Download E1 Lec 11 Disorders of Basal Ganglia

[A] OS 211: Integration, Coordination and Behavior
Lec 11: Disorders of the Basal Ganglia
December 5, 2013
Dr. Jamora, MD
OUTLINE
I. Basal Ganglia
A. Anatomy
B. Function
II. Movement Disorders
A. Approach of diagnosis
B.Terminologies
III. Athetosis
IV. Chorea
A. Huntington’s Disease
V. Ballism
VI. Dystonia
A. Classification
B. Types
C. Neuroimaging
D. Treatment
E. Other Dystonias
VII. Parkinsonism
A. Parkinsonism-Plus
Syndromes
B. Heredo-degenerative
Diseases
C. Primary: Parkinson
I. BASAL GANGLIA
A. ANATOMY
 Represents massive subcortical nuclei derived from the
telencephalon
 Corpus Striatum
o Concerned with somatic motor function
o Consists of two parts:
 Neostriatum (Caudate Nucleus and Putamen): receptive
component of the basal ganglia
 Paleostriatum (Globus Pallidus [Interna and Externa lateral to it:
putamen]): major outflow component of the basal ganglia
 More lateral to the externa is the putamen
o Amygdaloid Nuclear Complex
 A component of the limbic system
 Oldest part of the basal ganglia (archistriatum)
 Concerned with visceral, endocrine, and behavioral functions
Corpus
striatum
Striatum
Caudate Nucleus
Putamen
Globus Pallidus
Lentiform Nucleus
Figure 1. Parts of Basal Ganglia
B. FUNCTION
 To control and regulate the activities of the motor and the premotor
cortical areas via various reverberating circuits so that voluntary
movements can be performed smoothly
 Motor activity is intricately controlled by the interactions of 3 major
regions of the brain: cortex, cerebellum, and basal ganglia
 These three regions influence the lower motor neurons either:
o Directly via the pyramidal system
 Corticobulbar and corticospinal tracts
o Indirectly via the extrapyramidal system
 Basal ganglia circuit
Figure 1. Basal Ganglia Circuit
Transer’s understanding: The basal ganglia is responsible for the fine
tuning of motor activities, thus its general action is inhibitory (in order for
it to regulate movement and facilitate motor control). The internal globus
pallidus and substantia nigra pars reticulate have tonically active
inhibitory neurons which inhibit the brainstem and the VA/VL thalamic
nuclei. So for example, the person wants to move, the decision starts at
the cortex, and the cortex will give a signal (glutamate) to the striatum
(caudate and putamen), which activates either D1 or D2 receptors. The
effect depends on the receptors stimulated.
CHUA, COPE, CORALDE
1
If the D1 receptor is stimulated, the striatum will release GABA targeting
the GPI and nigra reticulate, inhibiting its inhibitory action to the
brainstem and thalamus. The thalamus will then send stimulatory signal
to the cortex by releasing glutamate. So basically, stimulation of D1
receptor is stimulatory to the cortex, saying go na yang move na yan!
Trivia: This is called the Direct Pathway.
If the D2 receptor is stimulated, the striatum will release GABA
enkephalin which inhibits the GP Externa (GPE). GPE normally inhibits
the subthalamic nucleus (STN) by releasing GABA; however, since GPE
is inhibited, less GABA is released. (Thus, D2 receptors inhibit the
inhibitor of STN) Therefore, the subthalamic nucleus will not be inhibited,
and it will release glutamate to excite the substantia nigra pars reticulate
and GP interna to inhibit the brainstem and thalamus. Stimulation of D2
receptor is inhibitory to the cortex, saying, no sobra na yung excitatory
signals, stop muna! Trivia: This is called the Indirect Pathway.
Dopamine from the Nigra compacta is stimulatory since it stimulates D1
receptors and inhibits D2 receptors.
Why is it important? Basically for hyperkinetic movement disorders there
is a problem in dopamine.
In Parkinsonism there is decrease dopamine so patient has slow
movements.
II. MOVEMENT DISORDERS
 Neurological syndromes in which there is either an excess of
movement (hyperkinetic) or a paucity of voluntary & automatic
movements, should be unrelated to weakness or spasticity
(hypokinetic); thus a stroke patient is not hypokinetic
 What these seemingly different clinical disorders share is that the
parts of the brain that are affected are part of the same system
 Almost all movement disorders stem from disturbances in the basal
ganglia or their connections
 The basal ganglia control system is a damping or modulating system.
Excess discharge in the basal ganglia produces slowing; a lack of
discharge produces hyperactivity. Lesions in the striatum produce
deficits in the ability to perform complex motor responses.
