PARKINSON’S DISEASE

What is the mandatory symptom of parkinson’s disease

Major cause of disability in PD patients

Bradykinesia

What is the most common symptom of parkinson’s disease

Tremors

Which symptom of parkinson’s has a late onset

Rigidity

Clinical manifestations of parkinsons:

• Onset type (Insidious/Sudden)

• Initially unilateral or bilateral?

• Mean time from inception of disease to chairbound state?

• 10% remain relatively mild and gradually progressive, almost stable for _____ years

Clinical manifestations of parkinsons:

• Insidious

• Initially unilateral

• 7.5 yrs

• 10 years

Slowness of movement and decrement in amplitude or speed (or progressive hesitations/halts) as movement continued

Bradykinesia

 reduction of amplitude of movement (decrementing)

Hypokinesia

 slow movement, difficulty initiating movement and loss of automatic movement

Bradykinesia

Limitation of facial expression

Hypomimia

small or cramped handwriting

Micrographia

fingers straighten, flexed, and adducted posture at MCP joints 

Striatal hand

Striatal hand but at toe

Striatal toe

rhythmic brief increases in resistance during passive movement 

Cogwheel rigidity

velocity-independent resistance to passive movement throughout ROM 

Lead-pipe rigidity

 helps elicit rigidity by contralateral motor activation of the hand (hand close/open or tapping on thigh) or with mental task like counting backwards or tracing circles in the air

Froment maneuver

4-6 Hz tremor in a fully resting limb suppressed during movement initiation and sometimes reemerges as the limb maintains a posture

Rest Tremor

Rest Tremor

Almost always ______, sometimes including lips and jaws  Rest tremor of hand ______ when walking, stress, or excitement  Classic ____________ → 4-per-second tremor of thumb and fingers; characteristic and seen in half of patients  Most ______ presenting symptom of PD (70%)

Rest Tremor

Almost always distally, sometimes including lips and jaws  Rest tremor of hand increases when walking, stress, or excitement  Classic pill-rolling tremor → 4-per-second tremor of thumb and fingers; characteristic and seen in half of patients  Most common presenting symptom of PD (70%)

Symptom that is not part of MDS-PD criteria (2015) for parkinsonism caused by PD and occurs in late stage PD

Postural Instability

Normal Pull test/retropulsion for testing postural instabiltity

2 steps

• 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

• Difficulty initiating steps and difficulty turning (en block turning)

• Overcome by visual cues

Freezing Phenomenon

• Shortened steps with compensatory increase in cadence

• Walking forward or backward seems to be chasing the body’s COG with a series of increasingly rapid short steps to avoid falling

• Frequent loss of balance

• Gait is improved by sensory guidance like holding the patient

Fenestration

Gait type observed on patients with fenestration

Shuffling gait

True or False:
Laboratory tests are used to definitively diagnose parkinson’s disease

False

What two examinations definitively diagnose parkinsons?

History and neurologic examination

Refer to jana’s trances for clearer pic of criteria

True or False:

• PD makes up 80% of parkinsonism

• PD is the fastest growing of all neurologic disorders

• Overall PD worldwide prevalence across all ages around 1% and decreases with age 

• Idiopathic PD is seen in all countries, ethnic groups, and socioeconomic classes

• Incidence in Asians is 1/3-1/2 higher than in whites

True or False:

• TRUE

• TRUE

• Overall PD worldwide prevalence across all ages around 1% and INCREASES with age 

• TRUE

• Incidence in Asians is 1/3-1/2 LOWER than in whites

Mean age of onset of PD

60 yrs

Mean age of onset of juvenile PD

20 yrs

age of young onset PD

20-50yrs

Enumerate Motor symptoms of PD

• Resting tremor

• Muscle Rigidity

• Bradykinesia

• Postural instability

• Gait instability

• Hypomimia

Enumerate non-motor symptoms of PD

• Neurobehavorial changes

• Autonomic failure

• Sleep Disorders

• Sensory impairments

• Miscellaneous (weight loss, osteo, malnutrition etc.)

