Parkinson's Disease Flashcards
Describe the concept of exercise is medicine
- Skilled exercise that entails perceptual & a higher level cognitive processyngtarget prefrontal & associated cortical circuits for executive function
- Aerobic exercise: brood increase in cerebral blood flow including brain circuits in the BG and cerebellum
- Global factors activated: reduced oxidative stress, reduced neuro-inflammation, increased expression of neurotrophic factors
Incidence of Parkinson’s
- 2nd most common neurodegenerative disorder after Alzhiemer’s
- Global data indicate that PD will become a pandemic
Risk factors for PD
- Risk increases with age: prevalence rises sharply after 50 y/o
- White Americans & europeans > black africans
- Family history: autosomal dominant Parkinsonism (synuclein, UCHL1, NURR1, LRRK2) and autosomal recessive disease (DJ1, PINK1, parkin)
- Toxic exposures: carbon monoxide, Manganese, Cyanide, Methanol, MPTP, Neuroleptics, Pesticides/Herbicides
- Infection exposures: Measles, Rubella, Herpes simplex 1 & 2
- Men 1.5x more than women
- More years of formal education increases risk
- Smoking may decrease risk
- High levels of physical exercise may lower one’s risk
Parts of the basal ganglia
- Striatum: caudate nucleus, putamen, & nucleus accumbent
- Lentiform nucleus: putamen & globus pallidus
- Globus pallidus: external and internal segments
- Substantia nigra: pars compacta & pars reticulata
- Subthalamic nucleus (STN)
What is the main input and output region of the basal ganglia (BG)
- Input: striatum
- Output: globus pallidus internal & substantia nigra reticulata
What does the Striatum, Globus pallidus internal, and Substantial nigra reticulata do
- Striatum: receives afferents from the cerebral cortex including motor & premotor, cingulate, & prefrontal cortices, & the intralaminar nuclei of the thalamus
- GPi & SNr: project to the thalamus modulating activity of cortical regions & to the brainstem
Describe goal directed behavior done by the BG
- Caudate head participates in evaluating the full context of potential actions and selects the appropriate action to take
Describe social behavior done by the BG
- Head of the caudate is part of the circuit that recognizes social cues, regulates self-control, and parses out relevant from irrelevant information
Describe emotional/motivation done by the BG
- Ventral striatum (also called the nucleus accumbens) and the ventral putamen involved in seeking rewards, an essential aspect of motivation
- Is involved in predictions when the outcome is unknown
What is the oculomotor function of the BG
- Patients with basal ganglia pathology demonstrate impaired saccadic eye movements
Describe the cortico-BG-thamalic motor circuit
- Hyperdirect pathway: “Stop”; stops ongoing movements
- Direct pathway: “Go”; facilitates desired movement
- Indirect pathway: “No-Go”; suppresses unwanted movements
Describe the Nigrostriatal pathway in the BG
- Composed of dopaminergic neurons whose cell bodies are located in the substantial nigra pars compacta
- Project to the BG and synapse in the striatum
- Parkinson’s: the nigrostriatal pathway degenerates = marked loss of dopaminergic neurons that project to the putamen; more modest loss of those that project to the caudate
Describe normal function of the basal ganglia (BG)
- Target 1: The inhibition of the motor thalamus contributes to a normal level of activity in the corticospinal tracts. This induces these tracts to provide a normal level of facilitation to the lower motor neurons that innervate voluntary muscles.
- Target 2: The IGP inhibits the PPN. Then the PPN inhibits the reticulospinal tracts, which in turn provide the normal level of facilitation to lower motor neurons that innervate postural and girdle muscles, thus controlling muscle tone.
- Target 3: The IGP inhibits the midbrain locomotor region. The midbrain locomotor region stimulates reticulospinal neurons that activate stepping pattern generators, facilitating walking or running.
What does an overactive globus pallidus internus excessively inhibit and result in
- Motor thalamus
- Pedunculopontine nucleus (PPN)
- Midbrain motor region
- Results in: inadequate facilitation of voluntary movement, overactivity of postural & girdle muscles (rigidity), inadequate facilitation of stepping pattern generators for walking
Parkinson’s versus Parkinsonism
- Parkinsonism is a general term that refers to a group of neurological disorders that cause movement problems similar to those seen in Parkinson’s disease such as tremors, slow movement and stiffness.
