PD

Question 1

Parkinson Disease

Answer 1

• A neurological disease that is the most common cause of parkinsonism, a syndrome manifested by rest tremor, rigidity, bradykinesia and postural instability.

Question 2

Pathophysiology Parkinsons Disease

Answer 2

• The critical abnormality in PD is a loss of neurons in the substantia nigra pars compacta of the midbrain.
• Dopamine depletion from the basal ganglia disrupts connections to thalamus and motor cortex resulting in the parkinsonium features.
• In basal ganglia there are two main pathways - direct and indirect which increases movements and decreases movements, respectively. In both of these pathways, the substantian nigra pars compacta plays an important role in modulating this activity. Ulimately, the result in PD is that the SNc cannot initiate more movement in the direct pathway and cannot prevent excessive reduction of movement in the indirect pathway, producing bradykinesia.
• The rigidty and tremor in PD are thoguht to be due to a dopamine/cholinergic imbalance

Question 3

Diagnosis of PD

Answer 3

Diagnosis is made by presence of essential criteria and supportive criteria, and absence of red flag critera (argue against PD diagnosis) and absolute exclusion criteria.

• Essential crtieria - Bradykinesia + Rest tremor or rigidity
  
  • Bradykinsease - slowness of movement or progressive halts as movement continues.
  • Rigidity - lead -pipe resistance to passive movements of major joint when patient is in relaxed position, or cogwheeling.
  • Rest tremor - tremor observed in fully resting limb and suppressed when initiating movements (usually starts unilaterally).
• Supportive criteria - clear benefit from treatment with dopaminergic drugs; presence of L-Dopa induced dyskinesia; rest tremor in limbs documents on previous or current exam; olfactory loss
• Red flag criteria - rapid progression of gait impairment requiring wheelchair use in 5 years, absence of disease progression over 5 years, early bulbar dysfunction, etc.
• Absolute exclusion criteria - unequivocal cerebellar abnormalities, downward or vertical supranuclear gaze palsy, diagnosis of probably FTD, etc.

Question 4

Clinical Manifestations PD

Answer 4

• Cardinal features - rest tremor, bradykinesia, rigidity, and postural instability (only occurs much later in disease course).
• Tremor - Tremor in PD is a rest tremor, meaning it is most noticeable when body part is supportive by gravity and not engaged in purposeful activity. If tremor is present during activity, it is much more severe at rest.
• Bradykinesia - generalized slowness of movement, decreased ability to initiate voluntary movement
  
  • Arms - tends to start distally making it difficult to perform dexterous movements of the fingers.
  • Legs - dragging of the legs, shuffing gait, feeling of unsteadniness, gait freezing, festination.
• Rigidity Increased resistance to passive movements about a joint.
  
  • Cogwheel rigidity - ratchety pattern of resistance and relaxation - thought to be due to tremor + increased tone.
  • Lead pipe rigidity - tonic resistance throughout entire range of passive movement.
• Postural instability - impairment of centrally-mediated postural reflexes that cause a feeling of imbalance and a tendency to fall with significant risk of injury. Tends to not occur until later in disease course.
• Nonmotor symptoms - MCI, dementia, psychosis and hallucinations, mood disorders, sleep disturbances, fatigue, autonomic dysfunction, olfactory dysfunction, gastrointestinal dysfunction, pain and sensory disturbances. dermatologic findings, rhinorrhea.

Question 5

Pharmacological Treatment PD

Answer 5

• Levodopa - most effective drug for symptomatic treatment. Particularly effective for bradykinesia. Combined with a peripheral decarboxylase inhibitor (carbidopa) to prevent conversion to dopamine in systemic circulation and liver before it crosses the BBB.
• Dopamine agonist (DA) - used as a monotherapy in early PD and in combination in more advance disease. Not effective in patients who don’t response to L-Dopa. Related to an increase risk of impulse control disorders, but may delay need for L-Dopa treatments, and is associated with fewer motor fluctuations. May want to start younger patients (<65) on DA as there is a higher rate of L-Dopa related dyskinesia in young-onset PD.
• Monoamine oxidase type B (MAO B) inhibitors - useful in early PD, but only has modest benefits as a monotherapy.
• Anticholinergic drugs - most effective as a monotherapy in younger patients with tremor, but without significant bradykinesia or gait disturbance. Also useful for those on L-dopa or DA with a persistant tremor. Should NOT be used in older patients or in demented patients.
  
  • Dopamine and acetlycholine are usually in a state of balance in the basal gaglia. In PD, dopamine creates state of cholingeric sensitivity so that cholingeric drugs enhances and anti-cholinergic drugs reduce parkinsonian symptoms.
• Amantadine - weak antiparkinsonian medication most useful in younger patients with early or mild PD. Thought to increase dopamine release, inhibit re-uptake, stimulate receptors, and possiblty exert central anticholinergic effects.
• COMT inhibitors (tolcapone and entacapone) - ineffective alone, but may prolong L-Dopa. words by reducing methylation of L-Dopa to dopamin increasing the half-life and producing more stable plasma concentrations. Only helpful if patient has motor complications.

Question 6

L-Dopa related complications

Answer 6

• Nausa, dizziness, headache, confusion, hallucinations, delusions, agitation, psychosis, and orthostatic hypotension
• Motor fluctuations - wearing-off phenomenon
• Dyskinesia - involuntary movements
• Dystonia - abnormal cramps and postures of the extremities
• There is a concern that L-Dopa may hasten degeneration of dopamine neurons in substantia nigra by promoting generation of free radicals and oxidative stress - this + sides effects is why it is recommended to delay the use of L-Dopa

Question 7

Dopamine Agonist Side effects

Answer 7

• N/V, sleepiness, orthostatic hypotension, confusion, and hallucinations
• Valvular heart disease
• Dopaminergic dysregulation syndrome - complusive use of dopamingeric drugs. Can be associated with cyclical mood disorder characterizeby by hypomania or manic psychosis. Tolerance to mood-elevating effects of DA may develop and withdrawal occurs.
• Impulse control disorders - pathological gamblings, compulsive sexual behaviour, or complusive buying
• DA withdrawal syndrome - symptoms resemble those of cocaine withdrawal.

Question 8

Basal Ganglia

Answer 8

• Basal ganglia is a collection of subcortical nuclei related by function, not anatomy.
• Components of the basal ganglia can be divided into input, intrinsic and output nuclei
  
  • Input (strucutres receiving incoming information from different sources) - caudate nucleus and putamen
  • Intrinsic (link input and output nuclei) - external globus pallidus, subthalamic nucleus, pars compacta of substantia nigra
  • Output nuclei (structures that send basal ganglia information to the thalamus) - internal globus pallidus, pars rectiularis of substantia nigra.

Question 9

Cranial Nerves

Answer 9

• S CN I - Olfactory - Smells
• S CN II - Optic - Sees
• M CN III -Oculomotor - Moves eyes, contricts puplis, accommodates
• M CN IV - Trochlear - Moves eyes
• B CN V - Trigeminal - Facial sensation (touch and pain), mastication
• M CN VI -Abducens - moves eyes
• B CN VII -Facial - moves face, tastes, salivation, lacrimation (cries)
• S CN VIII - Vestibular - Balance and hearing
• B CN IX - Glossopharyngeal - Tasts, salivates, swallows, monitors carotid body and sinus
• B CN X - Vagus - Tastes, swallows, lift palate, talks, communication to and from thoraco-abdominal viscera
• M CN XI - Accessary - Turns head, lifts shoulder
• M CN XII - Hypoglossal - Tongue movement