Neurological Disorders Flashcards
What is idiopathic Parkinson’s disease? Clinical features
Most people with Parkinson’s - Unknown cause
Neurodegenerative
Progressive
Motor symptoms improve with levodopa (unlike secondary/ atypical Parkinsonism)
Clinical features: tremor, rigidity, bradykinesia, postural instability, difficulty swallowing, speech problems
Non-motor manifestations: mood changes, pain, cognitive change, urinary symptoms, sleep disorder, sweating
Differentials for idiopathic Parkinson’s disease
Drug induced Parkinsonism- gait disorders e.g. Ketamine, anti-psychotics, valproate
Vascular
Progressive supranuclear palsy - eye movements
Multiple systems atrophy - autonomic dysfunction
Corticobasal degeneration - rare
Explain how the basal ganglia circuit in Parkinson’s causes impaired mobility
Loss of dopaminergic neurones in substantia nigra ->
Reduced inhibition in neostriatum ->
Allows increased production acetylcholine (excitatory) ->
To motor cortex + spinal cord
Diagnosing IPD
Clinical features
Exclude other causes
Responds to LDOPA
Structural Neuroimaging normal - can show vascular disease in basal ganglia
DAT scan - labelled tracer shows presynaptic uptake, abnormal in PD, if normal could be drug induced or resting tremor
How does L-DOPA work?
Can cross BBB (unlike dopamine) by active transport - competes with AAs so avoid high protein meals->
Taken up by dopaminergic cells in substantia nigra to be converted into dopamine using DOPA decarboxylase (if fewer cells remain less effective)
Why don’t we give levodopa/ L-DOPA alone orally?
90% inactivated in intestinal wall (monoamine oxidase & DOPA decarboxylase)
t1/2 2 hours - dosing 3-5/ day
9% converted into dopamine in peripheral tissues (DOPA decarboxylase) - less reaches Brain + side effects
Means <1% Enters CNS
How do we give L-dopa to avoid problems with giving alone?
Used in combo with a peripheral DOPA decarboxylase inhibitor
E.g. Co-careldopa or co-beneldopa
Reduces dose
Reduces side effects
Increases L-dopa reaching brain
L-DOPA advantages anddisadvantages
Advanatages:
Highly efficacious
Low side effects
Disadvantages:
Needs enzymes conversion
Long term loses efficacy
Involuntary movements
Motor complications (on/ off, wearing off, dyskinesia, dystonia, freezing)
Side effects (nausea/ anorexia, hypotension, psychosis, tachycardia)
Drug interactions (pyridoxine/ VB6 increases peripheral breakdown, MAOIs - monoamines (type B low dose ok) hypertensive crisis risk, many antipsychotic drugs block dopamine receptors)
Dopamine receptor agonists examples
Ropinirole & Pramipexole - oral
Rotigotine - patch
Apomorphine - subcutaneous (rescue - only for severe motor fluctuations)
De novo or add on therapy
Dopamine receptors agonists advantages and disadvantages
Advantages:
Direct acting
Less dyskinesias/ motor complications
Possible neuroprotection
Disadvantages:
Less efficacy then L-DOPA
More psychiatric
Expensive
Impulse control disorders/ dopamine dysregulation syndrome (pathological gambling, hypersexuality, compulsive shopping, desire increase dosage, punding)
Side effects (sedation, hallucinations, confusion, nausea, hypotension)
How do monoamine oxidase B inhibitors work?
Prevent metabolism of dopamine so increases concentration
E.g. selagiline/ rasagaline
Can be used alone
Or Prolong action L-DOPA
Smooth out motor response
May neuroprotective
How do catechol-O-methyl transferase (COMT) inhibitors work?
Reduce peripheral breakdown of L-DOPA to 3-O-methyldopa (competes for active transport into CNS)
No effect alone
L-DOPA sparing effect
Prolongs motor response to L-DOPA
Can use in combo with L-DOPA + peripheral dopa decarboxylase inhibitor e.g. stalevo
How do anticholinergics work in treatment of PD? Give examples
Acetylcholine May have antagonist effects to dopamine - minor role treatment
E.g. trihexyphenidydyl, orphenadrine, procyclidine
Advantages and disadvantages to anticholinergics in treating PD
Advantages:
Treat tremor
Not acting via dopamine systems
Disadvantages:
No effect on bradykinesia
Side effects (confusion, drowsiness, dry mouth, urinary retention, blurred vision)
How does amantadine work?
Unclear, possible - enhanced dopamine release/ anticholinergic NMDA inhibitors
Poorly effective
Few side effects
Little effect on tremor
When is surgery used to treat PD?
Highly selected cases - little dopamine responsiveness, significant side effects L-DOPA, no psychiatric illness
Stereotactically (halo MRI scan, localise neurones lesion areas) e.g. thalmus for tremor, globus pallidus interna for dyskinesias
Or deep brain stimulation of subthalamic nucleus
Pathophysiology of myasthenia gravis
Autoimmune
IgG Antibodies sit on Ach receptors and block/ damage so Ach rarely binds at neuromuscular junction
Characteristics of myasthenia gravis
Fluctuating, fatiguable (after a while of doing something), weakness skeletal muscle
- extraocular muscles commonest - ptosis, double vision
- blulbar involvement - dysphagia, dysphonia, dysarthria
- limb weakness - promixal symmetric
- resp muscle involvement - type 2 resp failure
Which drugs exacerbate myasthenia gravis?
Drugs affecting neuromuscular transmission
E.g. Aminoglycosides Beta blockers CCBs Chloroquine Magnesium ACE inhibitors
Complications of myasthenia gravis
Acute exacerbation = myasthenia crisis
Over treatment = cholinergic crisis (worsened myasthenia caused by treatment - depolarising block)
Therapeutic management of myasthenia gravis
- acetylcholineesterase inhibitors
- corticosteroids (decrease immune response)
- steroid sparing e.g. Azathioprine
- IV immunoglobulin (acute decline/ crisis)
- plasmapheresis (remove AChR antibodies and short term improvement)
How does pyridostigmine work? Side effects. Compare to Neostigmine
Acetylcholineesterase inhibitor
Oral
Prevents breakdown of Ach in NMJ - onset 30mins, peak 60-120mins, duration 3-6hrs Cholinergic side effects: Salivation Sweating Lacrimation Urinary incontinence Diarrhoea GI upset and hypermotility Emesis
Neostigmine: oral and IV, quicker action, duration up to 4hrs, significant cholinergic side effects