What disorders fall under Parkinsonism
- Progressive Supranuclear Palsy (PSP)
- Multiple System Atrophy (MSA) aka - - – - Shy-Drager Syndrome
- Vascular Parkinsonism (e.g. basal ganglia strokes)
- Dementia with Lewy Bodies
- Corticobasal Degeneration
- Drug Induced Parkinsonism (anti-psychotics, amphetamines, cocaine)
What is the 1st essential criterion for diagnosing Parkinson’s
- Parkinsonism, which is defined as bradykinesia in combination with at least 1 of either rest tremor or rigidity
Supportive criteria for diagnosis of Parkinson’s disease
1) Clear & dramatic beneficial response to dopaminergic therapy
2) Presence of levodopa-induced dyskinesia
3) Rest tremor of a limb documented in clinical exam
4) The presence of either olfactory loss or cardiac sympathetic denervation on MIBG scintigraphy
Absolute exclusion criteria for Parkinson’s (presence of any one of these features rules out PD)
- Unequivocal cerebellar abnormalities, such as cerebellar gait, limb ataxia, or cerebellar oculomotor abnormalities (eg, sustained gaze evoked nystagmus, macro square wave jerks, hypermetric saccades)
- Downward vertical supranuclear gaze palsy, or selective slowing of downward vertical saccades
- Diagnosis of probable behavioral variant frontotemporal dementia or primary progressive aphasia, defined according to consensus criteria within the first 5 yrs of disease
- Parkinsonian features restricted to the lower limbs for more than 3 yrs
- Treatment with a dopamine receptor blocker or a dopamine-depleting agent in a dose and time-course consistent with drug-induced parkinsonism
- Absence of observable response to high-dose levodopa despite at least moderate severity of disease
- Unequivocal cortical sensory loss (ie, graphesthesia, stereognosis with intact primary sensory modalities), clear limb ideomotor apraxia, or progressive aphasia
- Normal functional neuroimaging of the presynaptic dopaminergic system
- Documentation of an alternative condition known to produce parkinsonism and plausibly connected to the patient’s symptoms, or, the expert evaluating physician, based on the full diagnostic assessment feels that an alternative syndrome is more likely than PD
Red flags/indicators that PD is less likely
- Rapid progression of gait impairment requiring w/c within 5yrs of onset
- Absence of progression of motor symptoms over ≥5yrs
- Early bulbar dysfunction
- Inspiratory respiratory dysfunction
- Severe autonomic failure in first 5yrs of disease
- Recurrent falls bc of impaired balance within 3yrs of onset
- Disproportionate anterocollis (dystonic)
- Absence of any of the common non-motor features of disease despite 5yrs duration
- Pyramidal weakness or clear pathologic hyperreflexia
- Bilateral symmetric Parkinsonism
When is it timely to know a Parkinson’s diagnosis
- Earlier the better: early/asymptomatic: some people will want to know their risk
- Depends on availability of neuroprotective strategies: will only want to know if something can be done to alter risk/asymptommatic disease
- Some will only want to know when symptomatic
- Some may never want to know
Ideas that support early diagnosis of Parkinson’s
- Individual’s right to know
- Highlight opportunities for health improvement & potential disease modification
- Early access to support services
- Opportunity to interact with research
- Provide reason/understanding for symptoms
- Targeted treatment
- Wider window of opportunity to initiate dopamine replacement therapy
Ideas that support against early diagnosis of Parkinson’s
- Individual’s right to not know
- Limited access to specialist services for existing pts
- Impact on insurance/driving restrictions
- Lack of proven disease modifying treatment
- Risk of causing social/psychological harm
- Risk of over medicalization of aging & over diagnosis
- Stigma associated with diagnosis of PD
Subtypes of Parkinson’s Disease
- PIGD (postural instability gait difficulty): late onset PD, faster rate of cognitive decline & a higher incidence of dementia, rapid disease progression more common
- Tremor dominant: young onset PD, good prognosis with slow progression, often initially misdiagnosed as essential tremor
- Mixed Parkinson’s Disease
Staging of the Hoehn and Lahr classification of disability for Parkinson’s
- Stage I: minimal or absent, unilateral if present
- Stage II: minimal bilateral or midline involvement, balance not impaired
- Stage III: impaired righting reflexes, unsteadiness when turning or rising from chair, some activities limited but pt can live independently & continue some forms of employment
- Stage IV: all symptoms present & severe, standing & walking possible only with assistance
- Stage V: confined to bed or wheelchair
Common movement disorders in people with Parkinson’s Disease
