Levetiracetam monotherapy for late poststroke seizures in the elderly.
ABSTRACT Stroke is the most common cause of seizures in the elderly. Antiepileptic drugs are used to treat most patients with late poststroke seizures. The aim of this study was to evaluate the efficacy and tolerability of levetiracetam (LEV) in patients aged 60 or older with late-onset poststroke seizures. This prospective study evaluated patients 60 years of age or older, who had at least two late-onset poststroke seizures and were given LEV monotherapy. Demographic data and seizure and stroke characteristics were recorded. Outpatient visits were made after 2, 4, 6, 9, and 12 months and every 3 months thereafter, and the effectiveness and tolerability of LEV were investigated. Thirty-four patients with a mean age of 69.76+/-6.41 were included in this study. Average seizure frequency before treatment was 3.61+/-3.02/month. Mean follow-up time was 17.68+/-3.24 months. At daily doses of 1000-2000 mg, 82.4% of the patients were seizure free, and 7 patients (20.6%) had side effects. LEV was discontinued in one patient because of severe somnolence. Two patients were switched to another antiepileptic drug because of uncontrolled seizures despite an increase in dose up to 3000 mg/day. LEV monotherapy can be effective and well tolerated in elderly patients with late-onset poststroke seizures.
- SourceAvailable from: PubMed Central[Show abstract] [Hide abstract]
ABSTRACT: Levetiracetam (LEV) is an anti-epileptic drug commonly used for the treatment of partial onset and generalized seizures. In addition to its neuromodulatory and neuroinhibitory effects via its binding to the synaptic vesicle protein SV2A, multiple studies have suggested neuroprotective properties for LEV in both epileptic and non-epileptic conditions. The purpose of this review is to discuss the extent of LEV-mediated protection seen in different neurological conditions, the potential of LEV for easing epileptogenesis, and the possible mechanisms that underlie the protective properties of LEV. LEV has been found to be particularly beneficial for restraining seizures in animal models of spontaneous epilepsy, acute seizures, and status epilepticus (SE). However, its ability for easing epileptogenesis and cognitive dysfunction following SE remains controversial with some studies implying favorable outcomes and others reporting no beneficial effects. Efficacy of LEV as a neuroprotective drug against traumatic brain injury (TBI) has received much attention. While animal studies in TBI models have showed significant neuroprotection and improvements in motor and memory performance with LEV treatment, clinical studies suggest that LEV has similar efficacy as phenytoin in terms of its ability to prevent post-traumatic epilepsy. LEV treatment for TBI is also reported to have fewer adverse effects and monitoring considerations but electroencephalographic recordings suggest the presence of increased seizure tendency. Studies on stroke imply that LEV is a useful alternative to carbamazepine for preventing post-stroke seizures in terms of efficacy and safety. Thus, LEV treatment has promise for restraining SE-, TBI-, or stroke-induced chronic epilepsy. Nevertheless, additional studies are needed to ascertain the most apt dose, timing of intervention, and duration of treatment after the initial precipitating injury and the mechanisms underlying LEV-mediated beneficial effects.Frontiers in Neurology 01/2013; 4:172.
Article: Management of CADASIL syndrome[Show abstract] [Hide abstract]
ABSTRACT: Introduction: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary small-vessel disease. CADASIL is caused by mutations in the NOTCH3 gene on chromosome 19; its global incidence and prevalence are unknown, likely because of under-diagnosis. CADASIL is a multisystemic disease, but its main clinical manifestations are related to the involvement of the brain. Very few controlled studies have been specifically performed on therapeutic interventions for CADASIL and its clinical manifestations. Areas covered: Evidence is reviewed about possible effects of controlling risk factors for the disease, and about treatment of most common clinical manifestations: migraine, TIA/stroke, psychiatric disturbances and epilepsy, cognitive impairment and dementia. Expert opinion: Correction of risk factors, and in particular hypertension, seems to be mandatory for reducing risk of stroke. Antiplatelet agents in secondary prevention in CADASIL might be recommended for secondary but not for primary prevention. Antiepileptic drugs seem to be the best choice for prophylaxis of migraine and MA, when needed. Psychiatric symptoms should be treated with conventional drugs, after reaching correct clinical diagnosis. Treatment of cognitive impairment and dementia with cholinesterase inhibitors may be effective on executive functions, but no conclusive data are available about its usefulness.Expert Opinion on Orphan Drugs. 08/2013; 1(9).
