First Line Drugs
- Generalised epilepsy
- Valproate (male or non-reproductive female, SANAD II)
- Lamotrigine
- Levetiracetam
- Focal epilepsy
- Lamotrigine
- Levetiracetam
- Carbamazepine (oxcarbazepine)
General information
- Goals: seizure control: reduction of seizure frequency and severity to the point of permitting patient to live a normal lifestyle with minimal or no d
- 75% achieve seizure control with medication
- Side effect profile see first AID
Classification of AED
- Broad spectrum
- Valproic acid
- Lamotrigine
- Levetiracetam
- Narrow spectrum
- Phenytoin
- Carbamazepine
Drug of choice of AED
- Primary generalized
- Generalized tonic-clonic
- Valproic acid (VA): if no evidence of focality some studies show fewer side effects and better control than PHT
- Phenytoin (PHT)
- Absence:
- Ethosuximide
- Valproic acid (VA)
- Myoclonic
- Benzodiazepines
- Tonic or atonic:
- Benzodiazepines
- Felbamate
- Vigabatrin
- Partial (simple or complex, with or without secondary generalization)
- Ranked by the well controlled Veterans Administration Cooperative Study (based on seizure control and side effects) in this order:
- Carbamazepine (CBZ): most effective, least side effects
- Phenytoin (PHT): ⬇️
- Phenobarbital (PB): ⬇️
- Primidone (PRM): slightly less effective, more side effects
- Second line drugs for any of the above seizure types
- Valproate
- Lamotrigine
- Topiramate
Monotherapy versus polytherapy
- Increase a given medication until seizures are controlled or side effects become intolerable
- Do not follow therapeutic range as it is a range for most patient and not for that specific patient
- Try monotherapy with different drugs before resorting to two drugs together.
- 80% of epileptics can be controlled on monotherapy;
- Failure of monotherapy indicates an 80% chance that the seizures will not be controllable pharmacologically.
- Only 10% benefit significantly from the addition of a second drug.
- When> 2 AEDs are required, consider nonepileptic seizures
- When first evaluating patients on multiple drugs, withdraw the most sedating ones first (usually barbiturates and clonazepam)
Pharmacokinetics
- Dosing intervals
- Less than one half life
- Without loading dose it takes 5 Halves lives to reach stead state
- Many AEDs affect LFTs
- Rarely do the drugs cause enough hepatic dysfunction to warrant discontinuation.
- Guideline: discontinue an AED if the GGT exceeds twice normal.
- P450
- Inducers
- Carbamazepine
- Phenobarbital
- Phenytoin
- Felbamate
- Primidone
- Non-inducers
- Valproic acid
- Benzodiazepines
- Gabapentin
- Lamotrigine
Withdrawal
- Most seizure recurrences develop during the first 6 months after AED withdrawal
- Indications: None
- Factors predicting withdrawal success (Callaghan 1988, Anderson 1997, MRC 1991)
- Seizure type
- Number of seizures before control attained: ≥100 seizures before control had statistically significant higher relapse rate
- The number of drugs that had to be tried before single drug therapy successfully controlled seizures:
- EEG class
- Class 4 had worst prognosis for relapse.
