Download Movement disorders

Movement Disorder
Dr.Ghayath
Movement disorders
Movement disorders: (sometimes called extrapyramidal disorders)
impair the regulation of voluntary motor activity without directly affecting
strength, sensation, or cerebellar function. They include hyperkinetic disorders
associated with abnormal, involuntary movements and hypokinetic disorders
characterized by poverty of movement.
Hyperkinetic disorders of abnormal movements can be classified as
tremor, chorea, athetosis or dystonia, ballismus, myoclonus, or tics. And
example of Hypokinetic is Parkinson.
Parkinson disease
Parkinson's disease is one the commonest neurodegenerative disease.
Parkinson’s disease (PD) is a neurodegenerative disorder associated with a loss
of dopamine-producing neurons in the substantia nigra.
The disease was described by James Parkinson in 1817.
1
Movement Disorder
Dr.Ghayath
Link to anatomy (ADDED BY THE STUDENTS NOT INCLUDED IN THE LECTURE) this will
help you to understand the pathogenesis of all movement disorders:
• The basal ganglia play important motor functions in starting and stopping voluntary motor
functions and inhibiting unwanted movements. The basal ganglia consists of 3 nuclei
masses deep in the cerebrum (caudate nucleus, putamen, and Globus pallidus), one
nucleus in the midbrain (substantia nigra), and the sub thalamic nucleus of the
diencephalon. The striatum combines the caudate nucleus and the putamen while the
corpus striatum consists of these 2 nuclei plus the Globus pallid us.
• There are 2 parallel circuits (direct and indirect) through the basal ganglia. These circuits
receive extensive input from the cerebral cortex that project back to the motor cortex after a
relay in the ventrolateral (VL) nucleus of the thalamus. Both of these pathways demonstrate
disinhibition. The direct pathway increases the level of cortical excitation and
promotes movement. The indirect pathway decreases the level of cortical excitation
and suppresses unwanted movement.
• The striatum is the major input center and the Globus pallidus is the major output center
for the pathways through the basal ganglia. Critical to proper function of the striatum is
dopamine production by the substantia nigra. Dopamine excites the direct pathway
and inhibits the indirect pathway.
• Lesions of the direct pathway result in an underactive cortex, which produces
hypokinetic motor disturbances. The classic disorder caused by degeneration of
dopaminergic neurons of the substantia nigra is Parkinson disease.
• Hyperkinetic disorders result from lesions of the indirect pathway and cause an
overactive motor cortex. These movements occur spontaneously at rest and cannot be
controlled by the patient. Examples of these disorders include chorea (multiple quick
movements), athetosis (slow serpentine movements), and hemiballismus (violent flinging
movements). Hemiballismus results from hemorrhagic destruction of the contra lateral
subthalamic nucleus.
2
Movement Disorder
Dr.Ghayath
PD slightly more common in men than women. The mean age of onset is
about 60 years, but cases can be seen in patients in their 20s, and even younger.
Diagnosis of a parkinsonian syndrome
 Bradykinesia (slowness of initiation of voluntary movement with
progressive reduction in speed and amplitude of repetitive actions)
 Muscular rigidity
 4–6 Hz REST tremor
 Postural instability not caused by primary visual, vestibular, cerebellar
or proprioceptive dysfunction.
This box was added by the student it is not included in the lecture:
The muscular rigidity described as (cogwheel), and the resting tremor as (pill rolling)
3
Movement Disorder
Dr.Ghayath
Other Motor Features






Micrographia
Masked facies (hypomimia)
Reduced eye blink
Soft voice (hypophonia)
Dysphagia
Freezing
Nonmotor Features




Anosmia
Pain
Mood disorders (e.g. depression)
Sleep disturbances
Epidemiology and Pathogenesis
Hallmark features of PD are degeneration of dopaminergic neurons in the
substantia nigra.
The studies suggest that environmental factors likely play the more
important role in patients older than 50 years, with genetic factors being more
important in younger patients. Epidemiologic studies suggest increased risk
with exposure to pesticides, rural living, and drinking well water and reduced
risk with cigarette smoking and caffeine.
