Neurological Disorders

Question 1

What is idiopathic Parkinson’s disease? Clinical features

Answer 1

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

Question 2

Differentials for idiopathic Parkinson’s disease

Answer 2

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

Question 3

Explain how the basal ganglia circuit in Parkinson’s causes impaired mobility

Answer 3

Loss of dopaminergic neurones in substantia nigra ->
Reduced inhibition in neostriatum ->
Allows increased production acetylcholine (excitatory) ->
To motor cortex + spinal cord

Question 4

Diagnosing IPD

Answer 4

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

Question 5

How does L-DOPA work?

Answer 5

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)

Question 6

Why don’t we give levodopa/ L-DOPA alone orally?

Answer 6

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

Question 7

How do we give L-dopa to avoid problems with giving alone?

Answer 7

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

Question 8

L-DOPA advantages anddisadvantages

Answer 8

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)

Question 9

Dopamine receptor agonists examples

Answer 9

Ropinirole & Pramipexole - oral

Rotigotine - patch

Apomorphine - subcutaneous (rescue - only for severe motor fluctuations)

De novo or add on therapy

Question 10

Dopamine receptors agonists advantages and disadvantages

Answer 10

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)

Question 11

How do monoamine oxidase B inhibitors work?

Answer 11

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

Question 12

How do catechol-O-methyl transferase (COMT) inhibitors work?

Answer 12

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

Question 13

How do anticholinergics work in treatment of PD? Give examples

Answer 13

Acetylcholine May have antagonist effects to dopamine - minor role treatment

E.g. trihexyphenidydyl, orphenadrine, procyclidine

Question 14

Advantages and disadvantages to anticholinergics in treating PD

Answer 14

Advantages:
Treat tremor
Not acting via dopamine systems

Disadvantages:
No effect on bradykinesia
Side effects (confusion, drowsiness, dry mouth, urinary retention, blurred vision)

Question 15

How does amantadine work?

Answer 15

Unclear, possible - enhanced dopamine release/ anticholinergic NMDA inhibitors

Poorly effective
Few side effects
Little effect on tremor

Question 16

When is surgery used to treat PD?

Answer 16

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

Question 17

Pathophysiology of myasthenia gravis

Answer 17

Autoimmune

IgG Antibodies sit on Ach receptors and block/ damage so Ach rarely binds at neuromuscular junction

Question 18

Characteristics of myasthenia gravis

Answer 18

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

Question 19

Which drugs exacerbate myasthenia gravis?

Answer 19

Drugs affecting neuromuscular transmission

E.g.
Aminoglycosides
Beta blockers
CCBs
Chloroquine
Magnesium 
ACE inhibitors

Question 20

Complications of myasthenia gravis

Answer 20

Acute exacerbation = myasthenia crisis

Over treatment = cholinergic crisis (worsened myasthenia caused by treatment - depolarising block)

Question 21

Therapeutic management of myasthenia gravis

Answer 21

• acetylcholineesterase inhibitors
• corticosteroids (decrease immune response)
• steroid sparing e.g. Azathioprine
• IV immunoglobulin (acute decline/ crisis)
• plasmapheresis (remove AChR antibodies and short term improvement)

Question 22

How does pyridostigmine work? Side effects. Compare to Neostigmine

Answer 22

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