SEIZURE & EPILEPSY IN CEREBROVASULAR

DISEASE

M. Kurniawan, MD

Definitions•Post-stroke seizure

‘‘single or multiple convulsive episode/s (fit/s) after stroke and thought to be related to reversible or irreversible cerebral damage due to stroke regardless of time of onset following the stroke’’

•Post-stroke epilepsy‘‘recurrent seizures following stroke with confirmed diagnosis of epilepsy’

•Cerebrovascular disease (CVD)all disorders in which an area of the brain is transiently or permanently affected by ischemia or bleeding and one or more of the cerebral blood vessels are involved in the pathological process

Myint et al, Postgrad Med J 2006

Causes of Epilepsy

Introduction• Seizures may be the sign of stroke or TIA due to

acute or chronic derangement of the brain’s microcircuitry or metabolic environment

• The most important acute neurological complications of stroke1

• Related to early mortality and long-term functional outcome▫ acute seizure related to higher mortality in first 30-d post

stroke 2

• Stroke is the leading cause of seizure in elderly, causing >50% epilepsy in older people3

1. AHA-ASA Gudeline of Ischemic stroke, 20072. Szaflarski JP, et al. Epilepsia, 20083. Silverman et al, Arch Neurol, 2002

Classification

•Early onset seizure▫< 2 weeks after stroke onset▫ 45% in the first 24 h

•Late onset seizure▫> 2 weeks after onset▫Mostly occured in 6-24 months after onset

and sometimes as the symptom of recurrent stroke

DeReuck J, J Clin Neurol Neurosur, 2007

Epidemiology• Seizure occured in 2-23% of stroke patients• Early onset seizure :

▫ 2-33% ; which 50-78% occured in 24h after onset• Late onset : 3-67 %1

• Risk of 1 seizure in 5 year after stroke :▫ 10% of ischemic stroke survivor▫ 27 % in intracerebral hemorrhage and ▫ 34% of SAH patients

•Epilepsy develops in about 1/3 of early onset and ½ late onset seizures

1. AHA-ASA Gudeline of Ischemic stroke, 20072. Jose Vega, 2008

• Post Stroke Epilepsy :

▫ Incidence : 2-4%, 54-66% of those with late seizure▫ The most commonly identified cause of epilepsy in

adults older than 35 and accounts for >50% of all new cases of epilepsy in the elderly1

▫ Akershus Stroke Study : 2.5% in 4 weeks-1 year post stroke2

▫ Benbir Study : Incidence 3.6% Post-ischemic epilepsy in 70.6%, post-hemorrhagic

epilepsy in 21.6% and epilepsy following venous infarctions in 7.8%

2.7% of ischemic patients, 12.8% in hemorrhagic stroke and 26.6% in venous infarction3

1. Jose Vega, 20082. M. I. Lossius et al, Eor J Neurol, 20023. Benbir et al, Acta Neurol Scand, 2006

Frequency of Seizure & Epilepsy after Stroke

Pathophysiology & Pathogenesis

Early-onset seizure : Ishemic stroke

Increase in intracellular Ca and Na lower threshold for depolarisation

Glutamate excitotoxicity Hypoxia Metabolic dysfunction Global hypoperfusion, and Hyperperfusion injury (particularly after CEA)

•Hemorrhagic stroke Irritation caused by products of blood

metabolism Associated ischaemic area secondary to

haemorrhage

Late-onset seizure :

Ishemic stroke▫Persistent changes membrane properties,

deafferentation, selective neuronal loss, and collateral sprouting hyperexcitability and neuronal synchrony sufficient to cause seizures

▫Gliosis and the development of a meningocerebral cicatrix

Hemorrhagic stroke Haemosiderin deposits

Myint et al, Postgrad Med J 2006

Risk Factors• Ischemic stroke1,2

▫ Severity of the initial neurological deficit (HR, 10; 95% CI, 1.16 to 3.82)

▫ Severity of persistent disability after the stroke▫ Iinvolvement of multiple sites or a larger lesion▫ Cortical lesion (HR, 2.09; 95% CI, 1.19 to 3.68)▫ Hippocampus involvement ▫ Cardioembolic stroke

• Hemorrhage stroke1

▫ middle cerebral artery aneurysm in SAH, ▫ intraparenchymal haematoma ▫ Presence of structural brain lesions, EEG abnormalities, and

partial type seizures also carry a higher recurrence rate

1. Browne TR, et al. N Engl J Med, 20012. Marrero C, et al. Rev Neurol, 1998

Presentation• Typically follow a localisation-related (focal)

seizure semiology▫ 1/3 tonic-clonic (generalised) seizures ▫ 2/3 partial seizures

• Early onset seizures usually present with a focal type

• Late onset : generalised tonic-clonic seizures • Status epilepticus develops in 9% of cases

▫ Effect on mortality outcome still controversial▫ The type of stroke, topographic findings, size of the

lesion, or EEG pattern do not predict the progression to status epilepticus. 1. Rumbach L, et al. Neurology, 2000.

