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Epilepsy

Epilepsy. Naghme Adab. Objectives. Introduction to epilepsy to orientate you Know when it is appropriate to start an antiepileptic drug (AED) Have a framework for choosing an appropriate antiepileptic drug know how to manage status epilepticus Know when it is appropriate to withdraw an AED.

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Epilepsy

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  1. Epilepsy Naghme Adab

  2. Objectives • Introduction to epilepsy to orientate you • Know when it is appropriate to start an antiepileptic drug (AED) • Have a framework for choosing an appropriate antiepileptic drug • know how to manage status epilepticus • Know when it is appropriate to withdraw an AED

  3. How common is epilepsy • Incidence of isolated single seizure is 20/100,000 per year • Incidence of epilepsy 50/100,000 per year • Incidence in over 80s is 150/100,000 per year • Cumulative incidence of epilepsy ( ie risk of an individual getting epilepsy in their life time) is 3-5% • Prevalence of epilepsy 5/1000 ie 0.5% • In typical GP practice (1800 patients) 1-2 new patients with epilepsy per year and 8-10 cases of active epilepsy

  4. DiagnosisDon’t be afraid to say I don’t know • 20% misdiagnosis rate • Delay in Dx frequent ( 30% no firm Dx until 24mths) • In tertiary centre 5-10% of patients with refractory ‘epilepsy’ NEAD

  5. Investigations 1 • ECG • alone help in Dx of cause of syncope in 5% • EEG • Help classify seizures/epilepsy syndrome • Up to 0.5-2% of healthy young adults have epileptiform changes on their EEG, may be even higher in those with strong family Hx of epilepsy. • False negatives; up to 50% of routine wake recordings will be normal. False negative rate drops to 20% if repeated with sleep deprived recording.

  6. Investigation 2 • Neuroimaging • CT – Dx yield 4% but all patients had focal neurological signs or witnessed seizure • MRI – Dx yield of 17% in those with suspected focal or unclassified onset epilepsy • 44% of these were tumours ( 5% of the overall population with seizures) King MA et al, Lancet. 1998 Sep 26;352(9133):1007-11.

  7. A 55 year old male taxi driver comes to see you and tells you that the night before he had a blackout. His left hand began to jerk, and the jerking spread up his left arm. He then blacked out and came to some time later on the floor of his lounge. He had bitten his tongue and had been incontinent of urine. The attack was not witnessed. There have been no other attacks. He has a history of ischaemic heart disease. Two years ago he had 2 TIA and was found to be in atrial fibrillation and was started on warfarin.

  8. Issues • Focal onset seizures – right frontal onset most likely • High probability of focal pathology – CT/MRI • Driving regulations • Alcohol? • Treatment • Treat or not to treat • Interactions with warfarin – carbamazepine, phenytoin, topiramate and valproate

  9. Should we treat a first seizure?

  10. What we know… • ~50% do not experience a recurrence • Previous brain injury and abnormal EEGs can affect the rate of recurrence • Risk of future seizures increases with the number of previous seizures

  11. Treating single seizures • MRC funded MESS study • RCT, 1847 patients • Recurrence risk at 2 yrs ( time to 1st Seizure) • ~32% treated • ~39% untreated • No effect on the long term outcome or likelihood of remission (at 3 yrs 74% seizure free in immediate vs 71% in delayed Tx) • Those with immediate Tx more likely to complain about adverse effects ( 39% in immediate vs 31% in delayed) Lancet. 2005 Jun 11-17;365(9476):2007-13.

  12. Short-term benefits • Little evidence to suggest an overall improvement in QOL • Costs to the patient (Stigma, adverse events, ? preference) • Based on the individual

  13. Follow-up work • Low Risk (0 pts) 1 seizure, normal EEG, No neurological disorder, LD, DD • Medium Risk (1pt) • High Risk (2-4 pts)

  14. Prognosis after single seizure Lancet Neurol. 2006 Apr;5(4):317-22 0; 1 seizure 1; >1 seizure; 2 if >=4 1 if LD/ND 1 if EEG epileptiform activity Low risk=0 Medium risk= 1 High risk = 2-4