A. APPROACH OF DIAGNOSIS (INVOLUNTARY MOVT DISORDER)
 Careful history
 Physical examination
 Ancillaries:
o Thyroid function tests, RPR (for syphilis), LFTs (liver function tests)
o Heavy metal screen
o Urine/serum copper
o Ceruloplasmin
o Lumbar tap
o Serum/ urine organic & AA (useful for pediatric cases)
 Ophthalmologic exam for Wilson’s disease(slit lamp)- for Kayser
Flescher Rings
 Genetic testing (if available)
 Electrophysiological:
o EEG, EMG, EP
o ENG for nystagmus, PSG for sleep study
 Neuroimaging
 Neuropsychological testing
 Tissue biopsy
B. TERMINOLOGIES
 Excess of movement
o Hyperkinesia – excessive movement
▪ Akathisia (uncontrollable motor restlessness), ataxia (inability to
coordinate voluntary motor movements), athetosis, ballism,
chorea, dystonia, hyperekplexia, moving toes/fingers, periodic
leg movements of sleep, myoclonus, dyskinesia, restless legs,
tics, tremors
o Dyskinesia – any unnatural movement still excessive
 Paucity of movement
○ Hypokinesia – decreased amplitude of movement
▪ Parkinsonism (most common), blocking tics, cataplexy and drop
attacks; Catatonia, psychomotor depression, and obsessional
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Lec 11: Disorders of Basal Ganglia
OS 211
slowness (common psych patients); Apraxia, freezing
phenomenon, hesitant gaits, hypothyroid slowness, rigidity, stiff
muscles
○ Bradykinesia – slowness of movement
○ Akinesia – loss of movement
III.ATHETOSIS
 Slow, writhing, continuous, involuntary movements , DISTAL
 Speed can sometimes be faster and blend with those of chorea
(choreoathetosis)
 If not present in certain body parts at rest, it is brought out by having
the patient do voluntary movement elsewhere on the body (overflow)
 Movements not sustained
 Very distal, piano-like movements
 Basic patterns of movement include: alteration between extensionpronation and flexion-supination of the arm and between flexion and
extension of the fingers, the flexed and adducted thumb being
trapped by the flexed fingers as the hand closes.
 Other characteristic movements are eversion-inversion of the foot,
and alternate wrinkling and relaxation of the forehead or forceful
opening and closing of the eyelids.
 Choreoathetosis – from distal to proximal
IV.
CHOREA
 Involuntary, irregular, purposeless, non-rhythmic, abrupt, rapid,
unsustained movements of any part of the body due to overactivity of
dopaminergic neurons
 2016 trans: Proximal; Sir: Distal; Internet source: both proximal and
distal:P
 Flows from one body part to another
 Grander (bigger movements compared to athetosis), more proximal,
patient is usually unaware of the movements, described as nervous
by the family
 Unpredictable in timing, direction, and distribution
 Partially suppressible and often incorporated into semi-purposeful
movements – parakinesia
 Parakinesias: actions that attempt to hide the involuntary movement
(e.g. putting hand on hip or inside pockets, fixing the hair)
 Accompanied by motor impersistence – inability to maintain a
sustained contraction
 Seen in SLE (microinfarcts in the brain leading to chorea) and
Huntington’s disease
 HYPERGLYCEMIA CAN CAUSE choreoathetosis
A. HUNTINGTON’S DISEASE
 Prototype disease with chorea; problem in the indirect pathways
 Described by George Huntington in 1872; autosomal dominant
disorder; onset in adult life
 Trinucleotide disease: mutation in the huntingtin gene in
chromosome 4p16.3 (PATHOLOGY: excess of CAG repeats)
○ CAG repeats (9 -33) – unaffected
○ CAG repeats (34 -39) – intermediate
○ CAG repeats (> 40) – lead to Huntington’s
Figure 2. Basal Ganglia Circuit of Hyperkinetic Movt Disorders
So in Huntington’s disease,
There is less GABA from the D2 receptors D2 receptors won’t
release too much GABA so less inhibition on GPE GPE would then
release too much GABA inhibiting the subthalamic nucleus  Less
glutamate will be released  less excitation of IGP and Nigra reticulata
 Less GABA  More stimulation of the cortex using glutamate by
VA/VL thalamic nuclei thus more chorea form movements
Table 1. Commonly used medications in Huntington’s disease.
DOSE (INITIAL TO
MAXIMUM
SYMPTOMS
MEDICATION
RECOMMENDED)
Haloperidol
Chorea
(antipsychotics)
(anticipation): the more CAG repeats, the younger the onset
Mean age of onset: 40 years (range: 2-75 years)
5% of patients had the first signs before age 20 (juvenile form)
Mean duration of illness: 17-20 yrs max: of up to 45 years of age
Main COD (cause of death): pneumonia by aspiration or choking,
suicide and fall
 An incurable disease
 Triad of Huntington’s Disease:
○ Chorea
○ Dementia
○ Behavioral abnormalities (reason why patients consult psychiatry
first before neurology)
 Marked atrophy and gliosis of the caudate nucleus (severely
shrunken producing a marked dilatation of the lateral ventricle) and
putamen
 Loss of indirect pathways results in hyperkinesia (chorea)
 Diffuse degenerative disease, with widespread loss of cholinergic and
GABAergic neurons and secondary cerebral atrophy
 Luria test — test for executive dysfunction in Huntington’s disease
o
Patient cannot do the sequence: cognitive impairment
CHUA, COPE, CORALDE
12.5 to 100 mg daily, in
divided doses
Reserpine
0.1 to 0.3 mg daily, in
divided doses
Diazepam
Carbidopa/Levodopa
Trihexyphenidyl
Bromocriptine
Sertraline
Depression
Fluoxetine
Paroxetine
 Number of repeats inversely correlates with age at onset




Tetrabenzene
Clonazepam
Bradykinesia,
rigidity
Risepridone
Psychosis
0.5 to 30 mg daily
Olanzapine
Quetiapine
0.5 to 4 mg daily
1.25 to 20 mg daily
25/100. 1 tab QD to TID
1 mg BID to 5 mg TID
1.25 mg BID, increase
as tolerated
25 to 200 mg daily
10 to 80 mg daily
10 to 60 mg daily
0.5 to 6 mg daily
2.5 to 20 mg daily
25
o 750 mg daily
 Treatment: based on symptoms
○ No cure: treat symptoms only, not the disease
○ Give antipsychotics for symptomatic relief
○ Haloperidol, clonazepam, diazepam, risperidone
○ Genetic counseling
 On neurological examination:
○ Bradykinesia
○ On Luria test, cannot do palm, edge first – for frontal lobe
dysfunction
V.