- Bradykinesia: slowness of movement that is ongoing
- Akinesia: indicates failure of voluntary/spontaneous/associated movement
- Episodes of freezing
- Impaired balance & postural control
- Dyskinesia
- Tremor
- Rigidity
- Adaptive responses
Cardinal signs of Parkinson’s Disease
- Bradykinesia: slow movement
- Rigidity
- Resting tremor
- Postural instability
Describe bradykinesia
- General reduction of spontaneous movement; appears as abnormal stillness & decrease in facial expressivity (hypomimia=masked facies)
- Causes reduction in speed & amplitude of repetitive movements (finger tapping, walking)
Define hypokinesia
- Refers to movements that are smaller than desired in particular with repetitive movements
Define sequence effect
- Refers to amplitude reduction during movement repetition (reduction of hand writing = micrographia)
Although both speed and movement amplitude are affected in PD
- Speed is usually disproportionally more affected in off state and less normalized by levodopa than the movement amplitude, suggesting that they may be associated with partially separate mechanisms
What do ALL people with bradykinesia experience
- Difficulty in performing repetitive or sequential movements of the limbs
- Movement size progressively decreases during sequential actions
- When a person with PD stop a movement sequence to rest & begin again the movement size & speed start close to normal and begin to reduce as they continue the sequence
Describe rigidity
- Stiffness & inflexibility of the limbs, neck, and trunk
- Muscle (increased) tone of an affected limb is always stiff & does not relax sometimes contributing to a decreased ROM
- May manifest as: reduced arm swing, decreased trunk rotation, decreased dissociation of shoulder/hips, rolling/turning, reduced joint ROM during postural transitions & gait
Is rigidity more marked in flexor or extensor muscles
- More marked in flexor muscles
Is rigidity more remarkable during slow or fast stretching
- More remarkable during slow stretching
- Help differentiate PD rigidity from spasticity which is worse during fast displacement
Define Cogwheel phenomenon
- Result of coexisting rigidity and tremor
How can rigidity be detected
- Detected by slow passive movement of the affected body part while the person focuses their attention on a secondary task
Define axial rigidity
- Limits rotation & extension of trunk and spine = roll “en bloc”
Difference between lead pipe rigidity and cogwheel rigidity
- Lead pipe: slow and sustained
- Cogwheel: where tremor is superimposed on rigidity
Describe a resting tremor
- Initial onset: slight tremor in hand or foot on one side or (less commonly) in jaw or face (pill rolling tremor)
- Affected body part trembles when not performing an action
- Usually ceases when begins an action
- Exacerbated by stress or excitement
- Often spreads to other side of body as disease progresses
- Not all PD pts will develop tremor
- Typical frequency = 4-6 Hz
- Does NOT respond readily to dopaminergic tx
Describe the different types of tremor
- Resting: PD cardinal sign especially in the tremor-dominant subtype
- Action: aka reemergent tremor, reappears few seconds after transition from rest to posture & has a frequency similar to resting tremors
- Essential tremor
- Dystonic tremor
- Exaggerated physiological tremor
Describe postural instability
- Loos/slowing of reflexes needed for maintaining upright posture; may topple backwards if jostled
- Tendency to sway backwards when rising from chair, standing, or turning
- Difficulty when pivoting or making turns or quick movements
- Would perform a Pull Test
Describe a Pull Test
- Normal response = quick backwards step to prevent a fall
- Parkinson’s = most are unable to recover & would tumble backwards if the neurologist were not right there to catch them
Define freezing gait
- Defined as a “brief” episodic absence or marked reduction of forward progression of the feet despite the intention to walk
How can a freezing of gait (FOG) episode manifest
- Step size reduction (shuffling gait)
- Knee trembling
- Akinesia
- Typically described as feeling the feet as frozen or glued to the ground
FOG is often triggered or worsened by challenging situations or provocative environments such as
- Changing direction (turning hesitation)
- Approaching narrow doorways (tight quarter hesitation) or destinations (destination hesitation)
- Moving into crowded spaces
- Walking on a slippery surface
- Crossing thresholds or changes in floor
- Stepping into an elevator or entering a revolving door
- Dual tasking: walking and talking
All of the challenging situations or provocative environments that trigger or worsen FOG require what
- Require a dynamic adaption of motor schema because of an increased cognitive load
