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Module 202 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

List some jerky hyperkinetic movements

A 
Hyperkinesis
Hemiballismus
Tics
Chorea
Myoclonus
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2
Q

List some non jerky hyperkinetic movements

A

Dystonia

Tremor

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3
Q

List some hypokinetic movements

A

Hypokinesis

Parkinsonian conditions

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4
Q

What is ataxia?

A

Disturbance of co-ordination

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5
Q

What is apraxia?

A

Disturbance of planning

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6
Q

Describe ballismus

A

A high amplitude flailing of the limbs on one side of the body

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7
Q

Describe the pathophysiology of hemiballismus

A

Impairment of subthalamic nucleus

Therefore affects both indirect and hyperdirect pathway

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8
Q

What is the commonest cause of hemiballismus?

A

Stroke

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9
Q

Describe tic disorders

A

Brief repetitive stereotypes movements with a premonitory urge.

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10
Q

What are some simple tics?

A

blinking, coughing

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11
Q

What are some complex tics?

A

jumping or twirling

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12
Q

What is Coprolalia?

A

Swearing - rare

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13
Q

How are tics reduced?

A

distraction and concentration

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14
Q

How are tics worsened?

A

Anxiety or fatigue

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15
Q

What is the cause of tic disorder?

A 
Often associated with other co-morbid conditions.
50% have ADHD
33.3% have OCD
Up to 50% have anxiety
Complex genetic inheritance
Post infectious immune
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16
Q

Describe chorea

A

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

Patient appears fidgety, restless

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17
Q

Describe the pathophysiology of chorea

A

Impairment in subthalamic nucleus

Hyperdirect and indirect pathway impaired

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18
Q

What are the causes of chorea?

A

Common causes include:
Degenerative - Huntington’s disease
Drugs - Neuroleptics

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19
Q

Describe the genetics of huntington’s chorea

A

Trinucleotide repeat on chromosome 4
Autosomal dominant with complete penetrance
The longer the repeat sequence the earlier the disease presents
Repeat sequence unstable and tends to enlarge ‘anticipate’ with each generation

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20
Q

Describe the cognitive presentation of hungtingtons

A

Inability to make decisions, multitasking. Slowness of thought.

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21
Q

Describe the behavioural presentation of hungtingtons

A

Irritability, depression, apathy, anxiety, delusions.

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22
Q

Describe the physical presentation of hungtingtons

A

Chorea, motor persistence, dystonia, eye movements.

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23
Q

Describe myoclonus

A

Brief movement
Rapid onset and offset
Positive (muscular contractions) or negative (muscular inhibitions)

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24
Q

Describe the pathophysiology of myoclonus

A

Unknown
Possibly an imbalance between excitatory and inhibitory neurotransmitters.
Explain why it is treatable with antiepileptic drugs.
Perturbations of the motor control system leading to a brief disequilibrium
Explain why present at multiple levels e.g cortical, subcortical , spinal etc.

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25
Q

What are the causes of myoclonus?

A

Juvenile Myoclonic Epilepsy
Brain hypoxia
Prion disease

26
Q

Describe dystonia

A

Abnormal twisting posture – often axial/ facial/ truncal, may be associated with jerky tremor

27
Q

Describe the 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 suggested by:
dystonia being caused by blocking dopamine receptors
Some dystonias being Levodopa responsive.

28
Q

What are the causes of dystonia?

A 
Stroke
Brain injury
Encephalitis
Parkinsons disease
Huntingtdon’s disease
29
Q

What is tremor?

A

Involuntary, rhythmic, sinusoidal alternating movements of part of the body.

30
Q

Which parts of the body does tremor affect?

A

Limbs, head, chin, soft palate

31
Q

Describe the moment of occurence of tremor

A

Rest, Postural, Kinetic,

Most common is Essential tremor (simple kinetic tremor)

32
Q

Describe the pathophysiology of tremor

A

Postulated theory: Increased activity in the cerebellothalamocortical circuit.
PD: Dopamine dysfunction in the pallidum results in this.
ET: GABAergic dysfunction in the cerebllum causes this.

33
Q

Name some drug treatments of the hyperkinetic movement disorders (Tics, Chorea, Ballismus)

A

Dopamine (D2) receptor blocking agents
(eg haloperidol, chlorpromazine, pimozide, risperidone)

Dopamine depleting agents
(eg Tetrabenazine, Reserpine)

Atypical anti-psychotics
(eg Clozapine, Olanzapine, Aripiprazole)

34
Q

What can neuroleptics and other D2 blockers cause?