Differential diagnosis
 Secondary Parkinsonism







Drug-induced (Dopamine-blocking agents such as the Antipsychotic )
Infection
Vascular
Normal-pressure hydrocephalus
Trauma
Liver failure
Toxins (e.g., carbon monoxide, manganese, cyanide, hexane, methanol,
carbon disulfide)
4
Movement Disorder
Dr.Ghayath
 Other Neurodegenerative Disorders
 Wilson's disease
 Huntington's disease
Treatment of Parkinson's disease
A. Medical
1- Levo Dopa
Dopamine does not cross the blood-brain barrier (BBB), so clinical trials
were initiated with levodopa, a precursor of dopamine. Levodopa is routinely
administered in combination with a peripheral decarboxylase inhibitor
(carbidopa or benserazide) to prevent its peripheral metabolism to dopamine
and the development of nausea and vomiting levodopa is still the most potent
and effective symptomatic treatment for PD, and remain the ‘gold standard’.
It is usual to start with half a tablet of 25/100 (PDI/levodopa) strength
b.d. or t.d. for a couple of weeks, then doubling the dose and waiting to judge
the effect over time with continued treatment, however, the duration of benefit
following an individual dose becomes progressively shorter until it approaches
the half-life of the drug. This loss of benefit is known as the wearing-off effect.
At the same time, many patients develop dyskinesia, these tend to occur at the
time of maximal clinical benefit and peak plasma concentration (peak-dose
dyskinesia). In more advanced states, patients may cycle between "on" periods
complicated by disabling dyskinesia and "off" periods in which they suffer
severe Parkinsonism.
Link to pharmacology and psychiatry (This box were added by the students it is not
included in the lecture):
One of the side effects of anti-Parkinson medications is Psychosis because it was
hypothesized that psychosis is related to increase level of dopamine.
While one of the side effects of anti-psychotic medications is Secondary Parkinsonism
because they decrease the level of dopamine in the brain.
5
Movement Disorder
Dr.Ghayath
Strategies to treat motor fluctuations
End-of-Dose
Deterioration
At night ‘‘Off ’’
Dystonia
Peak-Dose Dyskinesia
(1) Increase LD/CD from 3 to 4 times daily
(2) Substitute sustained release LD/CD
(3) Add dopamine agonist
(4) Add COMT inhibitor
(1) Add sustained-release LD/CD at bedtime
(2) Add dopamine agonist at bedtime
(1) Smaller doses of levodopa taken more
frequently
(2) Add dopamine agonist, decrease levodopa
(3) Add amantadine
2-Dopamine agonists
Dopamine agonists stimulate dopamine receptors directly. Six oral
agonists (bromocriptine, lisuride, pergolide, cabergoline, ropinirole and
pramipexole), one transdermal agonist (rotigotine) and Apomorphine
administered SC are available, these agonist may be given before levodopa is
introduced especially in young age, these drugs cause fluctuations and
dyskinesia much less frequently.
3- Catechol-O-methyl transferase (COMT) inhibitors
Entacapone (peripheral) and tolcapone (peripheral and central COMT
inhibitor) block the conversion of levodopa to 3-O-methyldopa, its principal
metabolite so increase the duration effect of levodopa.A combined tablet
containing levodopa, carbidopa and entacapone (Stalevo) is available.
4-Monoamine oxidase B (MAO-B) inhibitors
Selegiline and rasagiline are inhibitors of MAO-B, the iso-enzyme
(MAO-B) responsible for catabolizing dopamine to homovanillic acid
(HVA).lead to increase the duration effect of levodopa.
6
Movement Disorder
Dr.Ghayath
5-Anticholinergics
Anticholinergics often restricted to reducing tremor. E.g. trihexyphynidyl,
procyclidin.
6-Amantadine
This drug has several actions: an amphetamine-like effect (releasing
presynaptic dopamine stores); a mild anticholinergic effect.
B. Surgery for PD
It was appreciated that lesions placed into the nucleus of the thalamus
reduced contralateral tremor without inducing hemiparesis, but these lesions did
not meaningfully help other more disabling features of PD. Lesions placed in
the GPi (globus palidus interna) improved rigidity and bradykinesia as well as
tremor.
C. Deep brain stimulation (DBS)
Most surgical procedures for PD performed today utilize deep brain
stimulation (DBS). Here, an electrode is placed into the target area and
connected to a stimulator inserted SC over the chest wall. DBS simulates the
effects of a lesion without necessitating a brain lesion, Stimulation of thalamus
lead to decrease tremor, stimulation of Globus Pallidus Interna lead to decrease
rigidity and bradykinesia.