  15. So when do we treat? • 2 or more unprovoked seizures • Diagnosis should be secure • No place for trial of AEDs to help clarify the diagnosis • May not be appropriate to start Tx if avoidable precipitant factors have been identified eg drugs, alcohol, some photosensitive mechanisms

  16. When you have decided to start Tx

  17. Antiepileptic drug treatment

  18. Next step is to classify epilepsy • Classify seizure type • Classify epilepsy syndromes • Why is this important? • Informs • choice of drug • Need for investigations • Prognosis

  19. Partial (focal) onset syndromes • 65% adult epilepsy • Seizures types • Simple partial seizures • Complex partial seizures • Secondarily generalised seizures • Epilepsy types • Temporal lobe epilepsy • Frontal lobe epilepsy

  20. Temporal lobe seizures

  21. Secondary generalised seizure

  22. Generalized onset epilepsy syndromes • Present in children and teenagers, and almost never over age 25 • 25% adult epilepsy • Seizure types • Generalized tonic clonic seizures • Absence seizures • Myoclonic seizures • Epilepsy types • Childhood absence epilepsy • Juvenile myoclonic epilepsy……

  23. Childhood absence 2

  24. Clues to classification • Type of seizure • simple partial Sz or aura • myoclonus • Age of onset • Time of seizures eg nocturnal, early morning • (febrile convulsions) • (Family history)

  25. questions • Which drugs are more efficacious? ie better at suppressing seizures • Do some exacerbate some seizure types? • Which better tolerated? • Do any modify the natural history of epilepsy ? • Competing risks of benefit vs side effects ie efficacy and effectiveness

  26. Mechanism of action of AEDs • AEDs redress the balance between neuronal excitation and inhibition • 3 major mechanisms • Modulation of voltage gated ion channels • Enhancement of GABA mediated inhibitory neurotransmission • Decrease of glutamate mediated excitatory neurotransmission

  27. Sills G Mechanisms of action of antiepileptic drugs, 2009

  28. First line AEDs and seizure types Generalized onset seizures Partial onset seizures Simple/Complex secondary generalized Partial tonic-clonic Myoclonus Absence Gen tonic-clonic 1st line: Valproate Alternatives: Lamotrigine Topiramate Levetiracetam 1st line: Carbamazepine Lamotrigine Alternatives: Topiramate Levetiracetam

  29. General Principles • use 1 AED • low and slow • titrate to seizure control or SE • no response add 2nd AED • (check compliance – ask pt/drug levels) • if responds to 2nd AED, consider withdrawal 1st AED • A degree of trial and error involved

  30. Prognosis in epilepsy • 60% will be well controlled on one drug • 47% on 1st monotherapy • 13% on 2nd monotherapy • 3-15% will be controlled on 2 drugs Kwan P and Brodie MJ, NEJM 2000 • Guidelines suggest that if two standard AEDs fail, epilepsy surgery should be considered where appropriate

  31. A 25 year old lady attends your clinic for the first time. She has had one episode of loss of consciousness. She felt odd, had a rising feeling of panic, and for a brief moment felt unable to speak. Her partner has noticed she looked blank for a brief moment then became stiff and fell to the ground. Her limbs jerked for approximately two minutes. She was briefly confused afterwards and drowsy for an hour. On further questioning she has had two brief spells in the last year when she has appeared unresponsive for a few minutes.

  32. What type of attacks are being described? • How would you clarify the history? • What investigations would you request? • Would you starttreatment? • What type of treatment would you consider? Are there any you would avoid? • How would you counsel her?

  33. Issues • Partial epilepsy – temporal lobe • Investigate for aetiology – CT/MRI • Prognosis • Driving regulations • Which is drug of choice • SANAD trial

  34. SANAD • Largest RCT in epilepsy • 95% FU • 370 in arm A in each drug group ( focal onset epilepsy) • Efficacy vs effectiveness • Effectiveness= LTG>CBZ>TPM Lancet. 2007 Mar 24;369(9566):1000-15.