PD patients with FOG are responsive to
- Visual cues: stepping over a small obstacle
- Auditory cues: following a rhythm to step to the beat
5 non-exclusive pathophysiological mechanisms that are hypothesized to underlie the manifestation of FOG
1) Dopaminergic insult in the sensorimotor striatum causing an over-activation of inhibitory GPi/SNr that in turn sends strong GABAergic projections to the brainstem and thalamic locomotor regions, thereby disrupting efficient processing of gait
2) Goal-directed strategies are spared and as a result, gait becomes less automated and vulnerable to interference from consecutive task demands that can paroxysmally disrupt gait control
3) Hyper-direct pathway becomes engaged as a result of increased response conflict, activating the GPi/SNr while also disrupting cerebellar processing involved with automated gait modulation. Altered 5-7 Hz oscillations between the STN and GPi may also cause ‘trembling in place’ often observed during FOG
4) Processing across competing yet complementary motor, cognitive and limbic cortico-basal ganglia loops results in cross-talk b/w competing inputs and further depletion of the gait-related sensorimotor striatum of dopaminergic resources thereby disrupting gait
5) Extra-nigral pathology impairs compensatory attentional gait strategies and contributes to L-dopa resistant FOG
Non-motor symptoms of PD
- Sleep disorders: increased Parkinsonism, restless legs syndrome, REM behavioral disorder, nightmares
- Cognitive dysfunction: bradyphrenia, dementia, hallucinosis, psychosis
- Affective disturbances: apathy, depression, impulse control disorder
- Anxiety/panic
- Dysautonomia: constipation, orthostatic hypotension, neurogenic bladder
Non-motor features of Parkinson’s disease as a result from multiple neurotransmitter deficiencies in the central and peripheral nervous system
- Psychiatric depression
- Neuropsychiatric symptoms (general anxiety, phobia, panic attacks)
- Apathy
- Hallucinations
- Delusions
- Autonomic Dysfunction: constipation, orthostatic hypotension, sexual dysfunction, urinary disturbances
- Cognitive impairment: involvement of executive functions, memory, and visuospatial functions up to dementia
- Sleep disorders: Restless legs, REM sleep disorder, excessive daytime somnolence, vivid dreaming, insomnia
- Olfactory dysfunction
- Pain
There is strong evidence that some non-motor features of PD may be the earliest disease manifestations, occurring years before any of the defining motor features are present, especially
- Hyposmia
- Constipation
- Rapid eye movement (REM) sleep behavioral disorder
What motor symptoms do not respond to Levodopa (L-dopa)
- Postural instability
- Autonomic dysfunction
- Freezing of gait
- Dysarthria
- Most non-motor symptoms
Medications for Parkinson’s disease
- Levodopa
- Carbidopa
- Catechol-O-Methyl Transferase Inhibitors
Describe Levodopa
- taken up by remaining dopaminergic neurons & converted to dopamine
- Improves rigidity, bradykinesia
- Becomes less effective over time, can lead to dyskinesias & motor functions
Describe Carbidopa
- Sinemet, typically used in conjunction with levodopa
- Inhibits breakdown of levodopa, decreases amount of levodopa required for therapeutic benefit
Describe Catechol-O-Methyl Transferase Inhibitors
- Entacapone
- Slow the breakdown of dopamine, reduce off times
Dopamine agonists
- Pramipexole (Mirapex)
- Ropinorole (Requip)
- Rotigotine (Neupro)
- Bromocryprine (Parlodel)
- Apomorphine (Apokyn)
Advantages and disadvantages of Dopamine agonists
- Dis: not as effective as L-dopa
- Adv: longer half life, less likely to cause long-term complications, helpful for restless legs
Side-effects of Dopamine agonists
- Nausea
- Orthostatic hypotension
- Dizziness
- Somnolence
- Impulse control disorders
- Psychosis
Describe COMT inhibitors
- Tolcapone (Tasmar) and Entacapone (Comtan, Stalevo)
- Do not have a therapeutic effect unless used in combination with L-dopa
List L-dopa extenders
- COMT inhibitors
- MAO-B inhibitors
Describe MAO-B inhibitors
- Selegiline (Eldepryl, Zelapar), Rasagiline (Azilect), and Safinamide (Xadago)
- Have a symptomatic effect independently of L-dopa
- Slows down the breakdown of L-dopa, improves efficiency
Describe Anticholinergics
- Trihexphenidyl HCI (Artane, Benztropine (Cogentin)
- Meant to restore acetylcholine/dopamine balance in the basal ganglia
- Sometimes helpful in treatment resistant tremor
- Common side effects: constipation, dry mouth, dry eyes, blurred vision, cognitive dysfunction, hallucinations, sleepiness
Descibre Amantadine
- Amantadine (Symmetrel, Gocovri)
- Useful in early PD, dyskinesias
- Common side effects: ankle edema, confusion, hallucinations
