1. Therapy for Post Stroke Epilepsy 台中榮總神經醫學中心 神經內科 R4 田怡婷 2014/08/23

2. Outline Background of poststroke seizure Etiology and pathogenesis Clinical presentation – Impact on stroke outcome of PSS Management of poststroke seizure Take Home Messages

3. increased prevalence of epilepsy with aging Werhan, Conrad “Epilepsy in the Elderly" Dtsch Arztebl Int. 2009; 106 (9): 135-142

4. Minnesota Werhan, Conrad “Epilepsy in the Elderly" Dtsch Arztebl Int. 2009; 106 (9): 135-142

5. Stroke is associated with a 23- to 35-fold increase in seizure incidence the risk of development of epilepsy (recurrent seizures) is 17-fold higher in stroke patients than in the general population. Drugs Aging 2012; 29 (7): 533-538

6. Etiology and pathogenesis

7. The Oxfordshire community stroke project 675 patients with a first stroke (1981-1986) – 357 (53%) women and 318 (47%) men, – Ages: 24% over 84 years – 81% had cerebral infarction, 10% primary ICH, and 5% SAH – Minimal follow up of two years BMJ 1997;315:1582–7.

8. Kaplan-Meier estimate of the risk of post stroke seizures after first stroke; bars indicate 95% confidence intervals. Burn J et al. BMJ 1997;315:1582-1587 ©1997 by British Medical Journal Publishing Group risk of developing post-stroke in 5 yrs: 11.5%

9. Kaplan-Meier estimate of post stroke seizures subdivided by type of stroke. Burn J et al. BMJ 1997;315:1582-1587 ©1997 by British Medical Journal Publishing Group

10. Kaplan-Meier estimates of post stroke seizures after cerebral infarction, subdivided by clinical subtype. Burn J et al. BMJ 1997;315:1582-1587 ©1997 by British Medical Journal Publishing Group

11. The incidence of seizures post stroke is highest in patients with supratentorial lobar or extensive haemorrhages (15%), followed by subarachnoid haemorrhage (8.5%) and cortical stroke, usually in the middle cerebral artery (MCA) [6.5%]. Epilepsia.Epilepsia. 1995 Apr;36(4):327-33.

12. Pathogenesis Early onset seizures after ischemic strokes. – increase in intracellular Ca2+ and Na+ – lower threshold for depolarisation – glutamate excitotoxicity, – hypoxia, metabolic dysfunction – global hypoperfusion, and hyperperfusion Arch Neurol 2002;59:195–201.

13. Pathogenesis Early onset seizures after hemorrhagic strokes – irritation by products of blood metabolism. – an associated ischemic area secondary to hemorrhage Late onset seizures – persistent changes in neuronal excitability and gliotic scarring – hemosiderin deposits Arch Neurol 2002;59:195–201.

14. 1.Immediate and early seizures were not independent predictors of in-hospital mortality. 2.A brief period of therapy soon after ICH onset may reduce the risk of early seizures in patients with lobar hemorrhage. Epilepsia, 43(10):1175–1180, 2002

17. Risk factors of post-stroke seizures In ischemic strokes – the initial severity of stroke – the severity of persistent disability – the involvement of multiple sites – a larger lesion, cortical damage – hippocampus involvement Embolic stroke is a recognised risk for early post-stroke seizures Postgrad Med J 2006;82:568–572.

18. Risk factors of post-stroke seizures In hemorrhagic stroke – subarachnoid hemorrhages – middle cerebral artery aneurysm – intraparenchymal hematoma – structural brain lesions – EEG abnormalities – partial type seizures Postgrad Med J 2006;82:568–572.

19. Cerebrovasc Dis 2010;30:584–589 A hospital based registry in Germany 58,874 patients with the diagnosis of TIA, IS or ICH within 24 h after symptom onset.

20. Cerebrovasc Dis 2010;30:584–589

22. Clinical presentation of poststroke seizures

23. Poststroke seizure type Early onset seizure (first two weeks post stroke) – peak within 24 hours: 45% Late onset seizure (after two weeks post stroke) – peak within 6 to 12 months – higher recurrence rate of up to 90% (seizures) in both ischaemic and haemorrhagic stroke “Epilepsy” develops in about one third of early onset and half of late onset seizures. Postgrad Med J 2006;82:568–572.

