Parkinson’s Disease Flashcards
1
Q
“Involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forward and to pass from a walking to a running pace, the senses and intellect being uninjured”
A
James Parkinson 1817
2
Q
Features of Parkinson Disease
A
Bradykinesia
Rigidity
Tremor
Postural Instability
Freezing phenomenon
3
Q
Most common clinical manifestation
A
Tremor
4
Q
Onset
A
Insidious
5
Q
Progression
A
Unilateral to bilateral
6
Q
Chairbound state
A
7.5 years
7
Q
Slowness of movement AND decrement in amplitude or speed (or progressive hesitations/halts) as movement continued
A
Bradykinesia
8
Q
- slow movement, difficulty initiating movement and loss of automatic movement
A
Bradykinesia
- inc D2 activity
9
Q
Reduction of amplitude of movement (decrementing)
A
Hypokinesia
-finger tapping
10
Q
Major cause of disability in PD patients
A
Bradykinesia
11
Q
(masked facies) with decreased blinking
(N: 12-20/min to 5-10/min)
Slight widening of the palpebral fissure, creating a stare
A
Hypomimia
12
Q
Speech
A
hypophonia (soft), aprosody, dysarthria, cluttered speech
Fewer shifts and adjustments in position
13
Q
Lumiliit yung handwriting
A
Micrographia
14
Q
failure to swallow spontaneously
A
Drooling
15
Q
fingers straighten, flexed and adducted posture at MCP joints
A
Striatal hand
16
Q
Upward flexed all the time
A
Striatal toe
17
Q
velocity-independent resistance to passive movement throughout the range of motion
A
Lead-pipe rigidity
18
Q
rhythmic brief increases in resistance during passive movement
A
Cogwheel rigidity
19
Q
rigidity of passive limb increases while another limb is engaged in voluntary active movement
A
Froment sign
20
Q
Starts with arms and spreads to involve entire body
• Rigidity of truncal muscles with flexors becoming predominant
A
Flexed posture
21
Q
Hz of rest tremor
A
4-6 Hz
22
Q
4-6H2tremor in a fully resting limb, suppressed during movement initiation and sometimes reemerges as the limb maintain a posture
A
Rest tremor
23
Q
Rest tremor is almost always
A
Distally
24
Q
Rest tremor of hand increases with
A
Walking, stress, or excitement
25
4-per-second tremor of thumb and fingers; characteristic, seen in ½ of patients
Classic pill rolling tremor
26
Most common presenting symptom of PD
Rest tremor
27
Not part of MDS-PD criteria (2015) for parkinsonism caused by PD
• Occurs in late stage PD
• Falling and eventual inability to stand unassisted
• Pull test - normal: 2 steps
Postural Instability
28
Pull test (retropulsion test) - normal:
2 steps backward
29
Transient inability to perform active movements
• Often affects legs, eye opening, speaking and writing
• Feet seem glued to the ground then becomes unstuck
Start hesitation and destination hesitation
Freezing phenomenon
30
Freezing phenomenon overcome by
Visual clues
31
Fenestration is aka
Shuffling gait
32
Frequent loss of balance
• Walking forward or backward seems to be chasing the body's center of gravity with a series of increasingly rapid short steps to avoid falling
Fenestration
33
Fenestration
Gait is improved by
sensory guidance like holding the patient
34
Other findings of PD
• Impaired upward gaze and convergence
• Delayed initiation of gaze to one side
• Slow conjugate eye movement
• Breakdown of pursuit into small saccades
• No sensory findings
35
Parkinson D
Dx is made by
history and neurologic examination
• No laboratory test to definitively diagnose PD
36
Mean age of onset
60 y/o
37
Juvenile parkinsonism
<20 y/o
38
Young onset
20-50 y/o
39
Inc prevalance
M>F (3:2)
40
Parkinsons disease
Motor symptoms
- resting tremor
- muscle rigidity
- bradykinesia
- postural instability
- gait in stability
- hypomimia
41
Neurobehavioral changes
Depression, anxiety, phobia, cognitive impairment, dementia and social interaction
42
Autonomic failure
Blood pressure abnormalities, gastrointestinal dysfunction, urinary dysfunction sexual abnormalities and thermoregulatory dysfunction
