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
stroke
1
• 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 people
3

1. AHA-ASA Gudeline of Ischemic stroke, 2007
2. Szaflarski JP, et al. Epilepsia, 2008
3. 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, 2007
2. 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 elderly
1
▫ Akershus Stroke Study :
 2.5% in 4 weeks-1 year post stroke
2

▫ 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 infarction
3

1. Jose Vega, 2008
2. M. I. Lossius et al, Eor J Neurol, 2002
3. 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 stroke
1,2
▫ 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 stroke
1

▫ 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, 2001
2. 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 2
nd
AED
▫ If 2
nd
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
THANK YOU