Parkinson's disease and drug therapy of basal ganglia disorders Flashcards
Condition with hyperkinetic movements
- Hyperkinesis
Conditions with jerky movements
- Hemiballismus
- Tics
- Chorea
- Myoclonus
Conditions with non-jerky movements
- Dystonia
- Tremor
Conditions with hypokinetic movements
- Hypokinesis
- Parkinsonian conditions
What is ataxia
- Disturbance of co-ordination
What is apraxia
- Disturbance of planning
What is ballismus
- A high amplitude flailing of the limbs on one side of the body
Pathophysiology of hemiballismus
- Inhibition of STN
- Therefore prevents hyperdirect and indirect pathways from functioning properly
Most common cause of hemiballismus
- Stroke
What are tic disorders
- Brief repetitive stereotypes movements with a premonitory urge
Types of tic disorders
- Simple - like blinking, coughing
- Complex - jumping or twirling
- Plus - motor disorder
- Coprolalia - Swearing - rare
What are tic disorders reduced by
- Distraction and concentration
What worsens tic disorders
- Anxiety
- Fatigue
Most severe expression of a spectrum of tic disorders
- Tourette syndrome
Causes of tic disorders
- Often associated with other co-morbid conditions
- Complex genetic inheritance
- Post infectious immune
What percentage of tic disorder patients have ADHD
- 50%
What percentage of tic disorder patients have OCD
- 33.3%
What percentage of tic disorder patients have anxiety
- up to 50%
What is chorea
- Jerky, brief, irregular contractions that are not repetitive or rhythmic, but appear to flow from one muscle to the next
How does a patient with chorea appear
- Fidgety, restless
Pathophysiology of chorea
- STN is disturbed in hyperdirect and indirect pathway
Causes of chorea
Degenerative - huntington’s disease
Drugs - neuroleptics
Genetic abnormality in huntington’s chorea
- Trinucleotide repeat on Chr 4
- Autosomal dominant with complete penetrance
What does a longer trinucleotide repeat on chr 4 cause in huntington’s chorea
- Causes the disease to present earlier
Normal and abnormal numbers of repeats in huntington’s chorea
- Normal - 10-28 repeats
- Disease - 36-121 repeats
How does huntington’s present clinically (cognitive)
Cognitive - inability to make decisions, multitasking. Slowness of thought
What is myoclonus
- Brief movement
- Rapid onset and offset
- Positive(muscular contractions) or negative(muscular inhibitions)
Pathophysiology of myoclonus
- Unknown
- Possibly an imbalance between excitatory and inhibitory neurotransmitters
- Perturbations of the motor control system leading to a brief disequilibrium
Common causes of myoclonus
- Juvenile myoclonic epilepsy
- Brain hypoxia
- Prion disease
What is dystonia
- Abnormal twisting posture - often axial/facial/truncal, may be associated with jerky tremor
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
What suggests abnormal dopaminergic activity in basal ganglia in dystonia
- Dystonia being caused by blocking dopamine receptors
- Some dystonias being L-dopa responsive
Causes of dystonia
- Stroke
- Brain injury
- Encephalitis
- Parkinson’s disease
- Huntington’s disease
What is a tremor
- Involuntary, rhythmic, sinusoidal alternating movements of parts of the body
- Affect different parts of the body such as limbs, head, chin and soft palate
Moment of tremor occurrence
- Rest, postural, kinetic
Most common type of tremor
- Essential tremor(simple kinetic tremor)
Pathophysiology of tremors
Postulated theory - Increased activity in the cerebellothalamocortical circuit
Pathophys of tremors in PD
- Dopamine dysfunction in the pallidum results in this
Pathophys of tremors in ET
- GABAergic dysfunction in the cerebellum causes this
What type of radiotherapy can be used for treatment of essential tremors
- Unilateral MRI-guided focused ultrasound thalamotomy for treatment-resistant essential tremor
Examples of dopamine(D2) receptor blocking agents used for treatment of hyperkinetic movement disorders
- Haloperidol
- Chlorpromazine
- Pimozide
- Risperidone
Examples of dopamine depleting agents used for the treatment of hyperkinetic movement disorders
- Tetrabenazine
- Reserpine
Examples of atypical anti-psychotics used to treat hyperkinetic movement disorders
- Clozapine
- Olanzapine
- Aripiprazole
Acute problems(over days/weeks) caused by neuroleptics and other D2 blockers
- Oculogyric crisis
- Neuroleptic malignant syndrome
Subacute problems(over weeks/months) caused by neuroleptics and other D2 blockers
- Drug induced parkinsonism
- or long term(tardive) dyskinesias(over months/years)
What is oculogyric crisis
- Very characteristic acute response to certain drugs
- Fixed stare, upward deviation of eyes
- Neck extension
- Trunk extension
- Jaw spasms +/- tongue protrusion
- ‘Acute dystonic’ reaction
What is neuroleptic malignant syndrome
- Acute medical emergency developing over hours/ days in response to D2 blocking drugs
Tetrad of features indicative of neuroleptic malignant syndrome
- Fever
- Rigidity(raised CPK)
- Autonomic instability(volatile BP/PR)
- Confusion
How can serotonin syndrome be distinguished from NMS
- SS occurs within 24 hours(days to weeks)
- SS: hyperreactivity
- NMS: hyporeflexia, severe muscular rigidity
What is tardive dyskinesia
- Choreic oral-facial movements (video), dystonic trunk posturing
Mechanism of tardive dyskinesia
- Exact mechanism unclear – likely dopamine supersensitvity of basal ganglia –ie secondary receptor/ plastic changes
Treatment for tardive dyskinesia
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
Switching to what drugs in hyperkinetic movement disorder management can cause tardive dyskinesia
- Atypical neuroleptics
What are some clinical manifestations of tardive dyskinesia
- chorea
- athetosis
- dystonia
- akathisia
- stereotyed behaviours
- rarely tremor.