BALLISM
 Greek word ‘ballein’, to throw
 Involuntary, irregular, large-amplitude flinging movement of the limbs
with poor pattern
 More proximal involvement: leg and arm flexion
 My be severe to cause physical exhaustion or injury
 Most common cause of hemiballism: stroke
Others: hypergylcemic hemiballism- diabetic, presentation was
hemichorea, if we control the sugar, chorea will disappear
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Lec 11: Disorders of Basal Ganglia
 Bilateral ballismus is very infrequent and usually asymmetrical.
Nonketotic hyperosmolar coma is the usual cause.
 Hemiballism – one side of the body, lesion in the contralateral
subthalamic nucleus (STN) or its connections, or to multiple small
infarcts in the contralateral striatum
 Biballism – bilateral lacunes in the basal ganglia
 May also be caused by levodopa overdose
 Tend to fall due to the involuntary movements
VI.
DYSTONIA
 Twisting, patterned movements that tend to be sustained at the
peak of the movement
 Frequently repetitive and often progress to prolonged abnormal
postures
 Agonist and antagonist muscles co-contract (to and fro movements)
 Often initially brought out by voluntary movements (action dystonia)
and can later become sustained and extend to other body regions
(Harrison’s, 17th Ed.).
 Can be aggravated by stress and fatigue and attenuated by relaxation
and sensory tricks such as touching the affected body part
(Harrison’s, 17th Ed.).
 Responsive to sensory tricks or “geste antagoniste” e.g. when you
have neck dystonia, if something touches the jaw there is reduced
muscle contraction, thus some patients wear masks to reduce the
dystonia
 There are at least 13 genetic loci for dystonia.
 Dystonia may occur as a part of neurodegenerative conditions such
as Huntington's disease, Parkinson’s disease, Wilson's disease,
corticobasal degeneration, progressive supranuclear palsy, the Lubag
form of dystonia-parkinsonism (DYT3) found only in Filipinos, and
mitochondrial encephalopathies. In contrast to the primary dystonias,
dystonia is usually not the dominant neurologic feature in these
conditions.
A. CLASSIFICATION
ACCORDING TO AGE OF ONSET
 Early (<26 years)
○ Tends to generalize
○ Starts from the leg or arm and progresses to the other limbs and
trunk.
 Late (>26 years)
○ Tends to remain localized/focal
○ Neck, face, or arms
OS 211
B. TYPES
CERVICAL DYSTONIA (Focal)
 Abnormal head and neck posture – spasmodic torticollis
 Example of a focal dystonia
 Jerky movements of the head and intermittent or constant head
deviation at rest; there is a “no-no tremor” as the patient tries to
position his head in the midline
 1.5 – 1.9 times more common in women
 Peak incidence is usually on the 5th decade
 Onset: 4th to 6th decade (70-90%)
 Deviations in any single plane or combinations of directions
○ Torticollis (neck turning) – ipsilateral SCM and contralateral
splenius capitis and levator scapulae are involved
○ Anterocollis (neck flexion) – bilateral SCM
○ Retrocollis (neck extension) – bilateral splenius capitii and
semispinalis capitii
○ Laterocollis (head tilt) – ipsilateral SCM, splenius capitis, and
scalene
○ Or combination of any of the above
 Muscle contractions can be painful and associated with dystonic tremor
and a secondary cervical radiculopathy.
 Treatment: Botulinum toxin injection costing Php 17 000 per vial (100
units), can last for 3-6 months
 Know the muscle to know where to inject the botulinum toxin
BLEPHAROSPASM (Focal)
 Intermittent closure or sustained bilateral eyelid closure as a result
of involuntary contractions of the orbicularis oculi muscles (very
frequent eye blinking)
 A focal dystonia
 Patients would sometimes have to pry open their eyes to be able to
see
 Mild spasms of the frontalis and the lower and middle facial muscles
 BSP (blepharospasm) + OMD (oromandibular dystonia) = Meige’s
syndrome
 How is it different from tics?
○ Tics can be controlled. They are myoclonic in origin – quick and
shock-like. However, after a few minutes they need to release
these (kept) tics. Blepharospasms cannot be controlled and are
sustained.
