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Year 2 - Theme 2 > Parkinson's disease and drug therapy of basal ganglia disorders > Flashcards

Parkinson's disease and drug therapy of basal ganglia disorders Flashcards

1
Q

Condition with hyperkinetic movements

A
  • Hyperkinesis
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2
Q

Conditions with jerky movements

A
  • Hemiballismus
  • Tics
  • Chorea
  • Myoclonus
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3
Q

Conditions with non-jerky movements

A
  • Dystonia

- Tremor

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4
Q

Conditions with hypokinetic movements

A
  • Hypokinesis

- Parkinsonian conditions

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5
Q

What is ataxia

A
  • Disturbance of co-ordination
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6
Q

What is apraxia

A
  • Disturbance of planning
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7
Q

What is ballismus

A
  • A high amplitude flailing of the limbs on one side of the body
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8
Q

Pathophysiology of hemiballismus

A
  • Inhibition of STN

- Therefore prevents hyperdirect and indirect pathways from functioning properly

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9
Q

Most common cause of hemiballismus

A
  • Stroke
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10
Q

What are tic disorders

A
  • Brief repetitive stereotypes movements with a premonitory urge
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11
Q

Types of tic disorders

A
  • Simple - like blinking, coughing
  • Complex - jumping or twirling
  • Plus - motor disorder
  • Coprolalia - Swearing - rare
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12
Q

What are tic disorders reduced by

A
  • Distraction and concentration
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13
Q

What worsens tic disorders

A
  • Anxiety

- Fatigue

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14
Q

Most severe expression of a spectrum of tic disorders

A
  • Tourette syndrome
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15
Q

Causes of tic disorders

A
  • Often associated with other co-morbid conditions
  • Complex genetic inheritance
  • Post infectious immune
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16
Q

What percentage of tic disorder patients have ADHD

A
  • 50%
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17
Q

What percentage of tic disorder patients have OCD

A
  • 33.3%
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18
Q

What percentage of tic disorder patients have anxiety

A
  • up to 50%
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19
Q

What is chorea

A
  • Jerky, brief, irregular contractions that are not repetitive or rhythmic, but appear to flow from one muscle to the next
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20
Q

How does a patient with chorea appear

A
  • Fidgety, restless
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21
Q

Pathophysiology of chorea

A
  • STN is disturbed in hyperdirect and indirect pathway
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22
Q

Causes of chorea

A

Degenerative - huntington’s disease

Drugs - neuroleptics

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23
Q

Genetic abnormality in huntington’s chorea

A
  • Trinucleotide repeat on Chr 4

- Autosomal dominant with complete penetrance

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24
Q

What does a longer trinucleotide repeat on chr 4 cause in huntington’s chorea

A
  • Causes the disease to present earlier
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25
Q

Normal and abnormal numbers of repeats in huntington’s chorea

A
  • Normal - 10-28 repeats

- Disease - 36-121 repeats

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26
Q

How does huntington’s present clinically (cognitive)

A

Cognitive - inability to make decisions, multitasking. Slowness of thought

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27
Q

What is myoclonus

A
  • Brief movement
  • Rapid onset and offset
  • Positive(muscular contractions) or negative(muscular inhibitions)
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28
Q

Pathophysiology of myoclonus

A
  • Unknown
  • Possibly an imbalance between excitatory and inhibitory neurotransmitters
  • Perturbations of the motor control system leading to a brief disequilibrium
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29
Q

Common causes of myoclonus

A
  • Juvenile myoclonic epilepsy
  • Brain hypoxia
  • Prion disease
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30
Q

What is dystonia

A
  • Abnormal twisting posture - often axial/facial/truncal, may be associated with jerky tremor
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31
Q

Pathophysiology of dystonia

A
  • Not fully understood
  • Functional PET studies suggest abnormal activity in the motor cortex, supplementary motor areas, cerebellum and basal ganglia
  • Abnormal dopaminergic activity in basal ganglia
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32
Q

What suggests abnormal dopaminergic activity in basal ganglia in dystonia

A
  • Dystonia being caused by blocking dopamine receptors

- Some dystonias being L-dopa responsive

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33
Q

Causes of dystonia

A
  • Stroke
  • Brain injury
  • Encephalitis
  • Parkinson’s disease
  • Huntington’s disease
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34
Q

What is a tremor

A
  • Involuntary, rhythmic, sinusoidal alternating movements of parts of the body
  • Affect different parts of the body such as limbs, head, chin and soft palate
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35
Q

Moment of tremor occurrence

A
  • Rest, postural, kinetic
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36
Q

Most common type of tremor

A
  • Essential tremor(simple kinetic tremor)
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37
Q

Pathophysiology of tremors

A

Postulated theory - Increased activity in the cerebellothalamocortical circuit

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38
Q

Pathophys of tremors in PD

A
  • Dopamine dysfunction in the pallidum results in this
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39
Q