What group of patients have a greater incidence of oral, facial and lingual dyskinesia
- Older adult patients
Clinical manifestations of tardive dyskinesia in older adult patients
- 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
Another name for parkinsonism
- Akinetic-rigid syndrome
Symptoms of parkinsonism
- Slowness of movement (also thought/ psychomotor retardation)
- Stiffness
- Shaking
Physical signs of parkinsonism
- Slowness and poverty of movement (bradykinesia) e.g. loss of facial expression and arm swing, difficulty with fine movements
- Rigidity
- Rest tremor.
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
Pathophys of PD
- 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
What is PD
- A neurodegenerative condition, primarily affecting dopaminergic cells of the substantia nigra
What is a histopathological hallmark of PD
- Lewy bodies - intraneuronal protein inclusion
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
Secondary causes of parkinsonism
Drugs (eg haloperidol, MPTP)
Cerebrovascular disease
Hydrocephalus
Toxicity/ metal deposition disoders
Genetic causes of parkinsonism
Metabolic - Wilson’s disease (copper deposition) Rare familial (dominant/ recessive) causes
What is amantadine
- Initially anti-flu agent
- NMDA antagonist
What is amantadine used to treat
- Is an antiviral agent to treat influenza A
Examples of anti-cholinergics
- Procyclidine, benzhexol
- May help with tremor
- Limited by side effects(confusion, urinary retention, dry mouth…)
Why are anticholinergics effective in parkinson’s patients
- 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
Other drugs used as treatment in parkinson’s disease
Mono-amine oxidase inhibitors
How do monoamine oxidase inhibitors work
- Prevent breakdown of monoamine chemical neurotransmitters
Types of monoamine oxidase neurotransmitters
- MAO-type A
- MAO-type B
Examples of MAO-type A neurotransmitters
- Serotonin, adrenaline, noradrenaline, dopamine
Example of MAO-type B neurotransmitter
- Dopamine
Example of a non-selective MAO-I
- Moclobemide
- For depression
Why is moclobemide rarely used now
- Due to problems with metabolising dietary amines/tryptophans - risk of hypertensive crisis - cheese, red wine, marmite
Examples of more selective MAO-IB for PD
- Selegiline
- Rasagiline
In what situation can an unselective MAOI precipitate a hypertensive crisis
- MAOIs inhibit the catabolism of dietary amines. Therefore tyramine containing foods with unselective MAOI can precipitate a hypertensive crisis
What is L-dopa always combined with
- Dopa decarboxylase inhibitor(to prevent peripheral conversion to dopamine
Commercial preparations of L-dopa
- Madopar, sinemet
- Immediate and controlled release
Side effect of l-dopa
- Dyskinesias
Benefit of L-dopa over disease progression
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
What is entacapone/tolcapone
- Reduces peripheral(to a lesser extent central) metabolism of L-dopa
Pros and cons of entacapone/tolcapone
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)
What is duodopa for advanced 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 expensive
Does not affect disease progression
Advantages of dopamine agonists
- Bypass degenerating nigrostriatal neurons
- Directly activate dopamine receptors.
- No need for enzymatic conversion.
- More stable and longer-acting.
Action of all dopamine agonists in PD patients and also cons
- All reduce frequency of motor complications
cons - dopamine dysregulation syndrome
What is apomorphine s/c infusion
- Dopamine agonist
- Given by subcutaneous(s/c) infusion
Pros of apomorphine s/c infusion
Very effective Instant effect.
Reduces dyskinesia by allowing continuous dopaminergic stimulation (pulsatile dopaminergic stimulation thought to prime basal ganglia for motor complications)
Cons of apomorphine s/c infusion
- Only for the right patients
- Skin nodules
Example of non-drug therapy for PD
- Deep brain stimulation
Features of DBS
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…..
How does huntington’s present clinically? (behavioural)
Behavioural - irritability, depression, apathy, anxiety, delusions
how does huntington’s present clinically? (Physical)
Physical - chorea, motor persistence, dystonia, eye movements