Arrange the chronological order of motor symptoms of PD:

• Fluctuations & Dyskinesia

• Bradykinesia, resting tremors, rigidity

• Postural Instability, Dysphagia, falls, gait disturbance (freezing)

Arrange the chronological order of motor symptoms of PD:

• Fluctuations & Dyskinesia (2nd)

• Bradykinesia, resting tremors, rigidity (First)

• Postural Instability, Dysphagia, falls, gait disturbance (freezing) (3rd)

True or False:
Neuropathology of PD includes loss of darkly pigmented cells in the SNPc and other pigmented nuclei (locus ceruleus, dorsal motor nucleus of vagus)

True

True or False:

Depigmentation directly correlated with the death of the dopaminergic neuromelanin-containing neurons in the SNPr and noradrenergic neurons in the locus ceruleus

FALSE

Depigmentation directly correlated with the death of the dopaminergic neuromelanin-containing neurons in the SNPc and noradrenergic neurons in the locus ceruleus

True or False:

Denervation of nigrostriatal pathway leads to diminished levels in the striatum 

True

What causes cardinal motor symptoms in PD

Reduction of dopaminergic signaling

Hallmark of PD 

Lewy body pathology

Lewy Body Pathology

Presence of cytoplasmic deposits within neuronal cell bodies which are immunoreactive for?

α-synuclein

pathologic protein aggregates in the brain are called?

Lewy bodies

Intracytoplasmic inclusions consisting of a granular and fibrillar core with surrounding halo

Primary structural component of LB

filamentous α-synuclein

Assessment of LB distribution

BRAAK staging

LB pathology spreads _____________, in a chronologically predictable sequence

Rostrocaudally

True or False:

All LB pathology follow the rostrocaudal pattern.

False

Identify the braak stage:

LB found in the temporal mesocortex

Stage 4

Identify the braak stage:

LB found in the dorsal motor nucleus of the vagal nerve and anterior olfactory structures

Stage 1

Identify the braak stage:

LB found in the lower raphe nucleus and locus ceruleus

Stage 2

Identify the braak stage:

LB found in the temporal mesocortex, sensory association and premotor areas

Stage 5

Identify the braak stage:

LB found in the substantia nigra, amygdala, nucleus basilis of meynert

Stage 3

Identify the predicted clinical presentations of the stage:

Stage 4

Previous symptoms worse, Emotional disturbance

Identify the predicted clinical presentations of the stage:

Stage 2

Affective impairment, anxiety, sleep disturbance

Identify the predicted clinical presentations of the stage:

BRAAK Stage 1

Olfactory loss, autonomic dysfunction

Identify the predicted clinical presentations of the stage:

Stage 5

Previous symptoms worsen, Cognitive changes

Identify the predicted clinical presentations of the stage:

Stage 3

Motor symptoms

Etiology of Lewy Body Pathology

Most are _________ Environmental:  _________→ street heroin contaminant  ? Pesticides and heavy metals → rural farming environment  Head injury  Negative associations with risk of developing PD (decreases risk)   Enumerate

Etiology of Lewy Body Pathology

Most are idiopathic  Environmental:  MPTP → street heroin contaminant  ? Pesticides and heavy metals → rural farming environment  Head injury  Negative associations with risk of developing PD (decreases risk)  Smoking  Coffee drinking  Use of anti-inflammatory medication  High plasma urate levels  Physical activity

1: MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE STRESS

Decreased _______ synthesis, build-up of free radicals causing oxidative stress  Reduced ________ → elimination of ROS (reactive oxygen species) Increased iron levels in _______→ catalyze the formation of highly reactive hydroxyl radicals from hydrogen peroxide

1: MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE STRESS

Decreased ATP synthesis, build-up of free radicals causing oxidative stress  Reduced glutathione→ elimination of ROS (reactive oxygen species) Increased iron levels in SN → catalyze the formation of highly reactive hydroxyl radicals from hydrogen peroxide

2: α-SYNUCLEIN MISFOLDING AND AGGREGATION

Found in _____________ of presynaptic neurons  Α-synuclein misfolds and adopts a ___________-like structure that is prone to aggregate

2: α-SYNUCLEIN MISFOLDING AND AGGREGATION

Found in axon terminals of presynaptic neurons  Α-synuclein misfolds and adopts a β-sheet amyloid-like structure that is prone to aggregate