- [Show abstract] [Hide abstract]
ABSTRACT: The armamentarium to treat epilepsy includes today more than twenty drugs. These are classically distinguished as standard, traditional or first generation antiepileptic drugs (AEDs), which include phenobarbital, phenytoin, carbamazepine, valproic acid, ethosuximide and benzodiazepines, and new or second generation AEDs, which are vigabatrin, lamotrigine, felbamate, gabapentin, oxcarbazepine, tiagabine, topiramate, stiripentol, pregabalin, levetiracetam, rufinamide, zonisamide. More recently, other four compounds have been introduced, i.e., lacosamide, retigabine, eslicarbazepine acetate and perampanel, also defined as third generation AEDs. The mechanism of antiepileptic action is mainly mediated by increase in inhibitory GABA activity and/or prolongation of sodium and/or calcium channel inactivation. From a pharmacokinetic point of view, the most relevant difference characterizing a number of the recent AEDs as compared to the traditional ones is the lack of or a milder induction of hepatic enzymes with consequent reduced risk of drug-drug interactions. Concerning therapeutic features, valproic acid exhibits the broadest spectrum of action and still remains the only AED which can be used to treat all types of seizures, from absences and other primarily generalized seizures to focal ones, and almost all syndromes. Among the recent compounds, lamotrigine, topiramate, levetiracetam and zonisamide have shown to be efficacious in primarily generalized seizures and in some idiopathic generalized epilepsies, but their effect against absence seizures is less potent than that of valproic acid or even irrelevant. All AEDs, except ethosuximide, exhibit similar efficacy against focal seizures and, apart from traditional drugs, lamotrigine, oxcarbazepine, gabapentin, topiramate and levetiracetam, and ZNS in Europe, have the indication of mono-therapy. Some of the new compounds have specific paediatric indications: vigabatrin against infantile spasms in West syndrome, felbamate and rufinamide against mixed seizures in the Lennox-Gastaut syndrome, and stiripentol against some types of seizures in Dravet syndrome. In spite of this variety of AEDs, the percentage of patients with refractory epilepsy has not changed over the last 50 years and is still stabilized around 30-40%. Adverse events are observed in one-third of patients on AED therapy. Frequent, unspecific and usually dose dependent CNS side effects occur with almost all AEDs and encompass sedation, somnolence, fatigue, and dizziness, usually attenuating or even disappearing over time. Acute idiosyncratic effects, such as skin rush, may be particularly troubling and may configure a hypersensitivity syndrome with rapid degeneration to a severe and even life-threatening condition. Felbamate and vigabatrin are used exceptionally because of high incidence of aplastic anemia and liver failure occurring with the first and irreversible loss of visual field occurring with the second one. Subtle and slowly developing adverse effects, like bone mineral density reduction associated especially with traditional enzyme-inducing AEDs, require a continuous monitoring of the patient clinical condition. Antiepileptic therapy has special implications for women of child bearing age with regard to contraception, pregnancy and teratogenicity. There is some evidence that teratogenic effects, particularly frightening with valproic acid, with > 400mg/day dose of carbamazepine, and with polytherapies, are less frequent with lamotrigine. Given the large number of available AEDs, opportunities to tailor drug therapy on the individual patient are various. Treatment decisions, however, are complex and need to be individualised on the basis of careful evaluation of a number factors related to drug, disease and the patient. Choice of first-line therapy for a specific form of epilepsy, the time at which the drug should be started, and which strategy is most appropriate after failure of the first drug are key decision steps. Patient-specific factors include age, sex, childbearing potential, co-morbidities, and concomitant medications. Future directions include discovery of drugs with an improved safety profile, with more potent anti-seizure effect, able to prevent epileptogenesis and, possibly, to interact with specific genetic substrates.Frontiers in Clinical Drug Research - CNS and Neurological Disorders, Volume 1 edited by Atta-ur-Rahman, 09/2013: chapter 6: pages 149-229; Bentham Science Publishers., ISBN: 9781608057597
Levetiracetam monotherapy for late poststroke seizures in the elderly
Gulnihal Kutlu*, Yasemin B. Gomceli, Yasemin Unal, Levent E. Inan
Department of Neurology, Ankara Research and Training Hospital, Ministry of Health, Ankara, Turkey
a r t i c l e i n f o
Received 21 March 2008
Revised 27 April 2008
Accepted 29 April 2008
Available online 6 June 2008
a b s t r a c t
Stroke is the most common cause of seizures in the elderly. Antiepileptic drugs are used to treat most
patients with late poststroke seizures. The aim of this study was to evaluate the efficacy and tolerability
of levetiracetam (LEV) in patients aged 60 or older with late-onset poststroke seizures. This prospective
study evaluated patients 60 years of age or older, who had at least two late-onset poststroke seizures and
were given LEV monotherapy. Demographic data and seizure and stroke characteristics were recorded.