7
Movement Disorder
Dr.Ghayath
Tremor
A tremor is a rhythmic oscillatory movement best characterized by its
relationship to voluntary motor activity, i.e., according to whether it occurs at
rest, during maintenance of a particular posture, or during movement so tremor
can be classified to: rest and action tremor
Action tremor is classified into:
Note by the students:
You can find a good summary of different
types of tremor on YouTube video (The
Approach to Tremor uploaded by
Stanford medicine).
 Postural tremor
 Intention tremor
Action tremor
1-Postural tremor
 Physiologic tremor
 Enhanced physiologic tremor causes are:




Anxiety or fear
Excessive physical activity or sleep deprivation
Sedative drug or alcohol withdrawal
Drug toxicity (lithium, bronchodilators, sodium valproate, tricyclic
anti-depressants)
 Thyrotoxicosis
 Carbon monoxide poisoning
 Familial (autosomal dominant) or idiopathic (benign essential) tremor
 Wilson disease
 Asterixis
2-Intention tremor
 Cerebellar disorders
 Wilson disease
 Drug toxicity (e.g., alcohol, anticonvulsants, sedatives)
8
Movement Disorder
Dr.Ghayath
Rest tremor
o Parkinsonism
o Wilson disease
Physiological tremor:
An 8- to 12-Hz tremor of the outstretched hands is a normal finding. Its
physiologic basis is uncertain.
Enhanced physiological tremor
Physiologic tremor may be enhanced by fear or anxiety. A more
conspicuous postural tremor may also be found following excessive physical
activity or sleep deprivation and other causes mentioned above.
Benign essential tremor
This is commonly inherited as an autosomal dominant trait. Most people
with essential tremor (ET) have little or no disability ET is a 4-Hz to 12-Hz
postural tremor, typically seen as adduction-abduction of the fingers or flexionextension of the wrist; pronation-supination of the wrist can occur, but it is more
typical of PD. The tremor may start on one side, but as a rule it becomes
bilateral with time. The handwriting remains large (unlike PD) but may often be
severely affected and illegible. The head is the next most frequent area to be
affected, with a vertical ‘‘yes-yes’’ or horizontal ‘‘no-no’’ tremor. The voice,
tongue, and chin may all be involved as well.
Criteria of essential tremor
Core Criteria
 Bilateral action tremor of the hands and forearms (not rest tremor)
 Absence of other neurologic signs
 May have isolated head tremor
9
Movement Disorder
Dr.Ghayath
Secondary Criteria
 Long duration (>3 years)
 Positive family history
 Beneficial response to alcohol
Treatment
A) Medical:
 Propranolol
About 50% of patients will experience relief with propranolol and other Badrenergic antagonists. Doses generally are rather large, with optimal response
in the 240 mg to 320 mg range.
 Primidone
Because the main side effect of primidone is sedation, it should be started at
25 mg at bedtime and increased very slowly by 25-mg increments. If needed, a
low dose may be added in the morning. Doses above 250 mg to 350 mg are
rarely needed.
 Topiramate
Have suggested some improvement in ET
B) Surgical treatment
 Stereotactic lesioning of the ventral intermediate
 Nucleus (VIM) of the thalamus has produced the greatest response in
patients with severe tremor.
 Deep brain stimulation (DBS) of the VIM nucleus of the thalamus ,
has become the surgical procedure of choice
Before treatment
After treatment
End
10
Movement Disorder
Dr.Ghayath
Note: the below appendix were added by the students (it’s not included in
lecture):
The diagnosis of Parkinson disease is a clinical one because there are no
specific tests till this moment except at autopsy by the presence of specific
neuropathological findings including Lewy bodies. (See the case below).
A 64-year-old Caucasian male presents to your office because he has had two falls within
the last month. He states that he loses his balance when he tries to turn or stop
suddenly while walking. Recently, he says, it has been taking him quite a while to get
himself out of bed. He also complains of hand tremors that started last year in his left
hand, but that now have been affecting both hands. Which of the following is the best
tool to confirm his diagnosis?
A.
B.
C.
D.