Pathophys of tremors in ET

A
  • GABAergic dysfunction in the cerebellum causes this
40
Q

What type of radiotherapy can be used for treatment of essential tremors

A
  • Unilateral MRI-guided focused ultrasound thalamotomy for treatment-resistant essential tremor
41
Q

Examples of dopamine(D2) receptor blocking agents used for treatment of hyperkinetic movement disorders

A
  • Haloperidol
  • Chlorpromazine
  • Pimozide
  • Risperidone
42
Q

Examples of dopamine depleting agents used for the treatment of hyperkinetic movement disorders

A
  • Tetrabenazine

- Reserpine

43
Q

Examples of atypical anti-psychotics used to treat hyperkinetic movement disorders

A
  • Clozapine
  • Olanzapine
  • Aripiprazole
44
Q

Acute problems(over days/weeks) caused by neuroleptics and other D2 blockers

A
  • Oculogyric crisis

- Neuroleptic malignant syndrome

45
Q

Subacute problems(over weeks/months) caused by neuroleptics and other D2 blockers

A
  • Drug induced parkinsonism

- or long term(tardive) dyskinesias(over months/years)

46
Q

What is oculogyric crisis

A
  • Very characteristic acute response to certain drugs
  • Fixed stare, upward deviation of eyes
  • Neck extension
  • Trunk extension
  • Jaw spasms +/- tongue protrusion
  • ‘Acute dystonic’ reaction
47
Q

What is neuroleptic malignant syndrome

A
  • Acute medical emergency developing over hours/ days in response to D2 blocking drugs
48
Q

Tetrad of features indicative of neuroleptic malignant syndrome

A
  • Fever
  • Rigidity(raised CPK)
  • Autonomic instability(volatile BP/PR)
  • Confusion
49
Q

How can serotonin syndrome be distinguished from NMS

A
  • SS occurs within 24 hours(days to weeks)
  • SS: hyperreactivity
  • NMS: hyporeflexia, severe muscular rigidity
50
Q

What is tardive dyskinesia

A
  • Choreic oral-facial movements (video), dystonic trunk posturing
51
Q

Mechanism of tardive dyskinesia

A
  • Exact mechanism unclear – likely dopamine supersensitvity of basal ganglia –ie secondary receptor/ plastic changes
52
Q

Treatment for tardive dyskinesia

A

Treatment -gradual withdrawal of offending agent, substitution with an atypical anti-psychotic ; use of a dopamine depleting agent (tetrabenazine); use of a benzodiazepine (clonazepam) if distressing

53
Q

Switching to what drugs in hyperkinetic movement disorder management can cause tardive dyskinesia

A
  • Atypical neuroleptics
54
Q

What are some clinical manifestations of tardive dyskinesia

A
  • chorea
  • athetosis
  • dystonia
  • akathisia
  • stereotyed behaviours
  • rarely tremor.
55
Q

What group of patients have a greater incidence of oral, facial and lingual dyskinesia

A
  • Older adult patients
56
Q

Clinical manifestations of tardive dyskinesia in older adult patients

A
  • Protruding and twisting movements of the tongue
  • Pouting, puckering, or smacking movements of the lips
  • Retraction of the corners of the mouth
  • Bulging of the cheeks
  • Chewing movements
  • Blepharospasm
57
Q

Another name for parkinsonism

A
  • Akinetic-rigid syndrome
58
Q

Symptoms of parkinsonism

A
  • Slowness of movement (also thought/ psychomotor retardation)
  • Stiffness
  • Shaking
59
Q

Physical signs of parkinsonism

A
  • Slowness and poverty of movement (bradykinesia) e.g. loss of facial expression and arm swing, difficulty with fine movements
  • Rigidity
  • Rest tremor.
60
Q

Non-motor symptoms of parkinsonism

A 
Mood: Depression, anxiety
Dementia: slowed thought, mental inflexibiity, 
Autonomic involvement
Postural hypotension, Hypersalivation
Sleep disturbance
Restless legs, REM parasomnia
Reduced sense of smell
61
Q

Pathophys of PD

A
  • Decreased dopamine input from SN to striatum leads to reduced activation of direct pathway and reduced inhibition (higher activity) of indirect pathway
  • This leads to reduced movements
62
Q

What is PD

A
  • A neurodegenerative condition, primarily affecting dopaminergic cells of the substantia nigra
63
Q

What is a histopathological hallmark of PD

A
  • Lewy bodies - intraneuronal protein inclusion
64
Q

Neurodegenerative causes of parkinsonism

A
  • (Idiopathic) Parkinson’s disease >80%
  • Diffuse Lewy body disease
  • Atypical Parkinsonism (MSA, PSP, CBD)
  • Multiple system atrophy, Progressive supranuclear palsy, Corticobasal degeneration
65
Q

Secondary causes of parkinsonism

A

Drugs (eg haloperidol, MPTP)
Cerebrovascular disease
Hydrocephalus
Toxicity/ metal deposition disoders

66
Q

Genetic causes of parkinsonism

A 
Metabolic - Wilson’s disease (copper deposition)
Rare familial (dominant/ recessive) causes
67
Q