24. Post Stroke Seizure Ischemic Stroke – 35% of early onset seizure develop into epilepsy – 90% of late onset seizure develop into epilepsy Hemorrhagic Stroke – 29% of early onset seizure develop into epilepsy – 93% of late onset seizure develop into epilepsy Silverman, Isaac, Restrepo, Lucas, Matthews, Gregory “Post-stroke Seizures." Archive of Neurology. 2002; 59: 195-202

25. Incidence of acute symptomatic seizures in Rochester, Minnesota, 1935-1984 Regarding the type of seizures – 60% are partial seizures 75% are simple partial motor and 25% become generalized. – 40% are generalized tonic-clonic Epilepsia.Epilepsia. 1995 Apr;36(4):327-33.

26. Hong-Kong A hospital-based cohort study 1000 consecutive patients in the acute stroke registry J Neurol.J Neurol. 2003 Jul;250(7):839-43.

27. J Neurol.J Neurol. 2003 Jul;250(7):839-43.

28. J Neurol.J Neurol. 2003 Jul;250(7):839-43.

29. Management of poststroke seizures

30. Mimics of PSS Syncope – vasovagal syncope, arrhythmia, orthostatism Transient ischemic attack Migraine narcolepsy Transient global amnesia Psychological conditions

31. Interaction between stroke medications and AEDs Seizure.Seizure. 2010 Sep;19(7):375-82

32. Drugs Aging 2004; 21 (10): 639-653

33. Spontaneous ICH, AHA, 2010 Seizures and Antiepileptic Drugs 1. Clinical seizures should be treated with antiepileptic drugs (Class I; Level of Evidence: A). (Revised from the previous guideline) Continuous EEG monitoring is probably indicated in ICH patients with depressed mental status out of proportion to the degree of brain injury (Class IIa; Level of Evidence: B). Patients with a change in mental status who are found to have electrographic seizures on EEG should be treated with antiepileptic drugs (Class I; Level of Evidence: C). Prophylactic anticonvulsant medication should not be used (Class III; Level of Evidence: B). (New recommendation)

34. AHA, 2013 Seizures An increased incidence of seizures after ischemic infarction is reported in patients with hemorrhagic transformation. No studies to date have demonstrated a benefit of prophylactic anticonvulsant use after ischemic stroke, and little information exists on indications for the long-term use of anticonvulsants after a seizure. Recommendation – Recurrent seizures after stroke should be treated in a manner similar to other acute neurological conditions, and antiepileptic agents should be selected by specific patient characteristics (Class I; Level of Evidence B). Stroke. 2013;44:870-947;

35. Neurologists have to first decide whether or not to give prophylactic AEDs after acute stroke, which AED to start after a first early post-stroke seizure. the risk for early seizures and the known adverse effects of AEDs ? the possibility of drug interactions ? – Hepatic enzyme induction by an AED (carbamazepine [CBZ] and phenytoin [PHT], for example) – Higher chance of toxic effects with aging. Drugs Aging 2012; 29 (7): 533-538

36. Adults with partial onset seizures – Level A (established): CBZ, LEV, PHT, and ZNS – Level B (probably): VPA – Level C (possible): GBP, LTG, OXC, phenobarbital (PB), TPM, and vigabatrin (VGB) – Level D (potential): clonazepam (CZP) and primidone (PRM)

37. Elderly adults with partial-onset seizures – Level A: GBP and LTG – Level C: CBZ – Level D: TPM and VPA Adults with generalized-onset tonic–clonic seizures – Level C: CBZ, LTG, OXC, PB, PHT, TPM – Level D: GBP, LEV, and VGB – 3 Class IV evidence suggests that CBZ and PHT may precipitate or aggravate generalized-onset tonic–clonic seizures (Guerrini et al., 1998; Genton, 2000; Somerville, 2009).

38. Take Home Messages Regarding the type of AED to choose, it has to be taken into consideration that first-generation AEDs, such as PHT, phenobarbital (PHB) and benzodiazepines (BNZ), may alter or delay functional outcome in stroke patients. PHB, PHT and CBZ are hepatic inducers, and PHT, BNZ and valproic acid (VPA) are highly protein bound, resulting in drug interactions with anticoagulants and antiplatelets, and have an influence on osteopenia and osteoporosis. The elderly population is more prone to side effects because of reduced hepatic clearance and renal elimination, resulting in increased plasma concentration of the free fraction.

39. Take Home Messages-cont’ In contrast, the new-generation of AEDs, including LTG, GBP, topiramate, oxcarbazepine and LEV, do not demonstrate significant interaction with anticoagulant or platelet therapy. The choice of whether or not to initiate AED treatment after a first or second post-stroke seizure should be discussed with the individual patient in order to make the right individualized decision. Many clinicians would probably agree that repeated post-stroke seizures require treatment with AEDs, and would choose the newer AEDs (LTG, GBP, LEV), but more research is still needed to assess the efficacy and tolerability of antiepileptic treatment of poststroke patients who are developing seizures.

40. Thank you !