1. Kuei-Cheng Lim, MD PhD 3 rd Annual Neuro Rehab Symposium March 7, 2015

2.  None

3.  Cynthia V Anderson is a 74 year old post-menopausal woman with atrial fibrillation on anticoagulation but stopped warfarin 4 days ago due to elevated INR with mild cognitive impairment and diabetes  She present to ED after waking up with right hemiparesis involving face and arm more than leg. She is aphasic.  Admitted for stroke evaluation. Six hours into hospitalization she had a convulsive seizure and returned to baseline after 2 hours post-ictal state.  What is her risk of another seizure?  What AED would you recommend?  How long would you keep AED going?  Does seizure affect her ability to participate in rehabilitation?

4.  Seizures and Epilepsy are not the same ◦ Seizure is the event and epilepsy is the disease ◦ Conceptual  Epileptic Seizure ◦ Transient occurrence of signs/symptoms due to abnormal excessive or synchronous neuronal activity in the brain  Epilepsy ◦ A disease characterized by an enduring predisposition to generate epileptic seizures and by the neurobiological, cognitive, psychological and social consequences of this condition ILAE website – www.ilae.org/Visitors/Definition-2014-Perspective.cfm

5.  At least 2 unprovoked (or reflex) seizures occurring more than 24 hours apart  One unprovoked seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after 2 unprovoked seizures, occurring over the next 10 years  Diagnosis of an epilepsy syndrome  Epilepsy is considered to be resolved for individuals who had age-dependent epilepsy syndrome but are now past the applicable age or those who have remained seizure-free for at least 10 years; with no seizure medications for the last 5 years Fisher RS et al. A practical clinical definition of epilepsy, Epilepsia 2014; 55:475-482

6. Hauser WA et al. Mayo Clin Proc 1996: 71; 576-86. Kim DW et al. Epilepsia 2014: 55; 67-75.

7. Modified from Hauser WA. “Ch. 8. Epidemiology of Acute Symptomatic Seizures.” in The Epilepsies; A comprehensive textbook. Ed. Engel and Pedley.

8. Modified from Banerjee PN and Hauser WA. “Ch. 5. Incidence and Prevalence” in The Epilepsies; A comprehensive textbook. Ed. Engel and Pedley.

9.  Cerebrovascular disease is a common cause of secondary epilepsy ◦ Especially in the elderly >60 years old population ◦ Accounts for about a third of epilepsy pts  Post-stroke seizures occur in 4-14% of strokes (some ranges from 5-20%)  Do early onset seizures develop into epilepsy? ◦ Risk of recurrent seizures varies with the definition of early versus late onset seizures ◦ Early seizures is 8-16 times more likely to have late onset seizures than those without early seizures ◦ About one-third of early onset seizures have recurrent seizures  Late onset seizures increase the risk of epilepsy ◦ About 50-90% of late onset seizures have recurrent seizures Silverman et al. Arch Neurol. 2002: 59; 195-202, Burneo et al Eur J Neurol 2010: 17; 52-58, Arboix A, et al. Stroke 1997: 28; 1590-4 Camilo V and Goldstein LB. Stroke 2004: 35; 1769-75

10.  0.2-0.8% of all strokes complicated by status epilepticus ◦ About 10% of early onset seizures are in status ◦ About 50-75% status cases are nonconvulsive ◦ Have higher functional disability and mortality  Risk of seizures increases with cortical location, ICH/SAH  Mortality and morbidity is higher in stroke patients with seizures ◦ Studies show that seizures increase risk of mortality by 2 to 3 times Silverman et al. Arch Neurol. 2002: 59; 195-202, Burneo et al Eur J Neurol 2010: 17; 52-58, Arboix A, et al. Stroke 1997: 28; 1590-4 Camilo V and Goldstein LB. Stroke 2004: 35; 1769-75

11.  Community stroke register of a population of 105,000 residents  2-6.5 years of follow-up 1981-1986 with follow-up to 1988  675 patients with 52 pts with one or more post stroke seizure  Onset seizure defined as <24 hours  Estimated 5 year risk of post-stroke seizure 11.5% (5-18% 95 CI) Burn J et al. BMJ 1997: 315; 1582-7

12. OnsetPost-stroke (%) Total67514536% IS54510440% ICH662150% SAH33200% Unknown3100 Burn J et al. BMJ 1997: 315; 1582-7

13. Any seizuresSingleRecurrent Total48232552% IS35171851% ICH73457% SAH63350% Unknown000 Burn J et al. BMJ 1997: 315; 1582-7

14. No sz / No pt% All strokes 37/9044.10%OR deep infarct 2/3560.60%1 (Ref) lobar infarct 20/3415.90%11 deep ICH 4/1014%8 lobar ICH 7/4914%25.3 SAH4/508%13.2 Labovitz DL et al. Neurology 2001: 57; 200-6

15.  1897 patients with IS/ICH stroke excluding brainstem strokes, AVMs, SAH, TIAs  168 / 1897 pts (8.9%) had a seizure ◦ Ischemic stroke 140 / 1632 (8.6%)  Early onset 78pts  Late onset 62pts  34 pts had recurrent seizures ◦ Hemorrhagic 28 / 265 (10.6%)  Early onset 21 pts  Late onset 7 pts  Patient with ischemic strokes and seizures had a worse prognosis, 30-d mortality 25% vs 7%  Seizures were more likely with cortical location of the stroke ◦ HR 2.09 (1.19 - 3.68) for a seizure ◦ HR 2.13 (0.60 - 7.53) for recurrent seizures  Late onset seizures have a HR of 12 for recurrent seizures Bladin CF et al. Arch Neurol 2000: 57; 1617-22.