43
Sleep disorders
Fragmented sleep due to rigidity. insomnia, restiess legs syndrome (RLS), excessive daytime sleeping (EDS) and nocturnal awakening
44
Sensory impairments
Visual impairment, smell problems, difficulty in color discrimination, dry eye syndrome and pain
45
Misc
Weight loss, malnutrition, osteoporosis, sarcopenia and fatigue
46
Course of PD
Neurodegeneration
Non motor sx
Slight motor signs
Clinical PD
47
Neuropathology
• Loss of darkly pigmented cells in the SNPc and other pigmented nuclei (locus ceruleus, dorsal motor nucleus of vagus)
• Depigmentation directly correlates with the death of the dopaminergic neuromelanin-containing neurons in the SNPc and noradrenergic neurons in the locus ceruleus
• Loss of approximately 60% of DA neurons in SNPc by motor symptom onset; dopamine content is 80% < normal
• Denervation of the nigrostriatal pathway leading to diminished levels in the striatum
• Reduction of dopaminergic signaling = cardinal motor symptoms
48
Hallmark of PD
Lest Body
49
Presence of cytoplasmic deposits within neuronal cell bodies which are immunoreactive for
A-synuclein
50
• These pathologic protein aggregates are called
Lewy bodies
51
• Intracytoplasmic inclusions consisting of a
granular and fibrillar core with surrounding halo
52
• Primary structural component of LB is
filamentous a-synuclein
53
• Assessment of LB distribution
• LB pathology spreads rostrocaudally, in a chronologically predictable sequence
• Not all follow this pattern
Braak staging
54
Olfactory loss, autonomic dysfunction Constipation
Stage 1: dorsal motor nucleus of the vagal nerve; ant olfactory struc
55
Affective impairment
Anxiety
Sleep disturbance
Stage II
Lower raphe nuclei
Locus coeruleus
56
Motor sx - clinical dx
Stage 3: Basal ganglia, substantia nigra, amygdala, nucleus basilis of meynert
57
Worsening motor sx, emotional disturbance
Stage 4 Temporal mesocortex, temporal limbic cortex
58
Worsening motor sx, cognitive disturbance
Stage 5: temporal neocortex, sensory assoc and premotor areas
59
PD Etiology
• Most are idiopathic
• Environmental:
• MPTP - street drug contaminant
• ? Pesticides and heavy metals - rural farming environment
• Decreased risk of PD in high level caffeine consumption and cigarette smoking
• Higher uric acid levels associated with decreased risk and slower progression of PD
60
Genetics of PD
10-15% report a family history
• 5% have Mendelian inheritance
• 23 PARK genes linked to PD
61
PD Pathogenesis
Neuroinflammation
Mitochondrial dysfunction and oxidative stress
a-synuclein misfolding and aggregation
Dysfunctional protein clearance systems
62
Mitochondrial dysfunction and oxidative stress
• Decreased ATP synthesis, build up of free radicals causing oxidative stress
• Reduced glutathione - elimination of ROS
• Increased iron levels in SN - catalyze the formation of highly reactive hydroxyl radicals from hydrogen peroxide
63
a-synuclein misfolding and aggregation
• Found in axon terminals of presynaptic neurons
• a-synuclein misfolds and adopts a B-sheet amyloid like structure that is prone to aggregate
64
Dysfunctional protein clearance systems
• Ubiquitin-proteasome system (UPS)
• Autophagy-lysosome pathway
65
Neuroinflammation
• Microglia and complement activation, T lymphocyte infiltration, increased concentration of pro-inflammatory cytokines in the SNPc and Striatum
• PET scan - increased microglial activation in early PD in the brainstem, basal ganglia and frontotemporal cortices and in the parietal and occipital cortices in those with PD dementia
66
assessment of motor and nonmotor symptoms of
Parkinson disease
• 0-203 - the higher the more severe
MDS-UPDRS
67
PD scale for clinical staging
Modified Hoehn-Yahr Scale
68
Unilateral involvement only
1.0
69
Unilateral and axial involvement
1.5
70
Bilateral involvement without impairment of balance
