons disease (primary parkinsonism)

Treatment

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

effects of L-Dopa
Noisea, vomiting
Postural hypotension
Psychosis: Hallucinations
delusions

Late Complications of L-Dopa

Motor Complications
1. 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

Treatment 3-5 yrs

-off

s e to
sym
pto

mati
c

treat
m

ent

8-10 yrs

Dem

entia

Post
ural
Insta
bility
Dysa
rthri
a, Pa
lilali
Flex
, sw
ed P
allow
ostu
ing p
re
Free
roble
zing
ms

Peak
dose
dysk
ines
Diph
ias
asic
dysk
ines
On-O
ia
ff ph
enom
enon
Yo-y
o-ing

Wea
ring

Goo
d res
pon

Motor
Honeymoon
Complications
Period
Symptoms unresponsive
to treatment

15-20
yrs

PD
Dementia

L-Dopa response at early stage

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

L-Dopa response at mid-stage

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

L-Dopa response at late stage

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

Clinical Features Excluding

Idiopathic PD
Stepwise progression of parkinsonian
symptoms and history of recurrent stroke
History of recurrent head trauma
History of encephalitis
Oculogyric crisis
Neuroleptic use
Sustained remission
Unilateral involvement after 3 years of
symptom-onset
Supranuclear gaze palsy

Clinical Features Excluding

Idiopathic PD

Cerebellar findings
Early severe autonomic symptoms
Early severe dementia
Babinski sign
Communicating hydrocephalus and
basal ganglionic lesions
Negative response to L-Dopa
MPTP intoxication

Multisystem Atrophy

Degenerative, sporadic, rapid progressive

Falls at early stages, severe dysarthria
Significant symmetry
Mild or absent tremor
Age at onset of the disease 30 years
Combination
Parkinsonizm: L-Dopa response is
poor/absent
Cerebellar symptoms
Pyramidal symptoms
Autonomic dysfunction

MSA - P

MSA-C

MSA
MRI (sensitivity %88-%60, specifisity
%93- %100)
Putaminal hypointensity
In the outer border of putamen
hyperintensity
Atrophy of the cerebellum, middle
cerebellar peduncles, midbrain
Increased signal intensity in pons
(hot cross bun)
Orta hat raphe ve transvers pontin liflerde sinyal art,
tegmentum, piramidal traktus ve superior serebellar
pedinkl etkilenmiyor

MSA MRI findings

A- Axial T2 weighted
imaging showing
putaminal hiperintens rim
(Spesifisite?, sensitivite?)
B- Axial T2 weighted
imaging showing
Hot cross bun sign

MSA C MRI bulgular

Progressive supranuclear
palsy (PSP)

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 adu

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

By

By etiology

age of onset
Childhood onset, 0-12 yr
Adolescent onset, 13-20 yr
Adult onset, >20 yr
distribution
Focal
Segmental
Generalized
Hemidystonia
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 12.58.2
In %95 of patients symptoms begin in an arm or leg a
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
(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 .

Wilson disease
(Hepatolenticular degeneration)

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.

Wilson disease
(Hepatolenticular degeneration)
Treatment
Initial phase of the treatment (toxic copper levels are
brought under control)
Penicillamine
Ammonium tetrathiomolybdate
Triethylene tetramine dihydrohloride (trientine)
Maintenance therapy
Zinc acetate
Trientine + Zinc acetate