- Epileptiform discharges on EEG serves to discourage AED withdrawal
- EEG class and seizure relapse rate
- Longer seizure-free period
- Use of only one AED (vs. multiple AEDs)
- Seizures other than tonic-clonic seizures
Relapse rate | Seizure type |
37% | Generalized seizures |
16% | Complex or simple partial |
54% | Complex partial with secondary generalization |
Relapse rate | Number of drug changes required |
29% | 1st drug worked |
40% | A change to a 2nd drug was needed |
80% | A change to a 3rd drug was needed |
Class | EEG description before treatment | EEG description before withdrawal | Relapse rate | No. of relapses/patients at risk |
1 | Normal | Normal | 34% | 11/31 |
2 | Abnormal | Normal | 11% | 4/35 |
3 | Abnormal | Improved | 50% | 2/4 |
4 | Abnormal | Unchanged | 74% | 14/19 |
- AED withdrawal
AED | Recommended withdrawal period |
Phenytoin, valproic acid, carbamazepine | 2-4 wks |
Phenobarbital | 6–8 weeks (25% per week) |
Clonazepam | 3–6 months |
Pregnancy and AED
- Women of childbearing potential with epilepsy should undergo counselling regarding pregnancy
- Birth control
- AEDs that induce P450 enzymes inc. the failure rate of oral contraceptives by 4x → try use barrier instead
- Complications during pregnancy
- Higher complications than normal but >90% of pregnancies have a favourable outcome
- Seizures during pregnancy
- Risk 17%, due to
- Noncompliance or
- Changes of free drug levels of AEDs during pregnancy
- Usual cause no problems but can be deleterious
- Inc. Risk of pre-eclampsia (or preeclampsia) and foetal loss
- Status needs to be treated aggressively
- Birth defects (fetal malformations)
- Risk: 4– 5% / 2x general population
- Inc. With polytherapy (has additive manner)
- Due to
- Genetic factors
- AEDs
- To take or not to take AEDs
- Each patient needs counselling
- Risk of seizures (with possible concomitant maternal and fetal hypoxia and acidosis) > teratogenic risk of most AEDs
- Some patients can try to wean off AEDs
- Swap to away from AEDs that has higher risk of teratogenic effects
- What to give:
- 1st line: Lowest dose of CBZ
- 2nd line: Valproic acid
- Give Folate to all s
- Risks involved
- Carbamazepine
- Inc. Incidence of minor malformations but not major
- Inc. Incidence of neural tube defects (NTD)
- Phenytoin
- Fetal hydantoin syndrome
- IQ lower by ≈ 10 points
- Phenobarbital
- Highest risk of major malformations (9.1%)
- Highest risk of fetal deaths
- Valproate
- Highest risk of NTD (1-2%)
- Benzodiazepine
- Given shortly before delivery → floppy infant syndrome
Outcome of seizure
- If fails 1st medication its bad because its likely to fail even more
Levetiracetam or Phenytoin management
- In children
- EcLipse study
- Lancet : 2019
- In Adults
- Chu et al – meta-analysis 543 cases
- Seizure 2020
- For SE in both studies: showing Keppra not worse than PHT and possibly has better safety profile
Summary of ASMs
Established ASMs
- Phenobarbital
- Cheap
- 1x/day
- Broad Spectrum
- Sedation
- Cognitive impairment
- Enzyme induction
- Bone loss
- Phenytoin
- Cheap
- 1x/day
- Sedation
- Saturation Kinetics
- Allergic reaction
- Enzyme induction
- Bone loss
- Carbamazepine
- 'Gold standard' for focal seizures
- Studied in elderly
- Neurotoxicity
- Allergic reactions
- Enzyme induction
- Hyponatraemia
- Bone loss
- Sodium valproate
- 'Gold standard' for generalised seizures
- Broad spectrum
- Extrapyramidal symptoms
- Weight gain
- Tremor
- Bone loss
Modern ASMs
- Lamotrigine
- Few interactions
- Good tolerability
- Studied in elderly
- Slow titration
- Dose-related rash
- Insomnia
- Topiramate
- Few interactions
- Broad spectrum
- Weight loss
- Slow titration
- Cognitive impairment
- Renal stones
- Gabapentin
- No interactions
- Studied in elderly
- No allergic reactions
- Sedation
- Dizziness
- Weight gain
- Levetiracetam
- No interactions
- No allergic reactions
- Sedation
- Behavioural problems
Even more modern ASMs
- Pregabalin
- Weight gain
- Good for agitation
- Lacosamide
- Well tolerated, similar efficacy
- Few interactions
- Perampanel
- Need to go slow
- Aggression, falls
- Brivaracetam
- Better behavioural profile than LEV
- Eslicarbazepine Acetate
- 1x/day
- Better side effect profile than CBZ
- Cenobamate
- 1x/day
- Promising
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