2.0
71
Mild bilateral disease with recovery on pull test
2.5
72
Mild to moderate bilateral disease; some postural instability; physically independent
3.0
73
Severe disability; still able to walk or stand unassisted
4.0
74
Wheelchair bound or bedridden unless aided
5.0
75
— + — = Dopamine
L-DOPA
DOPAdecarboxylase
76
What metabolizes dopamine
COMT and MAO
Kaya iinhibit para maincrease si L-DOPA at DOPAdecarboxyclase
77
Building blocks of Dopamine
L-Phenylalanine
L-Tyrosine
78
Peripheral decarboxylase inhibitors
• Permits a greater proportion of L-dopa to reach nigral neurons and reduces the peripheral side effects of L-dopa and dopamine
• Potentiate levodopa thus decreasing its dose by fourfold
Carbidopa and benserazide
79
• Peripheral decarboxylase inhibitors
• Permits a greater proportion of L-dopa to reach nigral neurons and reduces the peripheral side effects of L-dopa and dopamine
• Potentiate levodopa thus decreasing its dose by fourfold
• Carbidopa and benserazide
—-More levodopa available for CNS
80
Levodopa stimulate area postrema
Peripheral dopamine
— Kaya need si carbidopa, susuka sha
81
- short half life; dosing with levodopa
Entacapone
82
- longer half life; hepatotoxic
Tolcapone
83
Extend elimination half life of levodopa by preventing its breakdown
COMT inhibitors
84
delaying introduction of levodopa, delays the time to develop complications from chronic levodopa use
Early use of dopamine agonist
85
• Delays the need for levodopa for average of 9 months
• Used for treatment of early stage PD, mild symptomatic effect
• Neuroprotective
MAO B inhibitor
86
• Triphexyphenidyl, amitriptyline, diphenhydramine, cyclobenzaprine
• Less effective antiparkinsonian agent than dopamine agonist
• More effective against tremor
• Forgetfulness, psychosis, sialorrhea
• Anti-cholinergics
87
• Augment dopamine release, block reuptake of dopamine into presynaptic terminals but exact MOA is unknown
• Mild to moderate benefit for tremor, hypokinesia and postural symptoms
• Some anti-cholinergic and anti-glutaminergic effects
• Anti-dyskinesia
• SE: leg swelling, worsen CHF
Amantadine
— anti viral but also anti dyskinesia
88
• Most potent anti-PD medication
• Striatal dopamine is depleted in PD but the remaining diseased nigral cells are still capable of producing some dopamine by taking up its precursor
• Inadequate response to levodopa trial - consider other parkinsonism diagnosis
• Bradykinesia and rigidity respond best but tremor can be resistant
• Use lowest dose that give adequate symptom reversa
Levodopa (L-dopa or L-dihydroxyphenylalanine)
The number of remaining nigral neurons later on becomes inadequate and the receptivity to the dopamine of the striatal target neurons become excessive, possibly due to denervation hypersensitivity resulting to reduced response to L-dopa and to paradoxical and excessive movements with each dose
• Longer duration of disease and the higher the dose the more likelihood of motor complications to occur (75% of patients within 5 yrs)
• Fluctuations
• Dyskinesia
89
At risk: long term levodopa therapy especially those with onset before 40 yo
• End of dose deterioration - return of symptoms in <4hrs from last dose
• Off state comes faster and more profound
• Accompanied by mood changes, anxiety, thought, sensory symptoms, dysautonomia (may also be without motor symptoms during off state)
• Peaks and valleys of brain dopamine levels are thought to alter the striatal dopaminoceptive medium spiny GABAergic neurons and their synaptic connections with other striatal interneurons and cortical afferents that provide glutamatergic input
• What to do?: substitute levodopa, maintain plasma concentrations at constant therapeutic level by chronic infusion of levodopa diminishes the severity
Motor fluctuations (wearing-off)
90
• Chorea, ballism, dystonia