2. Velioglu SK, et al. Stroke, 2001.3. Camilo O, et al. Stroke, 2004

Management• No specific guideline for the management of post-

stroke seizure and epilepsy, including :▫ When to start treatment▫ Drug reccommendation▫ Duration of therapy

• SIGN guidelines Make a distinction between idiopathic generalised epilepsies and focal (localisation-related) epilepsies of which post-stroke epilepsy is an example

• International League Against Epilepsy (ILAE) Guideline Analysing The evidence for AED in elderly patients, age over 60

years• NICE guidelines

Suggest considering AED for a patient after a first unprovoked seizure if the patient has a neurological deficit or abnormality on brain imaging

•AHA/ASA Guideline

▫Pophylactic AED in ischemic stroke without seizure is not reccommended (Class III, level of evidence C)

▫In intracerebral hemorrhage, AED pprophylaxis can be given for 1 month, then tapped-off, and stopped if there is no seizure during treatment (Class V, level of evidence C)

Mechanism of action of AEDs•AEDs redress the balance between

neuronal excitation and inhibition•3 major mechanisms

▫Modulation of voltage gated ion channels▫Enhancement of GABA mediated inhibitory

neurotransmission▫Decrease of glutamate mediated excitatory

neurotransmission

Sills G, Mechanisms of action of antiepileptic drugs, 2009

•Drugs reccommendation :▫NICE & SIGN guidelines :

carbamazepine, sodium valproate, lamotrigine or oxcarbazepine as first line treatments for partial seizures and secondary generalised seizures.

▫ILAE Guideline : lamotrigine and gabapentin are as effective as carbamazepine in partial-onset seizures and that lamotrigine is better tolerated than carbamazepine in older people.

•Duration of treatment :▫NICE & SIGN guidelines recommend :

discontinuing AED after two years seizure free (generalised statement and not specific to post-stroke epilepsy).

General Consideration in Treatment

•Post stroke seizure patients are generally elderly

▫Pharmacokinetic factors Many drugs are renally excreted

Renal function decreases with age Polypharmacy is the norm

Many drug-drug interactions

▫Pharmacodynamic factors “Counter-regulatory” mechanisms that allow brain to

adapt to change decline with age Side effects are more likely & magnified AEDs can contribute to and exacerbate existing

cognitive deficits

Commonly used AED in older people

Other Drugs• Levetiracetam

▫ Advantages : Rapid titration No interactions Generally well tolerated Once-daily forms

▫ Disadvantages : Irritability common Not approved for monotherapy

• Gabapentin▫ Advantages :

Well tolerated in elderly No interactions Effective in neuropathic (diabetic) pain

▫ Disadvantages : Renally excreted Frequent (TID) dosing

British Stroke Physicians Survey, 2011

Treatment of Early Seizure• Use benzodiazepine (lorazepam) acutely

▫ Very effective for stopping seizures• Then either :

▫Load with a standard AED i.v.: phenytoin, divalproex, levetiracetam

▫Begin titrating an oral AED Any of above, or oxcarbazepine, lamotrigine

• Discontinue after ∼3 months unless compelling evidence for high recurrence risk

• Controversies : ▫AEDs may impair recovery from stroke▫Sedation, may reduce ability to participate in rehabilitation▫Must weigh benefits and risks for an individual

Treatment of Late Seizure•Likely to be long-term commitment, so

choose AED carefully•Start low and titrate slowly•First line : oxcarbazepine, lamotrigine,

divalproex•Second line: levetiracetam, gabapentin

Response to Treatment•VA Cooperative Study, 2005•50-60% new onset geriatric epilepsy

patients became seizure-free on first AED•But, only 50% remained in study at one

year•When treatment fails :

▫If first AED is not tolerated or does not control seizures, rapidly switch to 2nd AED

▫If 2nd AED fails, consider referral to Epilepsy Specialty Clinic

Other Treatment Considerations• No bathing, swimming alone• Safety alarm in home• Medical bracelet• Driver & Vehicle Licensing Agency (DVLA) :

▫ Following a first seizure, standard group 1 driving license is revoked for 6 months

▫ Group 2 licence (heavy goods vehicle or public service vehicle) is revoked for 5 years from the date of seizure

▫ In case of recurrent seizures or epilepsy the revoked period is one year (group 1 license) and 10 years (group 2 license) since the last seizure

▫ In cases where the AED is being withdrawn, the agency advises no driving for 6 months after commencement of withdrawal of medication

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