Early treatment after stroke for the prevention of late epileptic seizures: A report on the problems performing a randomised placebo-controlled double-blind trial aimed at anti-epileptogenesis

  • J.H. van Tuijl
    Correspondence
    Corresponding author. Present address: P.O. Box 9015, 6500 GS, Nijmegen, The Netherlands. Tel.: +31 24 8483148; fax: +31 84 8302894.
    Affiliations
    Department of Neurology, Maastricht University Medical Centre, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands
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  • E.P.M. van Raak
    Affiliations
    Department of Neurology, Maastricht University Medical Centre, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands
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  • M.C.T.F.M. de Krom
    Affiliations
    Department of Neurology, Maastricht University Medical Centre, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands
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  • J. Lodder
    Affiliations
    Department of Neurology, Maastricht University Medical Centre, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands

    School for Mental Health and Neuroscience, P.O. Box 616, 6200 MD, Maastricht, The Netherlands
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  • A.P. Aldenkamp
    Affiliations
    Department of Neurology, Maastricht University Medical Centre, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands

    Department of Behavioral Science, Epilepsy Centre Kempenhaeghe, P.O. Box 61, 5590 AB, Heeze, The Netherlands

    School for Mental Health and Neuroscience, P.O. Box 616, 6200 MD, Maastricht, The Netherlands
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Open ArchivePublished:January 31, 2011DOI:https://doi.org/10.1016/j.seizure.2010.12.012

      Abstract

      Introduction

      Epileptic seizures in stroke patients are a common complication and adversely affect neurological outcome. We tried to perform a trial aimed at preventing the development of late poststroke seizures using levetiracetam. Levetiracetam is assumed to have anti-epileptogenic properties and might be suitable to prevent late epileptic seizures in stroke patients.

      Methods

      Stroke patients with a cortical syndrome and a modified Rankin score ≥ 3 or NIHSS ≥ 6 were treated with either levetiracetam 1500 mg daily divided in two doses or placebo during 12 weeks following stroke. Treatment was started within 7 days following stroke onset.

      Results

      Only 16 patients were included in this trial. Problems during the execution of this prophylactic trial concerned the assessment of the occurrence of epileptic seizures, a very slow inclusion rate, the use of anticonvulsive co-medication, continuation of the trial medication after discharge, and the evaluation of possible side effects of the trial medication.

      Discussion

      Due to too few participants, no conclusions could be drawn regarding the ability of levetiracetam to prevent poststroke seizures. The problems encountered during execution of this trial seem to be inherent to performing a trial aimed at preventing the development of epileptic seizures in stroke patients.

      Conclusions

      A prophylactic trial in stroke patients aimed at preventing poststroke seizures and epilepsy seems not feasible.

      Keywords

      1. Introduction

      In the Netherlands 41,000 patients suffer a stroke annually.

      Werkgroep cijfers van de Nederlands hartstichting. Cerebrovasculaire aandoeningen: cijfers en feiten. Deel II. Prevalentie, incidentie en prognose van cerebrovasculaire aandoeningen. Hart Bulletin 2006;37:105–8.