16. Arntz R et al., PLoS One 2013;8: e55498

17. Type# patientsn seizures Incidence % Cumulative Risk % Total 6977911.314 IS 4256114.416 ICH 661116.731 TIA 20673.45 Arntz R et al., PLoS One 2013;8: e55498

18. Early seizure (n=25)Late seizures (n-54) TotalSingleMultipleTotalSingleMultiple IS 2014 (70%) 6 (30%) 4119 (46%) 22 (53%) ICH 43 (75%) 1 (25%) 71 (14%) 6 (86%) TIA 110633 Arntz R et al., PLoS One 2013;8: e55498

19.  Are the underlying causes of acute and late seizures different? ◦ Focal irritability ◦ Network irritability  Where is the line between early and late onset seizures? ◦ Cellular / Neuronal Death ◦ Gliosis ◦ Blood brain barrier  What is the natural history of acute symptomatic and remote symptomatic seizures?

20.  Rochester Epidemiology Project ◦ Rochester, Minnesota ◦ Limited population  Records-linkage system 1955-1984 ◦ All medical records are linked between medical facilities in Southeastern Minnesota ◦ Retrospective  Select patients first time seizures ◦ Classify as acute symptomatic versus remote symptomatic ◦ Assess for 30 day and 10 years mortality ◦ Assess for etiology of seizures Hesdorffer DC et al. Epilepsia. 2009: 50; 1102-8

21. AcuteRemote Total N 262148 N, subsequent seizures 3472 5 yr, Risk of subsequent seizure 19% (14-25%)65% (55-75%) Stroke 33% (21-50%)72% (60-82%) TBI 13% (7-25%)47% (30-66%) Infection 17% (10-28%)64% (21-99%) Hesdorffer DC et al. Epilepsia. 2009: 50; 1102-8

23. AcuteRemote Mortality, 30 days 56/262 (21.4%)5/148 (3.4%) Stroke42% (32-53%)5% (2-11%) TBI11% (6-20%)None Infection10% (5-19%)None Hesdorffer DC et al. Epilepsia. 2009: 50; 1102-8 Szalflarski JP et al. Epilepsia 2008: 49; 974-981 Caveat – Acute seizures may not be an INDEPENDENT risk factor for mortality but is associated with hemorrhagic strokes and larger infarct size and disability.

24.  Acute stroke is the 3 rd most common cause of SE (~20-36% of all SE cases)  8% of all post-stroke seizures present in SE  10-20% of early onset seizures are in SE  Subclinical seizures are missed unless there is continuous EEG monitoring ◦ Subclinical/nonconvulsive seizures are 4 times more likely to occur than convulsive seizures.  Patients in SE are at twice the risk of mortality Varelas PN and Hacein-Bey L. “Stroke and Critical Care Seizures” in Current Clinical Neurology: Seizures in Critical Care:.” Ed. PN Varels. Chapter 2, pg 21-82. Knaker et al. Epilepsia. 2006: 47; 2020-6.

25. DeLorenzo RJ et al. Neurology 1995: 46; 1029-35.

26.  232 patients with EEG in first 24hrs then followed up for 1 week  15 patients had seizures in first 24hrs (6.5%)  10% of EEGs had epileptiform discharges  6% had periodic lateralized epileptiform discharges (PLEDs) ◦ 71.4% evolved to status epilepticus  195/232 had diffuse or focal slowing only ◦ No seizures  23/232 had epileptiform discharges ◦ 3/23 had seizures  14/232 had PLEDs ◦ 10 were in status epilepticus (mostly convulsive) ◦ 2 had focal seizures ◦ 3/14 died compared to 30/218 without PLEDs Mecorelli O et al Cerebrovasc Dis 2011; 31: 191-8

27.  At least 2 unprovoked (or reflex) seizures occurring more than 24 hours apart  One unprovoked seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after 2 unprovoked seizures, occurring over the next 10 years  Diagnosis of an epilepsy syndrome  Epilepsy is considered to be resolved for individuals who had age-dependent epilepsy syndrome but are now past the applicable age or those who have remained seizure-free for at least 10 years; with no seizure medications for the last 5 years Fisher RS et al. A practical clinical definition of epilepsy, Epilepsia 2014; 55:475-482

28.  The risk of seizure recurrent  Risk of mortality  Underlying cause of seizure ◦ Is it self-limiting?  Medication interactions  Co-morbidities of the patient  Risk of adverse events

29.  Newer generation medications are preferred and are likely better tolerated ◦ Lamotrigine and gabapentin are better tolerated than carbamazepine  Older generation medications may interact with oral anticoagulation or anti-thrombotic medications  CYP3A4 induction/inhibition ◦ Phenytoin ◦ Carbamazepine, oxcarbazepine ◦ Phenobarbital ◦ Valproate  Electrolyte disturbances ◦ Topiramate, zonisamide (carbonic anhydrase activity) ◦ Oxcarbazepine (hyponatremia)

30.  Dementia/sundowning/psychosis ◦ Levetiracetam  Multiple drug rashes ◦ Lamotrigine, phenytoin, carbamazepine (HLA-B* 1502), zonisamide  Woman of child bearing age ◦ Valproate, carbamazepine, benzodiazepine, phenytoin, phenobarbital  Anemia ◦ Felbamate, valproate, carbamazepine  Kidney disease ◦ Topiramate, zonisamide