Outpatient visits were made after 2, 4, 6, 9, and 12 months and every 3 months thereafter, and the effec-
tiveness and tolerability of LEV were investigated. Thirty–four patients with a mean age of 69.76 ± 6.41
were included in this study. Average seizure frequency before treatment was 3.61 ± 3.02/month. Mean
follow-up time was 17.68 ± 3.24 months. At daily doses of 1000–2000 mg, 82.4% of the patients were sei-
zure free, and 7 patients (20.6%) had side effects. LEV was discontinued in one patient because of severe
somnolence. Two patients were switched to another antiepileptic drug because of uncontrolled seizures
despite an increase in dose up to 3000 mg/day. LEV monotherapy can be effective and well tolerated in
elderly patients with late-onset poststroke seizures.
? 2008 Elsevier Inc. All rights reserved.
In population studies, stroke is the most commonly identified
cause of epilepsy in adults older than 35 . In the elderly, stroke
accounts for more than half of the newly diagnosed cases of epi-
lepsy in which a cause is determined, ahead of degenerative disor-
ders, brain tumors, and head trauma . Forsgren et al. reported
that 45% of seizures starting after age 60 are due to stroke .
The frequency of poststroke seizures reported in studies varies
from 2.3%  to 43% . Poststroke seizures are classified as early
poststroke seizures within 14 days of stroke, or late poststroke sei-
zures when occurring more than 2 weeks after stroke. The risk of
experiencing late poststroke seizures is 3–5% in the first year after
stroke and 1–2% thereafter [5,6]. Several studies report that recur-
rence is more common for late poststroke seizures than for early
poststroke seizures [7,8]. Therefore, antiepileptic drugs are used
to treat most patients with late poststroke seizures .
Levetiracetam (LEV) has been approved as adjunctive treat-
ment for partial onset seizures in adults [10,11]. LEV exhibits lin-
ear pharmacokinetics, and the likelihood of accumulation in the
body is rare. LEV is eliminated entirely through renal excretion,
and the potential for drug interactions is absent or negligible
. Its pharmacokinetic profile includes minimal protein bind-
ing, lack of hepatic metabolism, and twice-a-day dosing .
The tolerability profile with respect to effects on memory and
cognitive function is also good . Among the antiepileptic
drugs, LEV is a good candidate for the treatment of elderly pa-
tients with epilepsy [15,16].
We report our experience on the use of LEV in monotherapy
against late-onset poststroke seizures in an elderly population.
A prospective study evaluated patients aged 60 or older, who had at least two
late-onset poststroke seizures and received LEV monotherapy in our epilepsy unit
between June 2004 and December 2006. Late-onset poststroke seizures were de-
fined as seizures occurring 2 weeks after stroke. Patients who had seizures only
in special circumstances, such as acute electrolyte imbalance and other metabolic
conditions, and those diagnosed with epilepsy before the stroke were not included
in this study.
Age, sex, detailed medical history, types of stroke and seizure, seizure fre-
quency, time of seizure occurrence from stroke onset, concomitant diseases and
medications, duration of follow-up, LEV dosage, seizure recurrence, and side effects
of LEV were collected for each patient. The radiological findings (brain tomography
and magnetic resonance imaging) of patients at the time of stroke were investigated
during the first evaluation in our epilepsy unit. Type of stroke was classified as
hemorrhagic or ischemic. The etiological subtype of ischemic stroke was classified
as cardioembolic or atherothrombotic. We used Commission on Classification and
Terminology of the International League against Epilepsy criteria to differentiate
between simple partial, complex partial, and secondarily generalized seizures. All
patients had an electroencephalogram (EEG) before beginning LEV monotherapy.
Patients signed an informed consent form before treatment. LEV was given at a
dose of 500 mg twice daily (1000 mg/day). For patients who experienced another
seizure, the dosage of LEV was increased gradually to a maximum of 3000 mg/
day. Patients were switched to another antiepileptic drug when they experienced
seizures at a daily LEV dose of 3000 mg/day.
1525-5050/$ - see front matter ? 2008 Elsevier Inc. All rights reserved.
* Corresponding author. Present address: Altay Mah Selcuklular Cad KC Goksu
Konutları A33/9, Eryaman-Ankara, Turkey. Fax: +00 90 312 4663626.
E-mail addresses: email@example.com, firstname.lastname@example.org (G. Kutlu).
