Parkinson's disease and drug therapy of basal ganglia disorders Flashcards
List some jerky hyperkinetic movements
Hyperkinesis Hemiballismus Tics Chorea Myoclonus
List some non jerky hyperkinetic movements
Dystonia
Tremor
List some hypokinetic movements
Hypokinesis
Parkinsonian conditions
What is ataxia?
Disturbance of co-ordination
What is apraxia?
Disturbance of planning
Describe ballismus
A high amplitude flailing of the limbs on one side of the body
Describe the pathophysiology of hemiballismus
Impairment of subthalamic nucleus
Therefore affects both indirect and hyperdirect pathway
What is the commonest cause of hemiballismus?
Stroke
Describe tic disorders
Brief repetitive stereotypes movements with a premonitory urge.
What are some simple tics?
blinking, coughing
What are some complex tics?
jumping or twirling
What is Coprolalia?
Swearing - rare
How are tics reduced?
distraction and concentration
How are tics worsened?
Anxiety or fatigue
What is the cause of tic disorder?
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
Describe chorea
Jerky, brief, irregular contractions that are not repetitive or rhythmic, but appear to flow from one muscle to the next.
Patient appears fidgety, restless
Describe the pathophysiology of chorea
Impairment in subthalamic nucleus
Hyperdirect and indirect pathway impaired
What are the causes of chorea?
Common causes include:
Degenerative - Huntington’s disease
Drugs - Neuroleptics
Describe the genetics of huntington’s chorea
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
Describe the cognitive presentation of hungtingtons
Inability to make decisions, multitasking. Slowness of thought.
Describe the behavioural presentation of hungtingtons
Irritability, depression, apathy, anxiety, delusions.
Describe the physical presentation of hungtingtons
Chorea, motor persistence, dystonia, eye movements.
Describe myoclonus
Brief movement
Rapid onset and offset
Positive (muscular contractions) or negative (muscular inhibitions)
Describe the pathophysiology of myoclonus
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.
What are the causes of myoclonus?
Juvenile Myoclonic Epilepsy
Brain hypoxia
Prion disease
Describe dystonia
Abnormal twisting posture – often axial/ facial/ truncal, may be associated with jerky tremor
Describe the pathophysiology of dystonia
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.
What are the causes of dystonia?
Stroke Brain injury Encephalitis Parkinsons disease Huntingtdon’s disease
What is tremor?
Involuntary, rhythmic, sinusoidal alternating movements of part of the body.
Which parts of the body does tremor affect?
Limbs, head, chin, soft palate
Describe the moment of occurence of tremor
Rest, Postural, Kinetic,
Most common is Essential tremor (simple kinetic tremor)
Describe the pathophysiology of tremor
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.
Name some drug treatments of the hyperkinetic movement disorders (Tics, Chorea, Ballismus)
Dopamine (D2) receptor blocking agents
(eg haloperidol, chlorpromazine, pimozide, risperidone)
Dopamine depleting agents
(eg Tetrabenazine, Reserpine)
Atypical anti-psychotics
(eg Clozapine, Olanzapine, Aripiprazole)
What can neuroleptics and other D2 blockers cause?
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)
Describe oculogyric crises
Very characteristic acute response to certain drugs Fixed stare, upward deviation of eyes Neck extension Trunk extension Jaw spasms +/- tongue protrusion ‘Acute dystonic’ reaction
Describe neuroleptic malignant syndrome
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
Describe tardive dyskineasea
Choreic oral-facial movements (video), dystonic trunk posturing
Exact mechanism unclear – likely dopamine supersensitvity of basal ganglia –ie secondary receptor/ plastic changes
How is tardive dyskinesia treated?
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
What is another word for Akinetic-Rigid Syndrome?
Parkinsonism
What are the symptoms of parkinsonism?
Slowness of movement (also thought/ psychomotor retardation)
Stiffness
Shaking.
List some physical signs of parkinsonism
- 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.
What are some non-motor symptoms of parkinsonism?
Mood: Depression, anxiety Dementia: slowed thought, mental inflexibiity, Autonomic involvement Postural hypotension, Hypersalivation Sleep disturbance Restless legs, REM parasomnia Reduced sense of smell
Describe the pathophysiology of parkinson’s disease
Decreased dopamine input leads to reduced activation of direct pathway and reduced inhibition (higher activity) of indirect pathway. This leads to reduced movements.
What is parkinsons disease?
A neurodegenerative condition, primarily affecting dopaminergic cells of the substantia nigra
Give a histological hallmark of parkinsons disease
Lewy bodies
Intraneuronal protein inclusion)
List some neurodegenerative causes of parkinsonism
(Idiopathic) Parkinson’s disease >80%
Diffuse Lewy body disease
Atypical Parkinsonism (MSA, PSP, CBD)
Multiple system atrophy, Progressive supranuclear palsy, Corticobasal degeneration
List some secondary causes of parkinsonism
Drugs (eg haloperidol, MPTP)
Cerebrovascular disease
Hydrocephalus
Toxicity/ metal deposition disoders
List some genetic causes of parkinsonism
Metabolic - Wilson’s disease (copper deposition) Rare familial (dominant/ recessive) causes
List some early drug therapies used to treat parkinsons disease
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
Describe monoamine oxidase inhibitors
Prevent breakdown of monoamine chemical neurotransmitters; 2 isoforms:
List the 2 isoforms of MAOi
MAO- type A : serotonin, adrenaline, noradrenaline, dopamine
MAO- type B : dopamine
Which MAOi is now most commonly used?
More selective MAO- IB- for Parkinson’s disease (Selegiline, Rasagiline) – no dietary restrictions
Which MAOi used to be used but now is not?
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
Describe L-dopa
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
Describe entacapone/Tolcapone. What are the pros and cons of each?
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)
Describe duodopa for advance PD
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
What are dopamine agonists and what are the benefits?
Bypass degenerating nigrostriatal neurons
Directly activate dopamine receptors.
No need for enzymatic conversion.
More stable and longer-acting.
Give some examples of dopamine agonists?
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
Describe apomorphine s/c infusion
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
Describe how deep brain stimulation works
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)
