Approach to pharmacological treatment of epilepsy

when and how to start medical treatment in epilepsy and how to manage afterward according to patient and drug characteristics

1. Approach to pharmacological treatment of epilepsy By/ Lobna Ahmed

2. When to start antiseizure drug?

3. First-time unprovoked seizure The decision of whether or not to start antiseizure drug therapy at the time of a first unprovoked seizure in an adult should be individualized. The clinical factors associated with increased risk of recurrence include: Epileptiform abnormalities on EEG. Remote symptomatic cause, as identified by clinical history or neuroimaging (brain tumor, brain malformation, head injury with loss of consciousness, prior central nervous system infection, or scarring from a prior brain injury or brain surgery). Abnormal neurologic examination, including focal findings and intellectual disability. A first seizure that occurs during sleep (a nocturnal seizure).

4. High risk of seizure >> most clinicians would start treatment. Low risk of seizure >> antiseizure drug therapy may be reasonably deferred until after a second unprovoked seizure.

5. Other potential risk factors for seizure recurrence with uncertain significance: A first presentation with status epilepticus or with multiple seizures within a single day. A history of prior febrile seizures. A family history of epilepsy.

6. Acute symptomatic seizure Acute severe neurologic illness or injury Patients with stroke, traumatic brain injury, meningitis, anoxic encephalopathy are often treated with antiseizure drugs in the acute setting because of the risk of prolonged recurrent seizures or aggravation of a systemic injury. Acute medical illness or metabolic disturbance There is a risk for seizure recurrence in the acute setting, not for future epilepsy. Short-term antiseizure drug therapy may be indicated if the metabolic disturbance is expected to persist or if the initial seizure is prolonged (SE).

7. Starting anti-seizure treatment

8. Choosing the right drug Monotherapy Do's and don't's in the epilepsy clinic: a guide on initialising pharmacological treatment ILAE Europe educational webinar

9. Efficacy spectrum Do's and don't's in the epilepsy clinic: a guide on initialising pharmacological treatment ILAE Europe educational webinar

10. Do's and don't's in the epilepsy clinic: a guide on initialising pharmacological treatment ILAE Europe educational webinar

11. NICE clinical guideline Epilepsies: diagnosis and management NICE guidline

12. Epilepsies: diagnosis and management NICE guidline

13. Epilepsies: diagnosis and management NICE guidline

14. Offer lamotrigine if are unsuitable, ineffective or not tolerated Epilepsies: diagnosis and management NICE guidline

15. Epilepsies: diagnosis and management NICE guidline

16. Do not offer carbamazepine, gabapentin, oxcarbazepine, pregabalin, tiagabine or vigabatrin Epilepsies: diagnosis and management NICE guidline

17. Prednisolone Tetracosactide Epilepsies: diagnosis and management NICE guidline

18. Epilepsies: diagnosis and management NICE guidline

19. Do not offer Carbamazepine Gabapentin Oxcarbazepine Pregabalin Tiagabine Vigabatrin Epilepsies: diagnosis and management NICE guidline

20. Benign epilepsy with centrotemporal spikes Panayiotopoulos syndrome Late-onset childhood occipital epilepsy (Gastaut type) Epilepsies: diagnosis and management NICE guidline

21. Can exacerbate myoclonic seizures Epilepsies: diagnosis and management NICE guidline

22. Do not offer carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine or vigabatrin Epilepsies: diagnosis and management NICE guidline

23. Epilepsies: diagnosis and management NICE guidline

24. Drug interactions Synergistic effect >> VPA+LTG PHT and Nasogastric tube (absorption). VPA vs PHT displacement from protein binding (distribution). Enzyme induction (CBZ-PHT-PHB). Enzyme inhibition(VPA).