• Restlessness, head wagging, grimacing, ingual-labial dyskinesia, blepharospasm
• Incidence and severity increase with luration and dose of levodopa, but may appear early in patients with severe parkinsonism
• Amantadine reduce severity
Dyskinesia
91
• Peak-dose dyskinesia Tx
Reduce levodopa dose
92
Diphasic dyskinesis - attects legs;
appear at beginning and end of dosing cycle Tx
Switch to dopamine agonist
93
Off dystonia - paintul cramps, relieved by next dose of levodopa Tx
Switch to dopamine agonist
94
Rarely done
• Placement of lesions in the GP, VL thalamus or STN contralateral to body side affected
• Best in young patients, unilateral tremor or rigidity
• Thalamotomy and thalamic stimulation (target: ventral and intermediate nuclei) - for contralateral intractable tremor
• Pallidotomy and pallidal stimulation (target: posterolateral GPi) - for contralateral dopa-induced dystonia and chorea
• Stimulation of the STN
• Ablative surgical therapy
95
target: ventral and intermediate nuclei) - for contralateral intractable tremor
Thalamotomy and thalamic stimulation
96
for contralateral dopa-induced dystonia and chorea
Pallidotomy and pallidal stimulation (target: posterolateral GPi)
97
• Implanted electrodes with electrical stimulator implanted in the chest
• STN for contralateral bradykinesia and tremor
• GPi - control dyskinesia
Deep brain stimulation (DBS)
98
PD mx
- ability to participate & self manage
- informed & engaged pt & caregivers
- multidisciplinary care
- conventional pharmacotherapy
- device aided therapies
99
Cardinal features of Parkinsonism
Bradykinesia
Rigidity
Tremor
PosturalInstability
100
Group of degenerative disorders that have some different symptoms and different changes in brain that respond to treatment differently
Primary Parkinsonism
101
Group of disorders that have different cause from PD
Secondary Parkinsonism
102
Secondary parkinsonism
• Vascular parkinsonism
• Normal pressure hydrocephalus
103
• Heredodegenerative
• Wilson disease
• XDP
104
Parkinson-plus syndrome
• MSA (MSA-P, MSA-C, MSA-A)
• PSP
• CBD
• DLB
105
Damage to the substantia nigra due to vascular disease or to a syndrome that closely resembles PD as a result of atherosclerotic white matter damage
• 2.5-5% of Parkinsonism
• Predominantly "lower half"
parkinsonism
B symmetrie
• Shuffling gate, freezing, falling are disproportionate to other features
• No tremor
Little or no response to L-dopa
• MRI: substantial white matter changes in both cerebral hemispheres
Vascular Parkinsonism
106
Wild wet wobbly
• Triad
ataxia, urinary incontinence and dementia
• Gait: short-stepped but not shuffling; feet leave the ground momentarily with each step
• More tendency to retropulsion
• P: increased resistance to outflow of CSF causing enlargement of the ventricles, abnormal CBF, the pressure exerted by the brain parenchyma and a rise in the water content
• Mechanical disruption of the basal ganglia causing inadequate blood flow to the nigrostriatal pathway
• LP improves motor symptoms
• Tx: VP shunt
Normal pressure Hydrocephalus
107
Shuffling gate, freezing, falling are disproportionate to other features
Vascular parkinsonism
108
NPH Triad
Ataxia
Urinary Incontinence
Dementia
109
Wilson disease aka
Hepatolenticular degeneration
The great mimic
110
- Brown discoloration near the limbus of the cornea representing copper deposition in the Descemet's membrane
- Pathognomonic
Kayser-Fleischer ring
111
NPH Tx
VP shunt
112
Wilson Disease Tx
Liver transplant
Reduction of dietary copper
• D-penicillamine - copper chelating agent
113
• Increased copper content of liver and brain
Increased urinary excretion of copper
• Low serum ceruloplasmin
• Protein that binds copper
• Low serum copper
• Transmission: AR autosomal recesdive
• Gene: ATP7B - codes for membrane-bound, copper-binding ATPase
• Inadequate functioning of the ATPase enzyme reduces the excretion of copper in bile