 Treatment: Botulinum toxin: 17000 per vial; lasts for 3-6 months; 4
sites around the eyes (eg. Inner and lateral canthi, upper and lower
eyelids, frontalis: less frowning), corrugators
○ uses 20units, 1/5 the vial
ACCORDING TO BODY DISTRIBUTION
 Focal
○ Single body part is affected (neck ayes hand)
○ Example: writer’s cramp, torticollis (neck dystonia), blepharospasm
(frequent eye blinking)
 Segmental
○ 2 or more contiguous areas affected
○ E.g. Meige’s Syndrome: blepharospasm and opening dystonia of
the jaw (eyes and mouth are affected)
 Multifocal
○ 2 or more non-contiguous areas affected
○ E.g. dystonia in legs and hands
 Generalized
○ One or both legs, the trunk, and some other parts of the body, or all
TASK SPECIFIC DYSTONIA
ACCORDING TO ETIOLOGY
X LINKED DYSTONIA-PARKINSONISM (XDP)
 Primary or Idiopathic
○ Oppenheim dystonia (DYT 1)
 Secondary or Symptomatic
○ Drug-induced (neuroleptics such as haloperidol), perinatal cerebral
injury (cerebral palsy patient), trauma, stroke, tumor, encephalitis,
Multiple sclerosis, metabolic, psychogenic
 Dystonia-plus Syndrome (non-neurodegenerative)
○ Dopa-responsive dystonia (DYT 5): Has a problem in metabolism
of dopamine (no tyrosine hydrolase) if you give levodopa, the
dystonia will disappear
 Diurnal pattern (better in morning but gets worse towards the
end of the day)
○ Myoclonus et dystonia (DYT 11)
 Heredo-degenerative
○ X-linked dystonia-parkinsonism (DYT 3)
○ Wilson’s disease
○ A Filipino disease
 Dystonia only found in Filipinos (mostly in Panay)
 DYT 3 (more specific term), “lubag” (more general term for abnormal
movements)
○ DYT3: called such because it was the 3rd dystonia to be described
○ “Lubag”: Ilonggo term for any twisting movement
 Adult-onset then generalized, predominantly male (99%); X linked
recessive; male manifests/female are carriers
 Severe, progressive movement disorder with high degree of
penetrance and a high frequency of generalization
 Sensory tricks: alleviate the dystonic movements (e.g. putting
something on the mouth, dancing, touching the face)
 Characterized by dystonic movements, usually starting in the 3rd or 4th
decade, spreading to generalization within 2-5 years (mean age: 39.4
years old)
 Mean age of death is 55
 Most common cause of death is suicide
 The dystonia co-exists with or is replaced by parkinsonism
usually beyond the 10th year of illness.
 Diagnostic Criteria of XDP
o Presence of a movement disorder manifesting as Dystonia alone or
in combination with Parkinsonian traits
o Mostly males (5 females as of 2011)
CHUA, COPE, CORALDE
 Seen in frequent repetitive movements
 Writer’s cramps (with index fingers pointing outwards, extension)
 Also described in milkers, seamstresses, cobblers, shoemakers,
musicians and others with work involving repetitive movements
 Athlete’s task-specific dystonia
 When patient is doing something, dystonia comes out.
 Dual Dystonia: Writer’s cramps + difficulty in buttoning the pants
 Mirroring: when you ask the right-handed patient to write with his left
hand, muscles of the right finger may also extend along with the left
(can be observed in most cases)
 Treatment: isolate the muscle group affected, inject with Botulinum
toxin
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Lec 11: Disorders of Basal Ganglia
 Sample Case from Sir: 57 y.o. woman with Turner’s syndrome
developed dystonia at 50 y.o.
o Adult onset
o Family history of XDP (must go back 2-3 generations to make
pedigree)
o Sample family: fourth generation men are >50% affected and the
third generation females are carriers
o S/Sx shown in the video: lingual tremors, protrusion, jaw opening,
lid retraction, truncal extension, hip flexion, lateral flexion, tip toeing
o Sensory Tricks e.g. disappearance of dystonia when dancing
 Origin of XPD cases (proportion may be attributed to health care):
○ Aklan – 17%
○ Capiz – 63% (where the doctors go frequently)
○ Antique – 2%
○ Iloilo – 12%
○ Guimaras – 0.23%
Table 2. Total number of XDP cases examined as of
2010=505 Total no of surviving patients= 312
PLACE/PROVINCE
Philippines
Panay Island
Capiz*
Aklan
Iloilo
Antique
Guimaras
OS 211
DYSTONIC MOVEMENTS
o Parkinsonism phase: atrophy of the caudate nucleus,
dilatation of frontal horn of the ventricle, BOTH striosomes and
matrix are severely depleted  PARKINSONISM hypokinetic
movements
 Reduced neuron specific expression of the Taf1 gene is
associated with X-linked dystonia-parkinsonism (Makino et al., 2007)
o Expression of TAF1 (TATA-binding protein-associated factor 1
gene) and dopamine receptor D2 gene (DRD2) in the caudate
nucleus is significantly decreased by a disease-specific SVA (short
interspersed nuclear element, variable number of tandem repeats,
and Alu composite) retrotransposon insertion in an intron of TAF1 ,
which encodes the largest component of TFIID complex.
o Abnormal pattern in DNA methylation in the retrotransposon in the
genome from caudate of the patient is also attributed to the
decreased expression of TAF1 gene.
o Genogram is useful for determining if the diseased is X-linked or
autosomally inherited.