Describe Botulinum toxin injections
- Dystonia can be a symptom of PD or a side effect of L-dopa and may respond to this treatment
End of dose failure (wearing off) of L-dopa
- Decrease L-dopa interval
- ER formulation (Rytary)
- Ass a dopamine agonist
- Add a L-dopa extender (COMT or MAO inhibitors)
- Consider advanced treatments: DBS or intestinal infusion
Peak dose dyskinesias of L-dopa
- Decrease individual dose & increase frequency
- ER formulation (Rytary)
- Add an agonist or an extendor & lower L-dopa dose
- Use amantadine or ER amantadine (Gocovri)
- Consider advanced treatments: DBS or intestinal infusion
Clinical relevance in PD related to motor fluctuations
- Regardless of medication status patients with PD demonstrate immediate improvements in performance on core outcomes across multiple domains of function following forced exercise cycling intervention
Describe motor fluctuations
- Include wearing off, delayed on, partial on, no on, and on off fluctuations
Describe dyskinesias
- Choreic, ballistic, or dystonic involuntary movements
- Can be classified into peak dose, biphasic, & square wave dyskinesia
- Dystonia often accompanies motor fluctuations & dyskinesia & may appear in off and on phases
Good versus poor candidate for DBS (deep brain stimulation) treatment
- Good: younger, fluctuations, appreciate response to L-dopa; no dementia/hallucinations/psychosis, no atrophy on MRI, no atypical features
- Poor: older, questionable response to L-dopa, dementia, psychosis, or hallucinations, brain atrophy, no fluctuations, severe speech impairment, severe depression, impulsive behaviors
Treating motor symptoms with DBS (deep brain stimulation) can, cannot, and may improve/worsen
Can improve: fluctuations of motor response, dyskinesia, rigidity, tremor, & bradykinesia, reduce the necessary amount of L-dopa to control sx
- Cannot improve: freezing that does not respond to L-dopa, postural instability or falling
- May worsen: cognitive decline, hallucinations, depression
Aerobic exercise guidelines for PD patients
- Moderate to high intensity training to improve oxygen consumption (VO2), reduce motor disease severity, & improve functional outcomes
- High evidence
- Strong recommendation
Resistance training guidelines for PD patients
- Should implement to reduce motor disease severity & improve strength, power, non-motor sx, & functional outcomes & QOL
- High evidence
- Strong recommendation
Balance training guidelines for PD patients
- Reduces postural control impairments & improve balance and gait outcomes, mobility, balance confidence & QOL
- High evidence
- Stong recommendation
Flexibility exercises guidelines for PD patients
- Improve ROM
- Limited evidence
- Weak recommendation
External cueing guidelines for PD patients
- Reduces motor disease severity & freezing of gait & to improve gait outcomes
- High evidence
- Strong recommendation
Community based exercise guidelines for PD patients
- Reduces motor disease severity, improve non-motor symptoms, functional outcomes, & QOL
- High evidence
- Strong recommendation
Gait training guidelines for PD patients
- Reduces motor disease severity, and improve stride length, gait speed, mobility, & balance
- High evidence
- Strong recommendation
Task specific training guidelines for PD patients
- Improve task specific impairment levels & functional outcomes
- High evidence
- Strong recommendation
Behavior change approach guidelines for PD patients
- Improve physical activity & QOL
- High evidence
- Strong recommendation
Integrated care guidelines for PD patients
- Reduces motor disease severity & improve QOL
- High evidence
- Strong recommendation
Telerehabilitation guidelines for PD patients
- Improves balance
- Moderate evidence
- Weak recommendation
Deep brain stimulation guidelines for PD patients
- More research is needed on effects of PT interventions in individuals undergoing deep brain stimulation
- Best practice recommendation
Expert care guidelines for PD patients
- Improves outcomes compared with services provided by those without expertise
- Best practice recommendation
Aerobic exercise recommendations
- 3 days/wk
- At least 30 min/session of continuous or intermittent exercise
- Moderate to vigorous intensity (3-4 = moderate and 5-7 = vigorous)
Strength train recommendations
- 2-3 days/wk, non-consecutive
- 30 minutes/session
- 10-15 reps for major muscle groups
- Focus on speed or power
- Target ON time
- Focus on extensors
Balance training recommendations
- 2-3 days/wk, ideally daily
- Multi-directional stepping
- Weight shifting
- Dynamic balance activities
- Large movements
- Yoga, dance, boxing
Stretching recommendations
- > 2-3 days/wk, ideally daily
- Sustained stretching with deep breathing
- Dynamic stretching before exercise
