Parkinson's disease and drug therapy of basal ganglia disorders

Question 1

Hyperkinetic movements

Answer 1

Hyperkinesis

Question 2

Jerky movements

Answer 2

Hemiballismus

Tics

Chorea

Myoclonus

Question 3

Non-jerky movements

Answer 3

Dystonia

Tremor

Question 4

Hypokinetic movements

Answer 4

Hypokinesis

Parkinsonian conditions

Question 5

Disturbance of co-ordination

Answer 5

Ataxia

Question 6

Disturbance of planning

Answer 6

Apraxia

Question 7

Ballismus

Answer 7

High amplitude flailing of the limbs on one side

Question 8

Hemiballismus

Answer 8

Commonest cause is a stroke

Question 9

Tic disorders

Answer 9

Brief repetitive stereotype movements with prmonitory urge

Reduced by distraction and concentration

Worse with anxiety or fatigue

Tourettes is more severe expression

Question 10

Tics

Answer 10

Simple: blinking and coughing

Complex: jumping or twirling

Plus: motor disorder

Coprolia: swearing (rare)

Question 11

Tic disorder causes

Answer 11

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

Question 12

Chorea

Answer 12

Jerky, brief, irregular contractions that are not repetitive or rhythmic

Patient appears fidgety, restless

Question 13

Chorea causes

Answer 13

Common causes include

• degenerative- huntington’s disease
• drugs- neuropletics

Question 14

Huntington’s chorea genetics

Answer 14

Trinucleotide repeat on chromosome 4

Autosomal dominant with complete penetrance

Longer the repeat sequence, earlier the disease presents

Repeat sequence unstable and tends to enlarge ‘anticipate’ with each generation

Question 15

Huntington’s clinical presentation

Answer 15

Cognitive
- inability to make decisions, multitasking, slowness of thought

Behavioural
- irritability, depression, apathy, anxiety, delusions

Physical
- chorea, motor persistence, dystonia, eye movements

Question 16

Myoclonus

Answer 16

Brief movement

Rapid onset and offset

Positive (muscular contractions) or negative (muscular inhibitions)

Question 17

Myoclonus pathophysiology

Answer 17

Unknown

Possible an imbalance between excitatory and inhibitory neurotransmitters

Perturbations of motor control system leading to brief equilibrium

Question 18

Myoclonus causes

Answer 18

Juvenile myoclonic epilepsy

Brain hypoxia

Prion disease

Question 19

Dystonia

Answer 19

Abnormal twisting posture

Often axial/ facial/ truncal

May be associated with jerky tremor

Question 20

Dystonia pathophysiology

Answer 20

Not fully understood

Functional PET studies suggest abnormal activity in motor cortex, supplementary motor areas, cerebellum and basal ganglia

Question 21

Dystonia causes

Answer 21

Stroke

Brain injury

Encephalitis

Parkinson’s disease

Huntington’s disease

Question 22

Tremor

Answer 22

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

Affect different parts of the body

Movement of occurence

Question 23

Tremor pathophysiology

Answer 23

Postulated theory: increased activity in the cerebellothalamocortical circuit

PD: dopamine dysfunction in the pallidum results in this

ET: GABAergic dysfunction in the cerebellum causes this

Question 24

Drug treatment of hyperkintetic movement disorders

Answer 24

Tics/ chorea/ ballismus

Dopamine (D2) receptor blockers

• haloperidol
• chlorpromazine

Dopamine depleting agents

• tetrabenazine
• reserpine

Atypical anti-psychotics

• clozapine
• olanzapine

Question 25

Response of basal ganglia to dopamine blocking agents

Answer 25

Neuropletics and other D2 blockers can cause acute problems - oculogyric crisis - neuroleptic malignant syndrome Subacute problems - drug induced parkinsoniusm Or long term dyskinesias

Question 26

Oculogyric crisis

Answer 26

Very characteristic acute response to certain drugs Fixed stare, upward deviation of eyes Neck extension Trunk extension Jaw spasms and tongue protrusion

Question 27

Neuroleptic malignant syndrome

Answer 27

Acute medical emergency developing over hours/ days in response to D2 blockers Rigidity/ muscle breakdown Fever Autonomic instability Confusion

Question 28

Tardive dyskinesia

Answer 28

Choreic oral facial movements Exact mechanism unclear Treatment - gradual withdrawal of offending agent - substitution with atypical anti-psychotic - use of dopamine depleting agent

Question 29

Parkinsonism

Answer 29

``` Slowness of movement Stiffness Shaking Rigidity Rest tremor ```

Question 30

Non motor symptoms of parkinsonism

Answer 30

Mood: depression, anxiety Dementia: slowed thought, mental inflexibility Autonomic involvement - postural hypotension, hypersalivation Sleep disturnace - restless legs, REM parasomnia Reduced sense of smell

Question 31

What is Parkinson's disease?

Answer 31

Neurodegenerative condition, primarily affecting dopaminergic cells of substantia nigra

Question 32

Causes of parkinsonism

Answer 32

Neurodegenerative - parkinson's disease >80% - diffuse lewy body disease - atypical parkinsonism Secondary - drugs - cerebrovascular disease - hydrocephalus - toxicity/ metal deposition disorders Genetic - metabolic- wilson's disease - rare familial causes

Question 33

Parkinson's disease early drug therapies

Answer 33

Amantadine - initially anti flu agent - glutamate agonist Anti-cholinergics (procyclidine, benzhexol) - may help with tremor - limite by side effects Mono-amine oxidase inhibitors

Question 34

Acetyl choline/ dopamine balance in basal ganglia

Answer 34

Striatum is rich in acetylcholine as well as dopamine Reduction of dopamine in Parkinson's disease leads to functional excess of acetylcholine Compensation can be achieved by reducing acetylcholine effect

Question 35

Monoamine oxidase inhibitors

Answer 35

Prevent breakdown of monoamine chemical neurotransmitters Type A: serotonine, adrenaline, dopamine Type B: dopamine Non selective for depression More selective for Parkinson's disease

Question 36

L-dopa

Answer 36

Available in several formulations Always combined with dopa decarboxylase inhibitor Commercial preparations

Question 37

Entacapone/ tolcapone

Answer 37

Reduced peripheral 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 dyskinesis worse, diarrhoea, liver disease (tolcapone)

Question 38

Apomorphine s/c infusion

Answer 38

Dopamine agonist Pros: very effective, instant effect, reduced dyskinesis Cons: only for the right patient, skin nodules