      Late epileptic seizures develop in 2.5–15% of stroke patients.
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      Epileptic seizures after a first stroke: the Oxfordshire Community Stroke Project.
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      Epilepsy after stroke.
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      Poststroke seizures in stroke rehabilitation patients.
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      • Coste J.
      • et al.
      Early and late seizures after cryptogenic ischemic stroke in young adults.
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      • Slapo G.D.
      • Mowinckel P.
      • Gjerstad L.
      Poststroke epilepsy: occurrence and predictors-a long-term prospective controlled study (Akershus stroke study).
      • Paolucci S.
      • Silvestri G.
      • Lubich S.
      • Pratesi L.
      • Traballesi M.
      • Gigli G.L.
      Poststroke late seizures and their role in rehabilitation of inpatients.
      Recurrent late symptomatic epileptic seizures develop in 48–89% of stroke patients with a first late seizure.
      • Bladin C.F.
      • Alexandrov A.V.
      • Bellavance A.
      • Bornstein N.
      • Chambers B.
      • Cote R.
      • et al.
      Seizures after stroke: a prospective multicenter study.
      • Burn J.
      • Dennis M.
      • Bamford J.
      • Sandercock P.
      • Wade D.
      • Warlow C.
      Epileptic seizures after a first stroke: the Oxfordshire Community Stroke Project.
      • Paolucci S.
      • Silvestri G.
      • Lubich S.
      • Pratesi L.
      • Traballesi M.
      • Gigli G.L.
      Poststroke late seizures and their role in rehabilitation of inpatients.
      • So E.L.
      • Annegers J.F.
      • Hauser W.A.
      • O’Brien P.C.
      • Whisnant J.P.
      Population-based study of seizure disorders after cerebral infarction.
      The occurrence of a late epileptic seizure or epilepsy in stroke patients may adversely affect their outcome. Bogousslavsky et al.
      • Bogousslavsky J.
      • Martin R.
      • Regli F.
      • Despland P.A.
      • Bolyn S.
      Persistent worsening of stroke sequelae after delayed seizures.
      described a persistent worsening of neurological outcome following epileptic seizures in stroke patients. De Reuck et al.
      • De Reuck J.
      • De Clerck M.
      • Van Maele G.
      Vascular cognitive impairment in patients with late-onset seizures after an ischemic stroke.
      described a lower Mini-Mental State Examination score and a higher modified Rankin score (mRS), implying worsening of neurological state in stroke patients with epilepsy compared to stroke patients without epilepsy. In patients with intracerebral haemorrhage, the occurrence of epileptic seizures is associated with an increase in midline shift and a worsening of neurological outcome.
      • Vespa P.M.
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      • Shah M.
      • Mirabelli J.
      • Starkman S.
      • Kidwell C.
      • et al.
      Acute seizures after intracerebral hemorrhage: a factor in progressive midline shift and outcome.
      In contrast with these results, Paolucci et al.
      • Paolucci S.
      • Silvestri G.
      • Lubich S.
      • Pratesi L.
      • Traballesi M.
      • Gigli G.L.
      Poststroke late seizures and their role in rehabilitation of inpatients.
      described no influence of epileptic seizures on rehabilitation outcome. The influence of epileptic seizures in stroke patients on mortality remains unclear.
      • Arboix A.
      • Comes E.
      • Garcia-Eroles L.
      • Massons J.B.
      • Oliveres M.
      • Balcells M.
      Prognostic value of very early seizures for in-hospital mortality in atherothrombotic infarction.
      • Vernino S.
      • Brown Jr., R.D.
      • Sejvar J.J.
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      • Petty G.W.
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      Cause-specific mortality after first cerebral infarction: a population-based study.
      • Alberti A.
      • Paciaroni M.
      • Caso V.
      • Venti M.
      • Palmerini F.
      • Agnelli G.
      Early seizures in patients with acute stroke: frequency, predictive factors, and effect on clinical outcome.
      • Szaflarski J.P.
      • Rackley A.Y.
      • Kleindorfer D.O.
      • Khoury J.
      • Woo D.
      • Miller R.
      • et al.
      Incidence of seizures in the acute phase of stroke: a population-based study.
      The pathophysiology of the development of early and late epileptic seizures is unclear. Several authors
      • Sun D.A.
      • Sombati S.
      • DeLorenzo R.J.
      Glutamate injury-induced epileptogenesis in hippocampal neurons: an in vitro model of stroke-induced “epilepsy”.
      • Camilo O.
      • Goldstein L.B.
      Seizures and epilepsy after ischemic stroke.
      suggested a different pathophysiological process underlying both conditions. Late seizures are assumed to be the result of the complex process of epileptogenesis during which the seizure threshold is lowered through a complicated chain of neuronal changes, whereas early seizures may rather be the result of acute excitatory activity due to glutamate release. Therefore, in our trial we focused on the prevention of late seizures only.
      In the ideal situation patients with a high risk of developing late epileptic seizures should be treated prophylactically with a drug that prevents epileptogenesis and has few side effects. Several antiepileptic drugs (AEDs) have been tested for their ability to prevent seizures associated with fever, alcohol, malaria, perinatal asphyxia, contrast media, tumors, craniotomy and traumatic brain injury, but not in stroke patients.
      • Temkin N.R.
      Antiepileptogenesis and seizure prevention trials with antiepileptic drugs: meta-analysis of controlled trials.
      So far, no controlled trial aimed at anti-epileptogenesis in stroke patients using an AED has been published. The need for such a trial was suggested by several authors.
      • Paolucci S.
      • Silvestri G.
      • Lubich S.
      • Pratesi L.
      • Traballesi M.
      • Gigli G.L.
      Poststroke late seizures and their role in rehabilitation of inpatients.
      • Arboix A.
      • Garcia-Eroles L.
      • Massons J.B.
      • Oliveres M.
      • Comes E.
      Predictive factors of early seizures after acute cerebrovascular disease.
      Recently, such a trial was also recommended in a Cochrane review.
      • Kwan J.
      • Wood E.
      Antiepileptic drugs for the primary and secondary prevention of seizures after stroke.
      In 2005 we started the ETLAS trial: ‘Early Treatment with Levetiracetam After Stroke for the prevention of late seizures: a randomised placebo-controlled double-blind trial’. The aim of our trial was to investigate whether prophylactic treatment with an AED following stroke reduced the risk of late epileptic seizures or postponed the onset of late epileptic seizures or epilepsy.
      For several reasons we were unable to complete this trial. In this paper we report the problems encountered by our group when performing this prophylactic trial. We wanted to report this negative result because in our opinion, the implementation problems of this trial are inherent to this area and seem unavoidable.

