Download Movement Disorders and Extrapyramidal System

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
Thalamus
Putamen GPe GPi
STN
SNr
SNc
Basal ganglia
subcortical nuclei:
caudate
putamen
globus pallidus
caudate,
putamen &
globus pallidus
are named
corpus striatum
Caudate
&putamen are
named
striatum
globus pallidus &
putamen are
named lentiform
nuclei
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
STRİATUM
D1
P Mad.
DA
GABA Glu
Glu
D2
ENK.
AK
Glu
GABA
SS
Glu
VA/VL
TALAMUS
GABA
Glu
SNpc
GPe
GABA
GABA
STN
GABA
GABA
Glu
Glu
GPi/SNpr
M. Spinalis
Ve
Beyin Sapına
GABA
Glu
PPN
PARKINSON HASTALIĞI
SEREBRAL KORTEKS
Glu
Glu
STRİATUM
D1
P Mad.
DA
GABA
D2/ENKEFALİN
DİNORFİN
AK
Glu
GABA
SS
VA/VL
TALAMUS
GABA
SNpc
GPe
GABA
STN
GABA
Glu
GABA
Glu
GPi/SNpr
M. Spinalis
Ve
Beyin Sapına
GABA
ERKEN DÖNEM HUNTINGTON HASTALIĞI
SEREBRAL KORTEKS
Glu
Glu
STRİATUM
D1
P Mad.
D2
ENK.
Glu
AK
GABA
SS
VA/VL
TALAMUS
DA
GABA
GABA
Glu
SNpc
GPe
GABA
Glu
GABA
GPi/SNpr
M. Spinalis
Ve
Beyin Sapına
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 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
• 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
Hastalığın premotor
belirtileri:
RBD
Ağrı
Depresyon
Koku duyumunda azalma
Konstipasyon
Erken dönemde başka
hastalıklar ile
karışabilen semptomlar:
<40 yaş distoni +
bradikinezi
Alt ekstremite
bradikinezisi
Distoni, 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
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.
Nigral Dopaminergic Neuron Terminals and
Striatal Receptors
Parkinson’s
Disease
Parkinson-plus
Syndromes
Drug-induced
Parkinsonizm
Parkinson’s 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 ?
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)
• 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 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
Parkinson’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
Parkinson’s 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”
Parkinson’s 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 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 Etkinlik
Kategori
Erken Evre Monoterapi
Levodopa
COMT
inhibitörleri
√
İleri Evrede L-Dopa ile
kombine
MAO-B
inhibitörleri
Antikolinerjikler
& amantadin
√
±
√ (pramipeksol,
ropinirol, pergolid)
√ (pramipeksol,
bromokriptin,
kabergolin, pergolid)
√(MF)
?
±
Dopamin agonistleri
Motor komplikasyonların
tedavisi
-
√(MF)
?
√ (D; amantadin)
- (MF)
Motor komplikasyonların
önlenmesi
-
?
- (D)
? (MF)
?
√ (pramipeksol,
ropinirol, kabergolin)
-(?)
?
?
?
√ (pramipeksol,
ropinirol)
Görüntülemede
dopaminerjik nöron
kaybında yavaşlama
√
±
?
0
etkin (maksimum kanıt)
olası etkinlik
Etkili değil
Yetersiz kanıt
çalışma 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.
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
Tanı
Tedavi kararı
HAYIR
EVET
Gözden geçir
Özürlülüğün belirlenmesi
Hafif motor özürlülük
1,2
Orta şiddette motor özürlülük,
kognitif yıkım yok
DA veya MAO-B inhibitörü başla
1, 2,3
DA başla
Tolere edilebilir maksimum
yanıta dek DA dozu arttır
Ek semptomatik etki gerekli
3
4
Henüz başlanmamışsa DA başla
4
Schapira AHV, Olanow CW. In: Principles of Treatment
in Parkinson’s Disease; 2005:127. © 2005
MAO-B inhibitörü eklenebilir
Tolere edilebilir maksimum
yanıta dek DA dozu arttır
Ek tedavi gerektiren özürlülük
Ek tedavi gerektiren özürlülük
L-Dopa başla
* Monoamin oksidaz B
5
Parkinson’s disease (primary parkinsonism)
Treatment
Therapeutic choices for Parkinson’s 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
Parkinson’s disease (primary parkinsonism)
Treatment
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
Parkinson’s 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
Motor
Honeymoon
Complications
Period
Treatment 3-5 yrs
Symptoms unresponsive
to treatment
8-10 yrs
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 artışı,
tegmentum, piramidal traktus ve superior serebellar
pedinkül 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 bulguları
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 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 spre
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