Physical examination
B. Lumbar puncture
CT scan of the head
Electroencephalography
Explanation:
This patient is most likely suffering from Parkinson disease (PO), a neurodegenerative
disorder caused by accumulation of alpha-synuclein within the neurons of the substantia
nigra pars compacta, which ultimately leads to the death of these neurons. The three
cardinal signs of PO are rest tremor, rigidity and bradykinesia. The presence of two of these
three signs suggests a clinical diagnosis of PO, which can be further confirmed by
physical examination. To date, there are no imaging or laboratory tests that can be used
to confirm this diagnosis with any greater accuracy than physical examination. The
most common presenting sign of PO is an asymmetric resting tremor in the distal part of an
upper extremity. To summarize, physical examination findings that contribute to a clinical
diagnosis of PO include:
Tremor: A resting 4 to 6 Hz tremor with a "pill rolling" quality • frequently first manifests in
one hand, and may then slowly generalize to involve the other side of the body and the lower
extremities.
Rigidity: Baseline increased resistance to passive movement about a joint which may be
uniform (lead pipe) or oscillating (cogwheel)
Bradykinesia: Difficulty initiating movements, as when starting to walk or rising from a chair
• Narrow-based, shuffling gait with short strides and without arm swing (festinating gait) •
Micrographia (small handwriting) • Hypomimia (decreased facial expression) • Hypophonia
(soft speech)
Postural instability: • Flexed axial posture • Loss of balance during turning or stopping •
Loss of balance when pushed slightly from a stationary bipedal stance • Frequent falls
So the answer is A
11
Movement Disorder
Dr.Ghayath
A 53-year-old man complains of "shaking" of his right hand. He first noticed this shaking
while resting in an armchair and watching lV. He reports that the shaking stopped when
he reached for the remote to change the channel. On physical examination, his vital
signs are within normal limits and all other organ systems appear normal. Which of the
following is most likely responsible?
A.
B.
C.
D.
E.
F.
Physiological tremor
Essential tremor
Cerebellar dysfunction
Basal ganglia dysfunction
Corticospinal tract lesion
Peripheral neuropathy
Explanation:
This patient describes a resting tremor, based on its tendency to affect his hand while it is at
rest and improve with activity. Resting tremor can be a manifestation of Parkinson's disease,
and is often the presenting symptom. Parkinson's disease is caused by progressive loss of
dopaminergic neurons in the basal ganglia. Its classic tetrad of symptoms includes: rigidity,
tremor, bradykinesia, and postural instability. Patients typically present in late adulthood and
their condition slowly deteriorates over several years.
The resting tremor of Parkinson's disease is a 5 to 7 Hertz tremor that typically starts in one
hand. The motion is often described as having a "pill rolling" quality. The tremor may
progress to involve the other extremities, as well as the jaw, face, and lips. Unlike essential
and cerebellar tremors, resting tremor will not involve the entire head.
So the answer is D
12
Movement Disorder
Dr.Ghayath
A 73-year-old male presents to your office for evaluation of a tremor. He states that over
the past several months he becomes tremulous when attempting to hold the newspaper
and when drinking his morning cup of coffee. The tremor is not noticeably worse
during any particular time of day. He denies any other medical problems other than
hypertension, for which he takes hydrochlorothiazide. His vital signs are normal. Physical
examination, including his gait, is normal. The patient did exhibit a tremor.
Which of the following is the most likely diagnosis?
A.
B.
C.
D.
E.
Parkinson disease
Huntington's chorea
Side effect from caffeine
Essential tremor
Spinocerebellar ataxia
Explanation:
This patient's clinical history and visualized tremor is typical of essential tremor, which is
diagnosed by the presence of an action tremor in the absence of additional neurologic signs.
Essential tremor is typically suppressed at rest, but becomes noticeable when the patient
attempts a task that requires fine motor movement.
So the answer is D
Which of the following is the next best step in the management of the previous patient?
A.
B.
C.
D.
E.
Carbidopa/levodopa
Propranolol
Genetic counseling
Deep brain stimulation
Advise him to stop drinking coffee
Explanation:
The treatment of essential tremor typically begins with the beta-blocker propranolol, which is
especially helpful if the patient also has coexistent hypertension. Other treatment
possibilities include anticonvulsants such as primidone and topiramate. Although
benzodiazepines such as alprazolam are effective in reducing the symptoms of essential
tremor, their use should be restricted due to the potential for dependence.
So the answer is B
Link to biochemistry:
The black color of substantia nigra (in Latin: black substance) is due to presence of high
levels of neuromelanin in dopaminergic neurons. This neuromelanin has a role
in neuroprotection (neuromelanin can chelate metals and xenobiotics). Neuromelanincontaining neurons in the substantia nigra undergo neurodegeneration during Parkinson's
disease that’s why it appears lighter in color.
13