Epilepsy & Behavior 13 (2008) 542–544
Contents lists available at ScienceDirect
Epilepsy & Behavior
journal homepage: www.elsevier.com/locate/yebeh
All patients were followed up at least 1 year. Seizure frequency was determined
using a seizure diary completed by each patient or his or her caregiver. Regular out-
patient visits were made after 2, 4, 6, 9, and 12 months and every 3 months there-
after. During the visits, the patients were evaluated with respect to seizure
frequency, type of seizures (as recorded seizure diary), LEV dosage, changes in other
medical conditions, and medications. Complete blood count and hepatic and renal
function tests were performed at each visit. Tolerability was evaluated at each visit
by monitoring possible side effects. Patients and/or caregivers were questioned
about nausea/vomiting, dyspepsia, dizziness, headache, somnolence, agitation
and/or behavioral changes, fatigue, weight loss/gain, and visual disturbance, and
these events were also recorded.
Statistical analysis was carried out using Statistical Package for Social Sciences
(SPSS 11.0 for Windows). The results of descriptive analysis were expressed as
means ± SD or number of cases and percentage. v2and independent sample t tests
were used to statistically compare the descriptive analysis between patients taking
1000 and 2000 mg daily. P values less than 0.05 was accepted as significant.
Thirty–four patients 60 years of age or older with late-onset
poststroke seizures and receiving LEV monotherapy were evalu-
ated in this study. Demographic characteristics of patients, seizure
types, and stroke etiologies are summarized in Table 1. Mean age
was 69.76 ± 6.41 (age range: 61–81). Nineteen (55.9%) patients
were male, and the remaining 15 (44.1%) were female. Mean sei-
zure frequency before LEV treatment was 3.61 ± 3.02/month. The
time from stroke onset to seizure was 14.26 ± 7.50 months. Corti-
cal strokes (73.5%) were more frequent than subcortical strokes
(26.5%). Ischemic strokes occurred in 25 (73.5%) patients. These
ischemic strokes involved middle cerebral artery (MCA) territory
in 21 (84%) cases. Thirteen of the 21 had a lesion involving at least
two lobes of the brain. The hematoma was lenticular in three
cases; however, lobar hematomas were found in the remaining
six patients. Lobar hematomas involved the frontotemporal lobe
in three patients and parieto-occipital lobe in two patients; tempo-
ral lobe localization of hemorrhage was determined in one patient.
Secondarily generalized partial seizures were found to be the most
frequent seizure type (61.8%). The most common EEG finding was
focal slowing, which occurred in 15 patients (44.1%). Twenty–se-
ven patients (79.4%) had concomitant diseases. Concomitant med-
ications were used by 82.4% of the patients; the mean number of
co-medications was 2.73 ± 1.94. Antihypertensive medication was
the most frequently used (16 patients, 47.1%), followed by anti-
platelet (15 patients, 44.1%), anti-diabetic (10 patients, 29.4%)
and anti-coagulant (8 patients, 23.5%) medications. Warfarin was
the anticoagulant used by these patients. Other concomitant med-
ications were anti-arrhythmic drugs and thyroid hormone. The
average follow-up time was 17.68 ± 3.24 (15–27) months.
At the end of 2 months of treatment, 22 of 34 patients (64.7%)
became seizure free at the dose of LEV 1000 mg/day and experi-
enced no seizures until the end of follow-up on the same dose. Se-
ven patients (20.6%) had side effects (headache in one patient,
dizziness in three patients, and somnolence in three patients)
attributed to LEV. LEV treatment was not stopped as these effects
were mild and disappeared after 7–20 days of treatment in six pa-
tients. One patient (2.9%), however, had very severe somnolence
within the first month of treatment. The dosage of LEV was de-
creased to 500 mg/day, but treatment was discontinued because
of continuing somnolence. This effect rapidly disappeared after dis-
continuation of LEV treatment. Other side effects of LEV include
nausea/vomiting, dyspepsia agitation and/or behavioral changes,
fatigue, weight loss/gain, and visual disturbances, but none of
these was reported by the patients. Patients and/or caregivers did
not mention agitation and/or behavioral changes. The dose of LEV
was increased to 2000 mg/day in the remaining 11 patients, who
had additional seizures.
At the end of 4 months of treatment, 7 of 11 patients were sei-
zure free at 2000 mg/day. Two of these 11 patients were lost to fol-
low-up at that time. One of them died from an acute myocardial
infarction, and the other gave no reason for failure to return. Sei-
zures continued in the remaining two patients despite a dose in-
crease up to 3000 mg/day; these two patients were switched to
another drug because of the uncontrolled seizures.