      2. Methods

      2.1 Design of the trial

      The ETLAS trial was designed as a multicentre, randomised, placebo-controlled, double-blind clinical trial. Primary endpoint of the trial was a first late epileptic seizure, defined as an unprovoked epileptic seizure more than 1 week after stroke.

      Guidelines for epidemiologic studies on epilepsy. Commission on epidemiology and prognosis, international league against epilepsy. Epilepsia 1993;34:592–6.

      Secondary endpoints were ‘time to event’ (period between stroke and the occurrence of a late epileptic seizure), occurrence of early epileptic seizures within 7 days after stroke, seizure severity, neurological function, neurocognitive function, handicap score, quality of life, and the occurrence of side effects of the trial medication. Fig. 1 illustrates the trial design.
      The trial was approved by the local medical ethics committee and board of directors of each participating centre. All patients or their legal representatives gave their written informed consent. Adult patients were recruited from the neurological ward at the University Hospital Maastricht starting in August 2005. From August 2006 the trial also started in the second centre, a large peripheral hospital in the south of the Netherlands. Patients with either lobar intracerebral haemorrhage or ischemic stroke with a cortical syndrome and mRS ≥ 3 or National Institutes of Health stroke severity (NIHSS) score ≥ 6 were asked to participate. Exclusion-criteria were previous history of epilepsy or treatment with an AED, life expectation less than 1 month due to stroke or other life-threatening comorbidity, and participation in another intervention trial. Treatment with thrombolytic drugs was no exclusion criterion. Trial medication was started between 48 h till 7 days after stroke. Patients were randomised to treatment with levetiracetam (LEV) or placebo. Trial medication, provided by UCB Pharma, consisted of either placebo tablets or 250 mg LEV tablets. These tablets were used to make boxes which were filled at random (according to a computerised randomisation list) by a pharmacist, and given consecutive numbers from 1001, 1002, etc. On each inclusion the trial medication with the lowest number was provided by the hospital pharmacist. The allocation of the trial medication was therefore blind to the patient and the investigators. The trial medication was gradually increased. On the first day of inclusion the patient received twice daily 1 tablet, the second day twice daily 2 tablets and the third day twice daily 3 tablets. When tolerated, this dose was kept constant for 12 weeks, after which the trial medication was tapered off by one tablet each 3 days and eventually discontinued. Total treatment time was therefore 14 weeks and 3 days. The target dose of LEV was two times daily 750 mg, but we allowed for lowering of the dose to twice daily 500 mg or even twice daily 250 mg when side-effects or medical problems, such as reduced renal clearance rate, occurred.
      We informed the staff, nurses at the neurology wards and the nursing home doctors at the referral nursing homes of first choice about our trial with an oral presentation and written information on trial details. Also, in each patient chart a coloured leaf was available with information on the trial and telephone numbers of the trial investigators. On discharge from the hospital, a letter, containing information about the trial, tapering schedule and contact information was provided along with the trial medication.