25. AED combinations “polytherapy rational” Conventional wisdom suggests that combining AEDs with different mechanisms of action is more likely to produce seizure freedom than prescribing those with similar or overlapping pharmacological properties The only supportive evidence for synergism is with sodium valproate and lamotrigine. Combining antiepileptic drugs—Rational polytherapy?Martin J. Brodie, Graeme J. Sills

26. Combining drugs that block voltage-dependent sodium channels is more likely to produce neurotoxic side-effects, such as dizziness, diplopia and ataxia. Introducing lamotrigine in patients established on sodium valproate produces a substantially greater risk of allergic rash than occurs in patients starting on the drug as monotherapy (due to the inhibitory effect of valproate on lamotrigine metabolism resulting in higher concentrations). Combining antiepileptic drugs—Rational polytherapy?Martin J. Brodie, Graeme J. Sills

27. Combining antiepileptic drugs—Rational polytherapy?Martin J. Brodie, Graeme J. Sills

28. Patient characteristic

29. Women of childbearing Hormonal contraception Enzyme inducing reduce efficacy of COC. LTG reduces progesterone levels of OCP. OCP increase the metabolism of LTG >> higher doses of LTG may be needed. VPA doesn’t affect COC but major risk of fetal malformations. Injectables and intrauterine devices are not affected by enzyme inducing AED. Offer folic acid 5 mg.

30. Catamenial epilepsy The mainstay of treatment of catamenial seizures is an antiseizure drug that is most effective for the woman's epilepsy syndrome. However, when catamenial seizures are not controlled clinicians may consider use of a continuous estrogen-progestin contraceptive.

31. Intermittent benzodiazepine treatment timed according to the vulnerable phase of the menstrual cycle is also a common strategy. Clobazam is the only benzodiazepine studied systematically for this purpose (20 to 30 mg/day was administered for 10 days in the high-risk phase). Very limited data suggest that appropriately timed acetazolamide may have some benefit in catamenial epilepsy.

32. AED in renal disease Renally excreted drugs include gabapentin, topiramate, zonisamide, lacosamide, levetiracetam, oxcarbazepine, and pregabalin. Renal disease can prolong the elimination of the parent drug or an active metabolite and lead to accumulation and clinical toxicity. Lower doses and longer inter-dose intervals may be necessary in these cases. Renal disease can also affect the protein binding, distribution and metabolism of a drug.

33. The renally excreted drugs and some others (phenobarbital, lamotrigine) are removed by hemodialysis, and a low dose should be supplemented after dialysis to maintain therapeutic levels. Topiramate and zonisamide are associated with nephrolithiasis and should probably be avoided in patients with a history of or who are prone to this condition

34. Dose adjustment in renal disease

35. AED in liver disease Valproate and felbamate and to a lesser extent, phenytoin and carbamazepine , are associated with hepatic toxicity and should be avoided in patients with preexisting liver disease. Liver disease can delay the elimination rate of the drug from plasma, leading to a prolongation of the half-life and drug accumulation.

36. Elderly population Altered pharmacodynamics and pharmacokinetics. Lower protein binding. Impairment of hepatic metabolic capacity. Change in receptors density and sensitivity. Polypharmacy increase risk of drug-drug interactions, drug toxicity, adverse effects. Advanced pharmacological treatment there is no such thing as a normal patient ILAE Europe educational webinars

37. Psychiatric co-morbidities Persons with epilepsy have a higher than expected prevalence of comorbid psychiatric disorders. Some antiseizure drugs (valproate, lamotrigine, carbamazepine, oxcarbazepine) appear to have mood stabilizing properties.

38. In contrast, some antiseizure drugs, in particular those that potentiate GABA neurotransmission (phenobarbital, tiagabine, vigabatrin, topiramate) , have been reported to cause or exacerbate a depressed mood and perhaps should be avoided in patients with comorbid depression. Levetiracetam, topiramate, vigabatrin, zonisamide, ethosuximide, and perampanel have been reported to provoke psychosis.

39. Osteoporosis risk Chronic use of AED have been associated with bone loss. Initially this association was observed for enzyme-inducing antiseizure drugs, but later was found to extend to valproate as well as to some of the newer non enzyme-inducing AED. The strongest evidence is with phenytoin. Monitoring of bone density, routine supplementation of calcium and vitamin D is recommended.

40. Thank you