C. NEUROIMAGING
PREVALENCE
(100,000)
0.31
5.74
23.66
7.72
1.43 (2001)
0.86
0.73
DYSTONIA WITH NO PARKINSONISM (DYSTONIC PHASE)
 T2W, T1W, and infrared (IR) images demonstrate mild caudate
atrophy and mild putaminal atrophy with high signal rim on T2W
represented by enlarged ventricles
Table 3. XDP statistics
Age at onset
Age at initial examination
Duration of illness from onset
Duration of illness from onset to
generalization*
Duration to predominant parkinsonism
Duration of survival
Age of surviving cases
Age at death
MEAN
39.67
RANGE
12-64 yrs
44
16
4
20-70 yrs
1-41 yrs
1-23 yrs
14
12.04
51.14
55.59
7-25 yrs
1-41 yrs
28-86 yrs
30-92 yrs
*84% generalized in 5 years; most of the patients commit suicide – low
duration of survival, bed sore infection aspiration, younger age of
surviving cases and age of death.
Figure 4. MRI of the brain of a patient with dystonia without
parkinsonism.
DYSTONIA WITH PARKINSONISM (PARKINSONISM PHASE)
 Normal curvature of the structures are also lost (like the ventricles),
severe caudate atrophy with ex vacuo dilatation of the frontal horns
and severe putaminal atrophy with slit-like high-signal intensity of
T2W and low signal intensity of T1W
Figure 5. MRI of the brain of a patient with dystonia with
parkinsonism.
Figure 3. Basal Ganglia Circuit of Dystonia and Parkinsonism
Phases
 Phases of XDP (Goto et al., 2005):
o Dystonia phase: striosomes atrophy, and are severely depleted,
matrix is relatively spared  hyperkinetic/dystonic disorders
(Dystonia is manifested in patients with XDP due to
disproportionate involvement of neostriatal compartments and their
efferent projections as postulated by Goto et al. (2005) based on
three-pathway model of basal ganglia. There is an imbalance in the
activity between the striosomal and matrix-based pathways leading
to dystonia.) LOSS OF STRIOSOMES IN THE STRIATUM HENCE
CHUA, COPE, CORALDE
D. OTHER DYSTONIAS
CRANIOFACIAL DYSTONIA
 Dystonia that affects the muscles of the head, face, and neck
o Blepharospasm, stare (lid retraction), mouth opening, neck
dystonia, some drool continuously; may have laryngeal
involvement (voice also affected); note hypertrophied SCM (very
prominent)
OROMANDIBULAR DYSTONIA
 Affects the muscles of the jaw, lips, and tongue. The jaw may be
pulled either open or shut, and speech and swallowing can be difficult
TRUNCAL DYSTONIA
 Involuntary activation of muscles of the chest, abdomen, or back.
o Involuntary back arching, extension torsion, or lateral bending
APPENDICULAR DYSTONIA
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 Some dystonic tremors, hyperextended extremities/fingers, a lot of
them have up-going toes (extension) so some cut off their toes, some
may have flexion
GAIT DYSTONIA
 “Bird walk”; hamstrings are tight
GENERALIZED DYSTONIA
 Hip flexion, still able to walk but with poor balance, bended forward,
torsional dystonia
After 10 years Parkinsonian (sensory tricks no longer applicable)
E. TREATMENT
 No definitive treatment; Zolfidem seems to be the best with optimal
effects in an hour but addictive and with decreasing effect with
chronic use.
GENERALIZED AND SEGMENTAL DYSTONIA
 Levodopa or carbidopa: up to 300 mg/day to diagnose doparesponsive dystonia
 Anticholinergics: biperiden, trihexyphenidyl
 Baclofen: muscle relaxant
 Benzodiazepines: sedative
 Dopamine depletors: to decrease peripheral dopamine; tetrabenozine
 Clonazapam, Clonadine
FOCAL DYSTONIA
 Botulinum toxin A injection precisely applied to the affected muscle
group
SURGICAL TREATMENT
 Bilateral chemopallidotomies or bilateral thalamotomies
 Deep brain stimulation
o Costs around 2.5M pesos
o 88.3% decrease of the BFM Dystonia Rating Scale, without
incurring any persistent adverse effects
o Generally safe & effective procedure for alleviating the disabling
symptoms of XDP in contrast to previous ablative surgeries
performed
o Rechargeable battery good for 8-9 years, must be replaced after,
costs around $25,000




OS 211
Axial rigidity is more prominent than appendicular rigidity
Pseudobulbar dysarthria
Frontal dysexecutive syndrome=Memory impairment
No available treatment. Initially improved in Levodopa
unsustained
but
MULTIPLE SYSTEM ATROPHY (MSA)
 Characterized clinically by parkinsonism, dysautonomia, cerebellar
dysfunction
 Hallmark: dysautonomia
o Patients have orthostatic hypotension, imppotence.