3: DYSFUNCTIONAL PROTEIN CLEARANCE SYSTEMS

_____________ (UBS) __________________ pathway

3: DYSFUNCTIONAL PROTEIN CLEARANCE SYSTEMS

Ubiquitin proteasome system (UBS) Autophagy-lysosome pathway

4. NEUROINFLAMMATION

Microglial and complement activation, ___________ infiltration, increased concentration of pro-inflammatory cytokines in the _____ and ________ ______ scan → increased microglial activation in early PD in the brainstem, basal ganglia, and frontotemporal cortices and occipital cortices in those with PD dementia

4. NEUROINFLAMMATION

Microglial 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 occipital cortices in those with PD dementia

Scale for lewy body parkinsonism clinical staging

Modified Hoen-Yahr scale

Used for assessment of motor and nonmotor symptoms of PD; measures progression of disease

MSD-UPDRS

To decrease dopamine what enzyme should be inhibited

DOPA decarboxylase

To increase dopamine what enzyme/s should be inhibited

MAO & COMT

To decrease DOPA what amino acid should be inhibited

L-DOPA & L-Dihydroxyphenylalanine

Drug/s that is/are a MAO inhibitor

Selegiline, Rasagiline, Safinamide

Drug that is a COMT inhibitor

Entacapone

Drug that is a dopamine precusor

Levodopa-Carbidopa

Drug that is a dopamine agonist

Pramipexole

Drug/s that is/are anticholinergic

Trihexyphenidyl, Benztropine mesylate

Drug/s that is/are antiglutamatergic

Amantadine

Drug/s that is/are Serotonin and Dopamine antagonist

Quetiapine

Indications for Levodopa-carbidopa

Motor symptoms, tremors, bradykinesia

Initating drug or add on for levodopa

Pramipexole, Selegiline

This drug prolongs levodopa

Entacapone

Add on for levodopa and/or dysikinesia

Safinamide

Indicated for young pt, Tremor dominant

Trihexyphenidyl

Add on for dyskinesia

Amantadine

Drug indicated for psychiatric symptoms

Quetiapine

True or False:

Pramipexole can cause dyskinesia and diarrhea as side effects

False:

Entacapone causes these side effects

What are the side effects expected when taking Levodopa-carbidopa

Nausa, Dyskinesa, Hallucinations

What are the side effects expected when taking Pramexipole?

Orthostatic hypotensive, sleepiness, hallucinations, impulse control disorders

What drug causes elevated BP with sympathomimetics as a side effect?

Selegiline

Which drug causes Dizziness and confusion as a side effect?

Rasagiline

Which drug causes Visual hallucinations as a side effect?

Safinamide

This drug causes dryness of mouth, constipation, urinary retention as side effects

Trihexyphenidyl

Which drug has side effects of confusion, hallucination, heart failure leg swelling, and worsens CHF

Amantadine

This drug can cause Worsening of PD symptoms

Quetiapine

• 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

Extend elimination half life of Levodopa by preventing its breakdown

COMT Inhibitors

short half life; dosing with Levodopa

Entacapone

longer half life; hepatotoxic

Tolcapone

delays the time to develop complication from chronic Levodopa use

Dopamine Agonists

• Delays the need for levodopa for average of 9 mos.

• Used for treatment of early stage PD, mild symptomatic effect

MAO B Inhibitor

• Less effective antiparkinsonian agent than dopamine agonist

• More effective against tremor

Anti- Cholinergics

• 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 anticholinergic and anti-glutaminergic effects

• Anti-dyskinesia

Amantadine

Most potent anti-PD medication

Levodopa (L-Dopa or L-Dihydroxy- Phenylalanine)

True or False:

Striatal dopamine is depleted in PD but the remaining diseased nigral cells are still capable of producing some dopamine by taking up its precursor

True

True or False:
Levodopa can treat bradykinesia, rigidity and tremors effectively

False:
Bradykinesia and rigidity respond best but tremor can be resistant

True or False:
Higher dosages of levodopa decreases the likelihood of motor symptoms to occur in PD

False:
Longer duration of disease and the higher the dose the more likelihood of motor complications to occur

• Rarely done

• Placement of lesion in the GP, VL thalamus or STN contralateral to body side affected

• Best in young pts, unilateral tremor or rigidity

Ablative Surgical Therapy

• Target: ventral and intermediate nuclei

• For contralateral intractable tremor 

• Stimulation of the STN

Thalamotomy and thalamic stimulation

• Target: posterolateral Gpi

• For contralateral dopa-induced dystonia and chorea

Pallidotomy and pallidal stimulation