  35. carbamazepine • Partial and secondary generalised seizures • Can make myoclonus and absence seizures worse • Min maintenance dose 600mg/day ( range 400-1200mg- use MR ) • Main mechanism of action – inhibition of voltage-dependent Na conductance • 75% protein bound • Main route of metabolism hepatic • Autoinduction- marked increase in clearance and drop in serum half-life in the first few weeks of therapy; auto-induction finished after 1 month • Interactions: OCP, warfarin, antispychotics, antidepressants, other AEDs, erythromycin

  36. CI AV conduction abnormalities, porphyria • Comon Adverse effects • 5-10% skin rash • Nausea, headache, ataxia, diplopia ( often dose limiting SE) • Hyponatraemia • Leucopenia • Rare SE • SJS v rare • Haematological; thrombocytopenia, pancytopenia • Hepatotoxicity

  37. Lamotrigine • In focal and idiopathic generalised epilepsy • Usual maintenance dose 100mg/day ( range 100-400mg); given bd • start 25mg day and increase every 2 weeks to avoid rash • Main mechanism of action – inhibition of Na channel conductance + block release glutamate • 55% protein bound • Metabolised by liver ( not P450) • Interactions: other AEDs, esp enzyme inducers reduce half-life and VPA increases half life.

  38. Emerging evidence interaction with OCP • Common SE • Headache, nausea, dizziness, diplopia, ataxia • Rash 3% approx • GI symptoms • Rarely behavioural change • Rare SE • Hypersensitivity syndrome • SJS • Aplastic anaemia

  39. UK Epilepsy and Pregnancy Birth Register Abnormal outcomes (MCM rate) J Neurol Neurosurg Psychiatry. 2006 Feb;77(2):193-8.

  40. Women of child-bearing ages: • Teratogenic effects: • Carbamazepine:  risk compared to background population • Sodium valproate: highest risk and relative  risk in NTD • Topiramate: teratogenic effects in animals, early results 4% MCM • ’ed risk if more than one AED used ( risk 8-20%) • LTG used to be first line but ? High risk in doses above 400mg • Offer folic acid (5mg per day) to all women of childbearing age

  41. Interactions with hormonal contraception • AEDs which have been shown to decrease the effect of OCP are PHT, CBZ, OxCBZ, TPM • Current advice is to double the dose of OCP (60mcg of oestrogen) • Recent evidence that LTG may reduce efficacy of OCP but no evidence of contraceptive failure • LTG levels may also drop in those starting OCP resulting in breakthrough seizures • Bear in mind risks of oestrogen induced SE • Depot progesterone should be increased from every 12 weeks to every 10 weeks • The progesterone only pill is likely to be unreliable

  42. You see a 20 year old girl with her partner. In the past 6 months she has had 2 convulsions which are well described by her partner. These also occur within an hour of waking, and one occurred following a night out with her friends.

  43. For the past 6 months she has reports being clumsy in the mornings, at which time she experiences jerks of her upper limbs and trunk. This is particularly so after a late night.

  44. SANAD • 230 in arm B (generalised or unclassified epilepsy) • Efficacy = VPA>TPM>LTG Lancet. 2007 Mar 24;369(9566):1016-26.

  45. Issues • Juvenile myoclonic epilepsy – (a generalized epilepsy) • Imaging not required, but EEG might help • Life style issues – alcohol, drugs sleep deprivation, driving • Valproate one drug of first choice • Side effects - Weight increase, Hair loss, Tremor…. • Teratogenic • Neural tube defects – probably dose related • Developmental delay – difficult to estimate size of risk • Lamotrigine an alternative • May not be as effective as valproate for seizure control • Teratogenicity – probably lower risk • Note interactions with the combined pill • Rash – slow introduction

  46. valproate • Main use idiopathic generalised epilepsy • Maintenance dose 1000mg ( range 600-3000mg) • Major mechanism of action: effects on GABA and glutamergic activity, and calcium and potassium conductance • 85% protein bound • metabolised by liver (in part P450) • Interactions: plasma levels reduced by CBZ, PHT. VPA can increase plasma levels of LTG, also PHT and CBZ Naproxen and salicylate can displace VPA and result in toxicity

  47. CI acute liver disease, porphyria, • Common AE • Weight gain • Hair loss • Tremor • GI SE • ?PCOS • Rare SE • Hepatotoxicity • Encephalopathy • Pancreatitis • thrombocytopenia

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