Parkinson’s and Epilepsy Sheelagh Harwell 0804462h@student.gla.ac.uk

1. Parkinson’s and Epilepsy Sheelagh Harwell0804462h@student.gla.ac.uk Please email me if any questions!

2. Parkinson’sDisease A chronic degenerative loss of dopamine-containing cells in the CNS causing a dopamine deficiency.

3. Parkinsonism TRAP • Tremor • Unilateral • 4-6 Hz • Pill- rolling • Worse at rest • Rigidity • Lead pipe • Cog-wheeling • Akinesia/Bradykinesia • Serpentine Stare (Hypomimia) • Reduced arm swing • Reduced frequency and amplitude of • repetitive movements • Worse with co-stimulation • Loss of Postural reflexes • Pull test • Difficulty turning around • Early falls

4. Non-motor Symptoms Autonomic • Constipation • Urinary urgency • Excessive salivation and sweating • Postural hypotension Sensory • Anosmia • Neuropsychiatric • Dementia • Depression • Anxiety

5. MEQ Tremor A 64 year old man attends his GP complaining of tiredness and “shakiness”. He finds it difficult to get started walking, feels unsteady on his feet and generally slower at activities. His wife states that the shakiness in his hands has gradually worsened and he gets frustrated trying to fasten buttons. She has also noticed that his writing has become very small and barely legible. The GP suspects this man may have idiopathic Parkinson’s disease. Bradykinesia Postural instability Micrographia

6. Clinical features of Parkinson’s disease comprise a classical triad. What are they? Suggest a feature of each that you would expect to see on examination. • TREMOR • RIGIDITY • BRADYKINESIA • What sensory signs would you expect to see in Parkinson’s disease? • ANOSMIA • Explain how the pathological process occurring in the brain results in the clinical features.

7. Idiopathic Parkinson’s Disease • Progressive degeneration of dopaminergic neurons of nigrostriatal pathway (Subtantia Nigra → caudate nucleus and putamen). • The loss of dopamine’s modulatory influence on the neuronal activity results in increased inhibitory drive of the excessively active GABAergic medial pallidum/nigra reticulata neurons. Thus, the end result of striatal dopamine loss is inhibition of cortically initiated movement (hypokinesia). • Symptoms arise when 60-80% of neurons are lost.

8. Management 1)Levodopa • Dopamine cannot cross the blood-brain barrier as it is too polar. • L-Dopa is a stereoisomer of Dopa, the natural amino acid precursor to Dopamine. • Can cross the BBB via LNAAT (large neutral amino acid transporter). • Converted to dopamine by DOPA Decarboxylase enzyme.

9. Management 2) DOPA Decarboxylase Inhibitor • Stops peripheral metabolism of L-Dopa. Inhibitor cannot cross the BBB. • Examples include: Carbidopa and Benserazide. • Increases bioavailability of L-Dopa from 3% to 33-66%. • Reduce side effects: • Postural hypotension • Nausea • Hallucinations

10. 3)COMT Inhibitors • Eg entcapone. Prevents peripheral breakdown of levodopa to 3-O-methyldopa. 4)MAO‐B inhibitor • Eg selegiline. Prevents breakdown of dopamine within synapse. 5) Anti-cholinergic • Eg atropine. Suppress cholinergic activity eg tremor, sialorrhoea. Not first line.

11. Slide by Joe Sharkey

12. Suggest 2 drugs which may be used in combination with L-Dopa to enhance its activity and reduce the dosage of L-Dopa needed. 2 Carbidopa, Benserazide, Entcapone • How do drugs used in combination with L-Dopa enhance its activity? 1 DOPA Decarboxylase Inhibitor stops the peripheral metabolism of L-Dopa and increases L-Dopa bioavailability.

13. Give 2 major adverse effects of chronic L-Dopa administration. 2 • End of dose dyskinesia • On-off phenomenon • Suggest 2 drugs which may be used as alternatives to L-Dopa therapy. 2 • Dopamine agonist – Ropinerole, bromocriptine. • MAO-B inhibitor – Selegiline.