 Previously described as: not used anymore
o Shy-Drager Syndrome
o Striato-nigral Degeneration (SND)
o Olivopontocerebellar atrophy (OPCA)
 MSA-P (if predominant symptom is parkinsonism) or MSA-C (if
predominant symptom is cerebellar dysfunction)
MSA is synonymous with striatonigral degeneration when parkinsonism
predominates (MSA-p), with olivoponto cerebellar atrophy (OPCA) when
MSA-c signs predominate, and with Shy-Drager syndrome when autonomic
failure is dominant (Shrivastava, 2007).
 More common in men, usually at the 6th decade; death occurs 7-8
years after the initial symptoms
 Pathology is in the dorsolateral striatum and ventrolateral portion of
the globus pallidus and substantia nigra: glial cytoplasmic inclusions
 Patients have difficulty standing up or with foot tapping. Severely
bradykinetic.
 Hot cross bun sign on MRI (“never mind not gonna come out.”)
The hot cross bun appearance is seen in patients with MSA-c. The sign is
due to a selective loss of myelinated transverse pontocerebellar fibers and
neurons in the pontine raphe with preservation of the pontine tegmentum and
corticospinal tracts.
Other investigators have demonstrated a similar pattern of neuronal loss in a
patient with parkinsonism, the neuronal loss being secondary to presumed
vasculitis, and proposed that the sign may reflect Wallerian degeneration of
transverse pontocerebellar fibers secondary to vasculitic infarction.
Regardless of the mechanism, this pattern of selective neuronal depletion
results in a cross-shaped hyperintensity in the pons on T2-weighted MR
images (Shrivastaya, 2007).
VII. PARKINSONISM
 A neurological syndrome manifested by any combination of 6 cardinal
features:
o Resting tremor
o Bradykinesia/hypokinesia/akinesia
o Rigidity
o Flexed posture of neck, trunk and limbs
o Loss of postural reflexes
o freezing
 Characterized by hypokinesias (in contrast to dystonia which is
characterized by hyperkinesias)
 Categories: Primary (Parkinson’s Disease), Parkinsonism-Plus
Syndromes (PSP, MSA, CBGD, Lytico-Bodig), Heredo-degenerative
Disorders (Hallervorden-Spatz Disease, Neuroacanthocytosis, Wilson
Disease)
 Antipsychotic drugs can cause parkinsonism
Figure 6. Transverse T2-weighted MR image of the brain of a
patient with multiple system atrophy (MSA) of the cerebellarpredominant subtype (MSA-c) shows the hot cross bun sign as a
cruciform hyperintensity in an atrophied pons (arrow). Cerebellum
and middle cerebellar peduncle (arrowheads) are also atrophied,
with increased signal intensity. (Radiology, 245:606–607)
A. PARKINSONISM-PLUS SYNDROMES
 Parkinsonism occurring with other signs, vertical gaze paresis,
hypotension, dysautonomias, and apraxia
 Exhibits poor response to levodopa (as compared to Parkinson’s
Disease which is responsive to levodopa)
 Endemic among Guamanians
PROGRESSIVE SUPRANUCLEAR PALSY (PSP)
 History of frequent falls due to postural instability is central to the
diagnosis of PSP
 Wrinkled or surprised look
 Vertical supranuclear gaze paresis (difficulty moving head) could
not move the eyes vertically can be overcome via vertical doll’s eye
maneuver
 Memory problem
 Unsteady gait with erect posture
 Postural instability
 Symmetric bradykinesia and hypokinesia
 Tremor is rare
CHUA, COPE, CORALDE
CORTICOBASAL GANGLIONIC DEGENERATION (CBDG)
 Also called corticodentatonigral degeneration with neuronal
achromasia and cortical-basal ganglionic degeneration
 Asymmetrical Parkinsonism
 Idiomotor Apraxia
 Presents in the sixth or seventh decade with a slowly progressive,
unilaterally jerky, tremulous, akinetic, rigid, and apraxic limb held in a
fixed dystonic posture and displaying the alien limb syndrome.
However, symptoms and presentations vary.
 The behavioral manifestations in CBD may also include language
disturbances and frontal lobe-type behavior.
 Barely follows
 Frontal executive dysfunction
LYTICO-BODIG DISEASE
 Endemic among Guamanians (LBD : Guam : XDP : Philippines)
B. HEREDO-DEGENERATIVE DISEASES
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Lec 11: Disorders of Basal Ganglia
WILSON DISEASE
 Inborn error of copper metabolism (low ceruloplasmin)
 Hepatic cirrhosis and basal ganglia damage (hepatolenticular
degeneration: lentiform nucleus)
 Autosomal recessive trait; chromosome 13q14.3
 Defective incorporation of copper into ceruloplasmin
o Low serum ceruloplasmin level
 Manifestation: Neurological in ~40% adult; hepatic in ~40% pediatric;
psychiatric illness in ~15%
 Wing-beating tremor: large-amplitude tremor when arms are
extended and after a short latency arms are thrown up and down;
lessened after chelation
 Kayser-Fleischer rings (EYES): brownish-yellow ring visible around
the corneo-scleral junction (limbus); consists of copper deposits in
Descemet’s membrane, extending into the trabecular meshwork;
can be seen via slit lamp
Figure 6. Kayser-Fleischer rings.