A

can cause acute problems (over days/weeks)
Oculogyric crisis
Neuroleptic malignant syndrome

Subacute problems (over weeks/months)
Drug induced Parkinsonism

Or long term (tardive) dyskinesias (over months/years)

35
Q

Describe oculogyric crises

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
36
Q

Describe neuroleptic malignant syndrome

A 
Acute medical emergency developing over hours/ days in response to D2 blocking drugs
Rigidity/ muscle breakdown – raised CPK.
Fever
Autonomic instability (volatile BP/PR)
Confusion
37
Q

Describe tardive dyskineasea

A

Choreic oral-facial movements (video), dystonic trunk posturing
Exact mechanism unclear – likely dopamine supersensitvity of basal ganglia –ie secondary receptor/ plastic changes

38
Q

How is tardive dyskinesia treated?

A

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

39
Q

What is another word for Akinetic-Rigid Syndrome?

A

Parkinsonism

40
Q

What are the symptoms of parkinsonism?

A

Slowness of movement (also thought/ psychomotor retardation)

Stiffness

Shaking.

41
Q

List some physical signs of parkinsonism

A
  • Slowness and poverty of movement (bradykinesia) e.g. loss of facial expression and arm swing, difficulty with fine movements
  • Voluntary movements harder to initiate (akinesia)
  • Rigidity
  • Rest tremor.
42
Q

What are some 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
43
Q

Describe the pathophysiology of parkinson’s disease

A

Decreased dopamine input leads to reduced activation of direct pathway and reduced inhibition (higher activity) of indirect pathway. This leads to reduced movements.

44
Q

What is parkinsons disease?

A

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

45
Q

Give a histological hallmark of parkinsons disease

A

Lewy bodies

Intraneuronal protein inclusion)

46
Q

List some 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

47
Q

List some secondary causes of parkinsonism

A

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

48
Q

List some genetic causes of parkinsonism

A 
Metabolic - Wilson’s disease (copper deposition)
Rare familial (dominant/ recessive) causes
49
Q

List some early drug therapies used to treat parkinsons disease

A

Amantadine – Initially anti-flu agent
Glutamate agonist

Anti-cholinergics – Procyclidine, Benzhexol
May help with tremor
Limited by side effects
(confusion, urinary retention, dry mouth…)

Mono-amine oxidase inhibitors

50
Q

Describe monoamine oxidase inhibitors

A

Prevent breakdown of monoamine chemical neurotransmitters; 2 isoforms:

51
Q

List the 2 isoforms of MAOi

A

MAO- type A : serotonin, adrenaline, noradrenaline, dopamine

MAO- type B : dopamine

52
Q

Which MAOi is now most commonly used?

A

More selective MAO- IB- for Parkinson’s disease (Selegiline, Rasagiline) – no dietary restrictions

53
Q

Which MAOi used to be used but now is not?

A

Non selective MAO-I – for depression (Moclobemide); rarely used now due to problems with metabolising dietary amines/ tryptophans – risk of hypertensive crisis – cheese, red wine, marmite

54
Q

Describe L-dopa

A

The old and gold standard

Available in several formulations. Always combined with Dopa decarboxylase inhibitor (to prevent peripheral conversion to dopamine).

Commercial preparations: Madopar, Sinemet
Immediate and controlled release

55
Q

Describe entacapone/Tolcapone. What are the pros and cons of each?

A

Reduces peripheral (to a lesser extent central) metabolism of L-dopa.

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, Diarrhoea (both)
Liver disease (tolcapone)
56
Q

Describe duodopa for advance 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 cumbersome / expensive (20K/year)
Does not affect disease progression

57
Q

What are dopamine agonists and what are the benefits?

A

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

58
Q

Give some examples of dopamine agonists?

A 
Pergolide (ergot), Cabergoline (ergot), 
Ergot dopamine agonists no longer used due to cardiac/pulmonary fibrosis.
Pramipexole, Ropinirole (non-ergot)
Rotigotine (patch)
Apomorphine (subcutaneous infusion)

All reduce frequency of motor complications

Cons- Dopamine dysregulation syndrome

59
Q

Describe apomorphine s/c infusion

A

Dopamine agonist:

Given by subcutaneous (s/c) infusion

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

Cons: Only for the right patients
Skin nodules

60
Q

Describe how deep brain stimulation works

A

Not clear how it works (but it does!)
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…..

Future – neurorestorative (stem cells)
Neuroprotective (growth factors)

Module 202 Theme 2 (12 decks)

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