What is amantadine

A
  • Initially anti-flu agent

- NMDA antagonist

68
Q

What is amantadine used to treat

A
  • Is an antiviral agent to treat influenza A
69
Q

Examples of anti-cholinergics

A
  • Procyclidine, benzhexol
  • May help with tremor
  • Limited by side effects(confusion, urinary retention, dry mouth…)
70
Q

Why are anticholinergics effective in parkinson’s patients

A
  • Dopamine and acetylcholine are normally in a state of electrochemical balance in the basal ganglia. In PD, dopamine depletion produces a state of cholinergic sensitivity so that cholinergic drugs exacerbate and anticholinergic drugs improve parkinsonian symptoms
71
Q

Other drugs used as treatment in parkinson’s disease

A

Mono-amine oxidase inhibitors

72
Q

How do monoamine oxidase inhibitors work

A
  • Prevent breakdown of monoamine chemical neurotransmitters
73
Q

Types of monoamine oxidase neurotransmitters

A
  • MAO-type A

- MAO-type B

74
Q

Examples of MAO-type A neurotransmitters

A
  • Serotonin, adrenaline, noradrenaline, dopamine
75
Q

Example of MAO-type B neurotransmitter

A
  • Dopamine
76
Q

Example of a non-selective MAO-I

A
  • Moclobemide

- For depression

77
Q

Why is moclobemide rarely used now

A
  • Due to problems with metabolising dietary amines/tryptophans - risk of hypertensive crisis - cheese, red wine, marmite
78
Q

Examples of more selective MAO-IB for PD

A
  • Selegiline

- Rasagiline

79
Q

In what situation can an unselective MAOI precipitate a hypertensive crisis

A
  • MAOIs inhibit the catabolism of dietary amines. Therefore tyramine containing foods with unselective MAOI can precipitate a hypertensive crisis
80
Q

What is L-dopa always combined with

A
  • Dopa decarboxylase inhibitor(to prevent peripheral conversion to dopamine
81
Q

Commercial preparations of L-dopa

A
  • Madopar, sinemet

- Immediate and controlled release

82
Q

Side effect of l-dopa

A
  • Dyskinesias
83
Q

Benefit of L-dopa over disease progression

A

Early disease - long duration of clinical benefit. Low incidence of dyskinesias

Mid-stage disease - diminshed duration of clinical benefit. Increased incidence of dyskinesias

Advanced disease - Clinical response mirrors levodopa plasma pharmacokinetic profile. On time is associated with dyskinesias

84
Q

What is entacapone/tolcapone

A
  • Reduces peripheral(to a lesser extent central) metabolism of L-dopa
85
Q

Pros and cons of entacapone/tolcapone

A

Pros - increases duration of action of L-dopa, increases efficacy of L-dopa, good for ‘wearing off’ with L-dopa between doses

Cons - Makes dyskinesia worse, diarrohea(both) liver disease(tolcapone)

86
Q

What is duodopa for advanced PD

A

L-dopa is absorbed in duodenum
Absorption affected by poor gastric motility/ constipation
and diet / protein load
Unpredictable bioavailability makes it very difficult to hit narrow
therapeutic window in advanced PD (for ON without dyskinesia)
Direct delivery of L-dopa to duodenum via infusion pump potentially very
useful strategy to manage motor fluctuations.
But very expensive
Does not affect disease progression

87
Q

Advantages of dopamine agonists

A
  • Bypass degenerating nigrostriatal neurons
  • Directly activate dopamine receptors.
  • No need for enzymatic conversion.
  • More stable and longer-acting.
88
Q

Action of all dopamine agonists in PD patients and also cons

A
  • All reduce frequency of motor complications

cons - dopamine dysregulation syndrome

89
Q

What is apomorphine s/c infusion

A
  • Dopamine agonist

- Given by subcutaneous(s/c) infusion

90
Q

Pros of apomorphine s/c infusion

A

Very effective Instant effect.
Reduces dyskinesia by allowing continuous dopaminergic stimulation (pulsatile dopaminergic stimulation thought to prime basal ganglia for motor complications)

91
Q

Cons of apomorphine s/c infusion

A
  • Only for the right patients

- Skin nodules

92
Q

Example of non-drug therapy for PD

A
  • Deep brain stimulation
93
Q

Features of DBS

A

Probably high freq stimulation
causing ‘jamming’(inhibition of
neurons by depolarising block)

Also disrupts abnormally
synchronous basal ganglia rhythms

Favoured target 
subthalamic nucleus (STN) for PD
Also pallidum (for dystonia) 
and thalamus (for tremor)
Disease will still progress 
and no effect on non-motor 
dementia, 
dysautonomia, 
postural instability…..
94
Q

How does huntington’s present clinically? (behavioural)

A

Behavioural - irritability, depression, apathy, anxiety, delusions

95
Q

how does huntington’s present clinically? (Physical)

A

Physical - chorea, motor persistence, dystonia, eye movements

Year 2 - Theme 2 (14 decks)

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