Symptoms:
o Akinetic-rigid syndrome
o Generalized dystonia
o Postural, intention tremor with ataxia, titubation, dysarthria
 Treatment:
o Chelators
 D-penicillamine with pyridoxine
 Trientine
 Zinc & tetrathiomolybdate
 Dimercapol (BAL)
o Liver transplant – best treatment
o Dietary restriction (avoid copper-containing food sources like
prunes, cocoa, black pepper, and yeast)

OTHERS
 Hallervorden-Spatz Disease
 Neuroacanthocytosis
C. PRIMARY: PARKINSON’S DISEASE
"It's like driving with the emergency brake on." - Patient with PD (You
want to speed up but you cannot.)
 Named after James Parkinson, who provided a detailed description of
what he termed "shaking palsy" in an essay published in 1817
 A chronic progressive disorder of motor function primarily of middle
to late life (no longer true because there are already young patients)
 Nine genetic linkage loci
 Can result from (1) decreased dopamine production, (2)
insensitive postsynaptic receptors or (3) early (or increased)
degradation on synaptic cleft by enzymes
o Factors leading to the degeneration of the substantia nigra are
uncertain
o Genetic susceptibility + environmental toxin
 In more than 90% of patients, the cause is unknown
 Gross examination of the brain in PD reveals mild frontal atrophy with
depigmentation of the substantia nigra
OS 211
 Microscopically, there is degeneration of the dopaminergic cells
with the presence of Lewy bodies in the remaining neurons and
processes of the substantia nigra pars compacta
The pathologic changes in the substantia nigra involve dopaminergic
neurons that project to the striatum and thus lead to depletion of
dopamine in the caudate nucleus and putamen. The depletion of
dopamine leads to complex changes in the striatal projection neurons,
with similar effects on thalamocortical projections over both the direct
and indirect pathway.
DIRECT PATHWAY: Decreased nigrostriatal excitation of D1
receptors decreases the striatal inhibition of neurons in the internal
segment of the globus pallidus and the substantia nigra reticulata.
Consequently, the pallidothalamic and nigrothalamic inhibition of
thalamocortical neurons become enhanced. END RESULT: decreased
cerebral cortical excitation over thalamocortical projection fibers.
INDIRECT PATHWAY: Decreased nigrostriatal inhibition of D2
receptors increases the striatal inhibition of neurons in the external
segment of the globus pallidus. This decreases the inhibitory effects of
external segment pallidal neurons on subthalamic nucleus neurons and
thereby enhances the excitatory effects of subthalamic projections on
the internal segment of the globus pallidus and substantia nigra
reticulata. Consequently, the pallidothalamic and nigrothalamic
inhibition of thalamocortical neurons becomes enhanced. END
RESULT:
decreased
cerebral
cortical
excitation
over
thalamocortical projection fibers.
Figure 8. Natural history of PD and symptomatic treatment. By the
time a patient is diagnosed, up to 80% of his dopaminergic neurons are
already gone.
DIAGNOSTIC CRITERIA UK PD BRAIN BANK CRITERIA
 Bradykinesia and at least 1 of the following:
o Rigidity
o Rest tremor
o Postural instability not caused by visual, vestibular or
proprioceptive dysfunction
 Exclude other causes of parkinsonism (neuroleptic drugs: haloperidol
or amlodipine, ciprofloxacin)
 At least 3 of the following supportive (prospective) criteria:
o Unilateral onset
o Rest tremor present
o Progressive disorder
o Persistent asymmetry (first side is severely affected)
o Excellent response to levodopa (70-100%)
o Severe levodopa-induced chorea or dyskinesia
o Clinical course of > 10 years
o GBA gene
o Antipsychotic drugs can cause Parkinsonism
SYMPTOMS
Figure 7. Substantia Nigra
CHUA, COPE, CORALDE
 Parkinsonian tremor: resting tremor
o Distal parts of the extremities and lips while the body portion is at
rest
o Re-emergent tumor: put arms forward, initially no tremor but
appears after a while
o Ceases upon active movement of the limbs, reemerges when the
limb remains in an antigravity posture
o If not resting, it must be an action tremor
 Rigidity: flexed posture
o Manifested in the distal limbs by a ratchet ‘give’ when moving a
joint throughout its range of motion (cogwheel rigidity)
o Accounts for flexed posture
 Bradykinesia
o Decreased frequency of blinking (dry eyes)
o Small, cramped handwriting (micrographia)
o Drooling (because of difficulty in swallowing)
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Lec 11: Disorders of Basal Ganglia
Bradyphrenia – delayed verbal response, not demented
Difficulty with hand dexterity – shaving, brushing,teeth
Loss of spontaneous movement – gesturing
Masked facies or hypomimia (face less expressive than usual)
Soft speech (hypophonia) with loss of inflection (aprosody:
monotonous voice)
o Slowness in raising shoulder and arm (may even “freeze” since