• Disturbance in copper metabolism
1. Reduced rate of copper incorporation into ceruloplasmin
2. Reduced biliary excretion of copper
• Tx: liver transplantation
Wilson Disease
(Hepatolenticular Degeneration)
114
Wilson disease onset
2nd to 3rd decade of life
115
Wilson disease clinical manifestation
• Acute to chronic hepatopathy eventually leading to multilobar cirrhosis and splenomegaly
• Increased transaminases
• Jaundice, thrombocytopenia and bleeding
• Hemolytic anemia
• Renal tubular changes
• Kayser-Fleischer rings
• Cerebral damage
Tremor - hand or head
Wing beating
• Parkinsonian syndrome
• Slownes
towness of oropharyngeal muscles leading to dysarthria dysphagia
hoarseness and
drooling
• Slowed saccades, limited upgaze
• Slowed finger movement
• Choreic movements or dystonic posturing of limbs
• Fixity of facial muscles with mouth agape "grinning or vacuous smile"
• Behavioral abnormalities
• Gradual impairment of intellectual faculties preceding other neurologic signs by more than 1 year
• Tendency for motor disorders to concentrate on bulbar muscles then spread caudally
116
DYT/PARK-TAF1
• Lubag (visaya: twisting)
• First described in 1976 by Lee
• Progressive neurodegenerative disease affecting mainly Filipino males, whose main ancestry come from the island of Panay
• Focal dystonia that eventually generalizes, with parkinsonism
X-Linked Dystonia Parkinsonism (XDP)
117
XDP Prevalence
• 0.31/100,000 Filipinos
• Capiz: 23.6/100,0000
• M>F 100:1
118
XDP age of onset
12-64 (3rd to 4th decade)
119
XDP Mean
Duration of illness: 16 yrs
Age of death: 55.6
120
XDP Course
Focal dystonia spreads in 97% of time and
generalizes within 5 years
• 2nd_ 7th year - dystonia is predominant
• 2nd year - parkinsonism starts to appear
• 7th to 10th year - dystonia and parkinsonism
• 15th year - 18.6% may become parkinsonism predominant but 68% remain dystonic
121
• Initial focal dystonia in 3rd or 4th decade (most common craniocervial dystonia)
• Dystonia spreads (97%) and 84% becomes generalized within 2-5 years
• Sensory tricks "geste antagonistique"
• Initial parkinsonism may occur in 14% of XDP cases, bradykinesia may coexist in dystonic phase of XDP
Manifesting females (from skewed x-inactivation), approximately 1:100 may have variable presentations
• Non-motor, neuropsychiatric features happen, with nearly a quarter having anxiety, about have having depression, and 10% with completed suicide
• Mild cognitive impairment
XDP
122
XDP Neuroimaging
Caudate and putaminal atrophy
Caudate atrophy
Hyperintense putaminal ring - dystonic and parkinsonian phases
Caudate head or putamen atrophy - parkinsonian phase
123
dystonic and parkinsonian phases
Hyperintense putaminal ring
124
parkinsonian phase
Caudate head or putamen atrophy
125
Xdp tx
• Mainly symptomatic
• BTX injections
• DBS
• Oral medications: benzodiazepines, clonidine, zolpidem, baclofen, anticholinergics but short term, limited symptomatic benefits
126
Parkinson-Plus Syndromes
• Multiple system atrophy (MSA)
• MSA-A
• MSA-P
• MSA-A
• Cortical-basal degeneration (CBD)
• Progressive supranuclear palsy (PSP)
• Dementia with Lewy Body
127
• Group of disorders characterized by neuronal degeneration in the SN, striatum,
ANS and cerebellum
• Despite overlap of features, each may occur in almost isolated clinical form
Multiple System Atrophy (MSA)
128
Predominant Parkinsonism
Striatonigral degeneration
MSA-P
129
Predominantly cerebellar ataxia
Olivopontocerebellar degeneration
(OPCA)
MSA-C
130
Parkinsonism +@utonomic disorder (Orthostatic hypotension, ED, anhidrosis, dry mouth, incontinence))
Loss of intermediolateral horn cells and pigmented nuclei of the brainstem
Shy drager syndrome
MSA A
131
• Extrapyramidal illness is more severe
• 40% of patients are confined to a wheelchair or severely disabled within 5 years