14. Differentials - Parkinsonism

15. Parkinson’s disease can be classified as an akinetic-rigid syndrome. • List three other examples of akinetic rigid syndromes? • Parkinsons plus syndromes – multiple systems atrophy, progressive supranuclear palsy. • Vascular parkinsonism. • Post-encephalitis parkinsonism

16. Akinetic Rigid Syndromes

17. VODKA signs Vascular events elsewhere (Vascular parkinsonism) Orthostatic hypotension and atonic bladder (MSA) Dementia and vertical gaze paralysis (PSP) Kayser-Fleisher rings (Wilson’s disease) Apraxic gait (cerebellar disorders)

18. Name two classes of drug (with one example of each) that can cause parkisonism. • Atypical antipsychotic eg haloperidol, chlorpromazine. • Anti-emetics eg metclopramide

19. a) A 78 year old man with known Parkinson’s disease presents to his GP as he feels that his symptoms are worsening. He complains that one minute his arms completely lock off and he can’t move them at all, then the next they are shaking like a leaf. Idiopathic parkinson’s disease Drug-induced parkinsonism Post-encephaliopathic parkinsonism Gilles de la Tourette syndrome ‘End of dose’ effect ‘On-off effect’ Huntington’s chorea Wilson’s disease Progressive supranuclear palsy Multisystem atrophy Parkinsonism: select the most likely diagnosis:

20. b) A 52 year old woman presents with a 6 month history of falls associated with dizziness. On examination she has marked postural hypotension and is ataxic. Idiopathic parkinson’s disease Drug-induced parkinsonism Post-encephaliopathic parkinsonism Gilles de la Tourette syndrome ‘End of dose’ effect ‘On-off effect’ Huntington’s chorea Wilson’s disease Progressive supranuclear palsy Multisystem atrophy Parkinsonism: select the most likely diagnosis:

21. c) A previously fit and well 71 year old man presents to the GP with a productive cough. However, while he is there the GP notices that he has a stooped posture, takes small shuffling steps when he walks and has poor ‘swing through’ of the right upper limb. He also notes cogwheel rigidity of the right upper limb. Idiopathic parkinson’s disease Drug-induced parkinsonism Post-encephaliopathic parkinsonism Gilles de la Tourette syndrome ‘End of dose’ effect ‘On-off effect’ Huntington’s chorea Wilson’s disease Progressive supranuclear palsy Multisystem atrophy Parkinsonism: select the most likely diagnosis:

22. d) A 48 year old man presents to his GP with what he describes as increased frequency of tics. He has uncontrollable, brief, jerky movements that flit from one part of the body to another. Idiopathic parkinson’s disease Drug-induced parkinsonism Post-encephaliopathic parkinsonism Gilles de la Tourette syndrome ‘End of dose’ effect ‘On-off effect’ Huntington’s chorea Wilson’s disease Progressive supranuclear palsy Multisystem atrophy Parkinsonism: select the most likely diagnosis:

23. A 19 year old man is referred to neurology outpatients with ‘features of parkinson’s disease’. His liver function tests are deranged and he has reduced copper and caeruloplasmin levels. Idiopathic parkinson’s disease Drug-induced parkinsonism Post-encephaliopathic parkinsonism Gilles de la Tourette syndrome ‘End of dose’ effect ‘On-off effect’ Huntington’s chorea Wilson’s disease Progressive supranuclear palsy Multisystem atrophy Parkinsonism: select the most likely diagnosis:

24. Epilepsy • Recurrent transient paroxysmal attacks of disturbed consciousness and sensorimotor function, resulting from abnormal electrophysiological discharges of cerebral neurons. • Anti-epileptic drugs (AEDs) are usually recommended after 2nd seizure. • Epilepsy remits in 70%.

25. AEDs • Valproate – generalised seizures. Broad spectrum. Teratogen. Monitor LFTs. • Carbamazepine – partial seizures. Few side effects. Interacts with p450 system. • Phenytoin – narrow therapeutic window. Monitor. Many side effects. • Lamotrigine – works for almost all forms. Interacts with valproate. Not teratogenic. Severe skin reactions in 3% especially children.

26. Epilepsy A 16 year old schoolgirl with known epilepsy is brought into hospital by her mother. The girl is obviously having a prolonged tonic-clonic seizure. Her mother is very anxious, as the seizure has lasted more than 30 minutes. • What is the diagnosis? Status epilepticus Medical emergency

27. b) The girl’s mother says her daughter has been going through a ‘difficult stage’ and is unsure if she has been taking her anti-epileptic medication regularly. Suggest 3 other causes for this presentation? • Alcohol • Recreational drugs • Infection • Inadequate drug/dose

28. c) You obtain IV access immediately and send off urgent bloods. Suggest 3 important tests in this situation? • Anticonvulsant levels • Toxicology • Calcium • Glucose • FBC • LFTs • U&E

29. d) What two immediate treatments do you institute? • 60% Oxygen via a trauma mask/oropharyngeal tube. • IV lorazepam single dose 4mg. Repeat once if necessary after 10 minutes.

30. e) The girl is still fitting so you start an IV infusion. What is your drug of choice? • IV phenytoin infusion (15ml/kg over 20 minutes). • ECG monitoring (dysrhythmias). If seizures continue for >30mins despite tx, then GA (thiopentone iv bolus then infusion) for >12 hours. Monitor EEG.

31. Thanks!