they are not swinging their arms)
o Difficulty arising from a chair and turning in bed
 Loss of postural reflexes
o Occurs later in the disease (falls easily, stooped posture, no arm
swing)
o Pt has difficulty righting himself after being pulled off-balance
o Do the “pull test” (pull the patient  if he falls without any
resistance or effort to stop the fall, it’s a (+), or (-) righting reflex)
 Freezing
o Affects the gait, begins with start-hesitation (feet takes short,
sticking, shuffling steps before patient can begin walking)
o Feet eventually become ‘glued to the ground’ in crowded spaces;
difficulty passing through small doors
o Destination-freezing – stopping before reaching the final
destination (e.g. Pt falls down upon reaching the door knob)
o Visual and auditory cues may help (ex: patient steps on the lines in
the floor to guide them while walking)
o Motor fluctuations – occurs during severe parkinsonisms and
happens when medications are not taken; there is a sudden off to
their movement
o
o
o
o
o
MEDICAL TREATMENT
 Dopamine precursor: levodopa
 Decarboxylase inhibitor: carbidopa, benserazide
 Levodopa must be given with carbidopa so that levodopa will not be
converted to dopamine peripherally so it can cross the blood-brain
barrier
 COMT inhibitor: prevents breakdown of dopamine (which is degraded
by MAO and COMT); entacapone
 MAO-B inhibitor: also prevents breakdown of dopamine; selegiline
 Dopamine releaser: amantadine (antiviral)
 Dopamine agonist: bromocriptine, pergolide, piribedil, ropinirole,
pramipexole, apomorphine (injectable dopamine)
 Meds lose their effect after continuous use (~20 years)
 Too much levodopa will lead to motor fluctuations (dyskinesia)
OS 211
Motor fluctuations
Lesioning
Therapies
Deep Brain
Stimulation
One surgery
Little follow up required
No implantable device
Cheaper
Adjustable
Reversible
Bilateral
Surgical risks irreversible
Cannot be done on both
sides of the brain (bilaterally)
Surgical risks
Follow up
Device-related complications
Expensive
END OF TRANSCRIPTION
CHUA: Happy holidays Block A! and Blo
have supported Project H2O, thank you so much! Let’s all contribute to
help the victims in the Visayas! AFTG!
COPE: Merry Christmas Block A. Happy valentine’s day??? Block B!
Hahaha. Hello sa researchmates ko, sana matapos na tayo. Hi Jana
(Ayan binati na kita. Bayad na ako.)
CORALDE: Hello sa crush ko. nilagay to ni Cope. Pero sige hello na
din!:)) Excited nako! Bukas na ang TRP guys! Let’s sing with all our
hearts! Alam nyo nung sinulat ko yung kanta, wala lang, dahil yun ang
interpretation ko sa theme na Med and Beyond. Pero nung nameet ko
yung mga taga Palo, Leyte last week tapos nagkwento sila tungkol sa
nangyari sa kanila dun nung Yolanda, at kung pano kakailangan ang
mga doktor sa communities nila, mas nafeel ko yung kanta natin Sana
kayo rin, find a reason to sing the song in a way that you really mean it.
Ayun lang. good luck to us!:) Bilang last trans namin to for the year,
Merry Christmas and thank you Block A and 2017 for a happy 2013! 
Dopamine (being a very large molecule) cannot cross the BBB; therefore, we
must give a precursor such as levodopa. Levodopa should not be given
alone because it will be quickly converted to dopamine before it even crosses
the BBB. Decarboxylase inhibitor is given to prevent this.
Dopamine is easily metabolized by MAO or COMT. Therefore, it must be
given with either a MAO inhibitor or a COMT inhibitor.
SURGICAL OPTIONS
 Thalamotomy of the opposite side (Michael J Fox had this!)
 Ablative lesions of the pallidum and subthalamic nucleus
 Deep brain stimulation
o Pacemaker-like technology delivers electrical pulses to targeted
structures in the brain
o Electrical pulses may block brain signals that cause symptoms of
PD
o Implanted device can be programmed non-invasively to maximize
benefit and minimize side effects
o Thalamic stimulation for parkinsonioan tremor and essential tumors
o With 4 contact points on each side of the brain
o Bilateral subthalamic nuclei stimulation for Parkinson’s disease(
only in cardinal santos)
o It is preferred because it is adjustable, programmable and
reversible
o Surgery is done with the patient awake to check its positive effects
or complications right there and then
o Battery must be replaced after 3-5 years
o Chemotherapy after surgery but on lower dose to lessen the
complication/side effects (dyskinesias and hallucinations)
o Criteria
 Age < 70
 5 years with the disease
 No psychosis or depression
 Not demented
 Must be levodopa responsive prior to surgery
o Side effects: bleeding, seizures, infection, fractured electrodes
Table 4. Advantages and disadvantages of the treatment options.
ADVANTAGES
DISADVANTAGES
Medication side effects
Levodopa
Ease of use
increase over
Therapy
Adjustable
time;hallucinations;
CHUA, COPE, CORALDE
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