One patient who was being treated with LEV 2000 mg/day had a
seizure 9 months after beginning treatment. However, the dose
was not changed because the patient had a severe pulmonary
infection and fever at the time of the seizure. This patient was sei-
zure free in the remaining follow-up period. None of the other pa-
tients under treatment with LEV 2000 mg/day had a seizure during
follow-up. When compared with respect to age, seizure frequency
before treatment, seizure type, time from stroke onset to seizure,
and types of stroke and seizure, the 1000 and 2000 mg/day treat-
ment groups did not differ (P > 0.05).
During the follow-up period, 29 (85.3%) patients used LEV at
doses between 1000 and 2000 mg/day. Twenty–eight of 34 pa-
tients (82.4%) were seizure free; 3 patients discontinued LEV be-
cause of side effects (1 patient) and ineffectiveness of treatment
(2 patients). Two of 34 patients were lost to follow up.
Stroke is the most common cause of seizures in the elderly, and
seizures are among the most common neurological sequel of
stroke. About 10% of all stroke patients experience seizures from
Demographic data and main findings of the study
Time from stroke onset
69.76 ± 6.41
14.26 ± 7.50 months
3.61 ± 3.02/month
Partial + secondary generalization
Type of stroke (ischemic/hemorrhagic)
Number of concomitant medications
2.73 ± 1.94
Focal slowing + epileptiform activity
No side effects
Unresponsiveness to treatment
G. Kutlu et al./Epilepsy & Behavior 13 (2008) 542–544
onset until several years later . Cortical localization is among
the most reliable risk factors for poststroke seizures. Poststroke
seizures are more likely to develop in patients with larger lesions
involving multiple lobes of the brain than in those with single-lobe
involvement. However, any stroke, including those with only sub-
cortical involvement, may be associated with seizures . Cortical
localization and large lesions involving more than one lobe of the
brain were more common in our patients.
fects of antiepileptic drugs as a result of age-dependent changes in
pharmacokinetics and pharmacodynamics . Pharmacokinetic
epileptic drugs may be preferred for late-onset poststroke seizures
otrigine and carbamazepine treatment in the treatment of newly
diagnosed symptomatic poststroke seizures. This study included
only patients who had ischemic strokes, and the authors concluded
that lamotrigine treatment for poststroke seizures is as effective as
carbamazepine and relatively better tolerated . The efficacy
andtolerabilityof gabapentininpatients withlate-onsetpoststroke
seizures have also been investigated. Among 71 patients with post-
stroke seizures evaluated, seizures recurred in 18.3%; side effects
were recorded in 29 cases (38%), and required discontinuation of
the drug in only 2 cases. The authors suggested that gabapentin
monotherapy is useful and safe for late poststroke seizures .
To our knowledge, this is the first investigation of the use of LEV
monotherapy in patients with late-onset poststroke seizures re-
ported in the English literature. Previously, only one Spanish-lan-
guage article mentionedthe
poststroke seizures in elderly. Those authors found that 89.5% of
patients under treatment were seizure free and that 28% of pa-
tients experienced side effects of LEV, but not severe enough to
stop treatment. They concluded that LEV could be a safe, effective
therapeutic option for elderly patients who experience epilepsy
following a stroke .
In our study, LEV at daily doses of 1000–2000 mg was effective
in 85.3% of patients; 82.4% of the patients were seizure free. One
patient had only one seizure in special circumstances (fever and
pneumonia). LEV monotherapy did not control seizures in two pa-
tients despite increases in dose up to 3000 mg/day, so the antiep-
ileptic treatment was changed. An increase to 3000 mg of LEV
could be discussed for patients unresponsive to a daily dose of
2000 mg, although there was no change in seizure control between
2000 and 3000 mg/day in our study. However, the number of pa-
tients was too small to make a conclusion and further studies are
necessary to confirm the finding. The incidence of side effects
attributed to LEV was 20.6%. These side effects were all mild and
well tolerated, except for one patient (2.9%) for whom LEV treat-
ment was discontinued because of severe somnolence. This study
use ofLEV monotherapyin
had one limitation: After beginning LEV treatment, patients and/
or caregivers were asked to report agitation and/or behavioral
changes. Although these effects were not reported, the patients
were not evaluated for depression and other mood disorders in
In conclusion, our study suggests that LEV may be a good choice
for treatment of late-onset poststroke seizures in the elderly. It ap-
pears to be very effective and well tolerated. LEV monotherapy in
poststroke patients should be compared with other antiepileptic
drugs in future clinical trials.
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