• Relative symmetry of signs, rapid course, absence or minimal tremor, early presence of autonomic disorders, lack of response to L-dopa
• Anterocollis or dystonia of the lower facial muscles
Multiple System Atrophy (MSA)
132
MSA
• Histopathologic hallmark:
• Glial cytoplasmic inclusions
• Also made up of a-synuclein
133
Multiple System Atrophy (MSA) MRI
• T2 hyperintensities in the pontocerebellar tracts
• Pons (hot cross bun sign in MSA-C)
• MCP
• Cerebellum
• Abnormal putaminal signal in MSA-P
• Reduced GRE and T2 signal relative to globus pallidus and red nucleus
• Abnormally high T2 linear rim surrounding the putamen (putaminal rim sign)
• Disproportional atrophy
• MSA-C - cerebellum and brainstem (especially olivary nuclei and MCP)
• MSA-P - putamen
134
• Onset typically in 6th decade (45-75yo) - balance, falls, visual and ocular disturbances, slurred speech, dysphagia, personality changes
• Characterized by rigidity and dystonic postures of the neck and shoulders, staring and immobile facial expression and a tendency to topple when walking
• Gradual stiffening and extension of the neck (camptocormia)
• Staring, worried expression with furrowed brow due to tonic contraction of the procerus
• Inability to produce vertical saccades, progressing to paralysis of upward and downward gaze then eventual loss of lateral gaze
Progressive Supranuclear Palsy
135
PSP Onset
6th decade
136
• Characterized by rigidity and dystonic postures of the neck and shoulders, staring and immobile facial expression and a tendency to topple when walking
Progressive Supranuclear Palsy
137
Elderly
Imbalance
> falls c preserved consciousness
Dystonia of neck
Ocular palsy
PSP
138
Atrophy of the dorsal mesencephalon (superior colliculus and red nuclei)
Mouse ear sign / morning glory sign
139
Selective atrophy of dorsal midbrain on
mid-sagittal image.
Hummingbird sign
140
• Bilateral loss of neurons and gliosis in the periaqueductal gray matter, superior colliculus, subthalamic nucleus, red nucleus, pallidum, dentate nucleus, and pretectal and vestibular nuclei, and to some extent in the oculomotor nucleus
• Neurofibrillary degeneration of the residual neurons
• Neurofibrillary tangles are thick and often composed of single strands, either twisted or in a parallel arrangement
PSP
141
PSP Tx
• L-dopa - slight and unsustained benefit
• Zolpidem - GABA agonist; help with akiniseia and rigidity
• Benztropine and trihexyphenidyl - reduce dystonia
• Botulinum toxin injections
142
• Corticobasal degeneration (CBD)
• Progressive asymmetrical extrapyramidal rigidity with signs of corticospinal disease and ideomotor apraxia
• Early dementia, cortical sensory loss, apraxia, limb dystonia
• Alien limb phenomenon characterized by autonomous movements
• Unresponsive to L-dopa
• Pathology:
• Cortical atrophy mainly in the frontal motor-premotor and anterior parietal lobes
• • Degeneration of the substantia nigra and of dentatorubrothalamic fibers
• Asymmetric cerebral hemispheres
• Moderate gliosis in cortex and white matter
• Tau deposition
• Neuronal achromasia - ballooned and chromatolytic neurons with eccentric nuclei
• Posterior frontal and parietal neurons
Corticobasal Ganglionic Degeneration (CBGD)
143
Case of corticobasal syndrome presenting with a 'useless right hand'
Coronal FLAIR images demonstrate cerebral atrophy, most pronounced
in the left parietal region (arrows indicate sulcal enlargement)
Corticobasal Degeneration
144
Diffuse involvement of the cortical neurons with LB inclusions
• Absence or inconspicuous amount of NFTs and amyloid plaques
Lewy Body Dementia
(Diffuse Lewy Body Disease, DLB)
145
Symmetric parkinsonism
Fluctuations in behavior and condition
Recurrent hallucinations
REM sleep behavior
Extreme sensitivity to neuroleptics - increased confusion and worsening of parkinsonism
Lewy Body Dementia
(Diffuse Lewy Body Disease, DLB)
