Strokes and Seizures:

what we knowKuei-Cheng Lim, MD PhD

3rd Annual Neuro Rehab SymposiumMarch 7, 2015

None

Disclosure

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?

Case to ponder

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

Defining Epilepsy

ILAE website – www.ilae.org/Visitors/Definition-2014-Perspective.cfm

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

Operational (Practical) Clinical Definition of Epilepsy

Fisher RS et al. A practical clinical definition of epilepsy, Epilepsia 2014; 55:475-482

Age related diagnosis of epilepsy

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

Head Trauma

16%

Cerebrovascular 16%

Infection 15%Brain Tumor 8%

Metabolic 9%

Toxic 6%

Withdrawal 14%

Other 10%

Encephalopathy 5% Eclasmpsia 2%

Causes of Acute Symptomatic Seizures

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

IdiopathicCryptogenic

62.4%, Stroke 9.3%

Trauma 8.8%

Tumor 2.7%Infection 2.2%,

Alcohol 5.8%

Neuro-degenera-tive 4.0% MR/CP 3.5%, Other 1.3%

Etiology of Epilepsy

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

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

General overview of seizures and strokes

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; 1590-4Camilo V and Goldstein LB. Stroke 2004: 35; 1769-75

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

General overview of seizures and strokes

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; 1590-4Camilo V and Goldstein LB. Stroke 2004: 35; 1769-75

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)

Oxfordshire Community Stroke Project

Burn J et al. BMJ 1997: 315; 1582-7

Onset Post-stroke (%)

Total 675 14 5 36%

IS 545 10 4 40%

ICH 66 2 1 50%

SAH 33 2 0 0%

Unknown 31 0 0

Occurrence of post-stroke seizure after onset seizure

Burn J et al. BMJ 1997: 315; 1582-7

Any seizures Single Recurrent

Total 48 23 25 52%

IS 35 17 18 51%

ICH 7 3 4 57%

SAH 6 3 3 50%

Unknown 0 0 0

Post-stroke seizures > 24 hrs

Burn J et al. BMJ 1997: 315; 1582-7

Cortical / Lobar strokes are more likely to have seizures

Burn J et al. BMJ 1997: 315; 1582-7

No sz / No pt %

All strokes 37/904

4.10% OR

deep infarct

2/356 0.60%

1 (Ref)

lobar infarct

20/341 5.90%

11

deep ICH 4/101 4% 8

lobar ICH 7/49 14% 25.3

SAH 4/50 8% 13.2

Labovitz DL et al. Neurology 2001: 57; 200-6

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

Seizure after Stroke Study Group

Bladin CF et al. Arch Neurol 2000: 57; 1617-22.

Risk of first seizure is greatest in the first 1-2 years

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

Type # patients n seizures Incidence%

Cumulative Risk%

Total 697 79 11.3 14

IS 425 61 14.4 16

ICH 66 11 16.7 31

TIA 206 7 3.4 5

Risk of seizures in young stroke patients (FUTURE study)

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

Early seizure (n=25) Late seizures (n-54)

Total Single Multiple Total Single Multiple

IS 20 14 (70%)

6 (30%)

41 19 (46%)

22 (53%)

ICH 4 3 (75%)

1 (25%)

7 1(14%)

6(86%)

TIA 1 1 0 6 3 3

Late onset seizures are more likely to Recur

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

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?

Treatment of Early versus Late Onset Seizures

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

Mortality of symptomatic seizures study

Hesdorffer DC et al. Epilepsia. 2009: 50; 1102-8

Acute RemoteTotal N 262 148

N, subsequent seizures 34 72

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%)

Risk of Recurrent Seizures

Hesdorffer DC et al. Epilepsia. 2009: 50; 1102-8

Probability of Recurrent SeizuresGreater with Remote Symptomatic

Hesdorffer DC et al. Epilepsia. 2009: 50; 1102-8

Acute Remote

Mortality, 30 days

56/262 (21.4%)

5/148 (3.4%)

Stroke 42% (32-53%) 5% (2-11%)

TBI 11% (6-20%) None

Infection 10% (5-19%) None

30 day Mortality is greater with Acute Symptomatic Seizures

Hesdorffer DC et al. Epilepsia. 2009: 50; 1102-8Szalflarski 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.

Acute stroke is the 3rd 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

Status Epilepticus in Stroke

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.

Causes of status epilepticus

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

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

EEG and Strokes

Mecorelli O et al Cerebrovasc Dis 2011; 31: 191-8

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

Operational (Practical) Clinical Definition of Epilepsy

Fisher RS et al. A practical clinical definition of epilepsy, Epilepsia 2014; 55:475-482

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

Before starting treatment consider:

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)

Medication interactions

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

AEDs to avoid based onPatient characteristics