      2.2 Follow-up and outcome scores

      Follow-up visits took place at week 1, 6, 16 and 52 after inclusion, either at the outpatient clinic, in the nursing home, rehabilitation centre or at the patients’ home. At week 26 and week 39, the patients or their caregivers were contacted by telephone to inquire about the occurrence of possible epileptic seizures. We recorded the degree of handicap using the mRS, a six item scale ranging from ‘0 = no symptoms at all’ to ‘6 = dead’, at inclusion, week 6, 16, and 52. The NIHSS, a 15-item impairment scale which total scores ranging from 0 to 42, with higher values reflecting a higher stroke severity, was recorded at inclusion and at week 52. The Barthel index (BI), which is a 10 item questionnaire about independence in activities of daily living (ADL), with scores ranging from 0 to 20, in which ‘0’ signifies total dependence and ‘20’ total independence, was recorded at week 6, 16 and 52. The EuroQol, a generic quality of life measure, was recorded at the same follow-up moments as the BI. The side-effect in AED treatment questionnaire (SIDAED) was recorded at week 1 and week 6. This is a 46-item scale, which includes items in several categories such as general CNS, behaviour, depressive symptoms, and cognitive function (in Fig. 2 all categories are listed). Of each item the severity of the problem (mild, moderate, or severe) and the duration of the problem (several weeks, several months, longer than 6 months) was recorded.
      • Uijl S.G.
      • Uiterwaal C.S.
      • Aldenkamp A.P.
      • Carpay J.A.
      • Doelman J.C.
      • Keizer K.
      • et al.
      A cross-sectional study of subjective complaints in patients with epilepsy who seem to be well-controlled with anti-epileptic drugs.
      Figure thumbnail gr2
      Fig. 2Results of side-effect of antiepileptic drug (SIDAED) questionnaire.
      Neurocognitive function was tested using the Computerised Visual Searching Task (CVST), an adaptation of Goldstein's Visual Searching Task, which is part of the FePsy computerised neuropsychological test method.
      • Aldenkamp A.P.
      • Alpherts W.C.
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      • Overweg J.
      • Vermeulen J.
      Cognitive side-effects of phenytoin compared with carbamazepine in patients with localization-related epilepsy.
      The CVST assessed mental speed. Patients had to compare a centred grid pattern with 10 surrounding patterns, one of which was identical to the target pattern. The test consisted of 20 trials and gave an indication of the speed of information processing and perceptual mental strategies.

      2.3 Sample size estimation

      Sample size calculation was based on the following assumptions: (1) patients with a cortical syndrome and mRS ≥ 3 have a risk of 13% of late seizures,

      Heuts-van Raak L. Seizures following a first cerebral infarct: risk factors and prognosis. Thesis, University of Maastricht, Maastricht; 1996.

      (2) treatment reduces this risk (13%) to 5% (RRR = 62%). The primary factor type-1 (α) was chosen at the 5% level. Statistical power was chosen to be 1 − β = 80%. The power calculation based on percentage difference (change from 13% to 5% epilepsy) then yielded 200 patients per arm.

      2.4 Discussion of the design

      2.4.1 Trial population

      The advantages of prophylactic medication in terms of prevention of epileptic seizures must be balanced against the disadvantages of treating all patients, which means taking medication daily and being exposed to the risk of side effects, especially for patients who would never had developed epileptic seizures. To improve the balance between efficacy of the drug and the occurrence of side effects, an effective drug with few side-effects should be selected and only patients with a high risk of developing poststroke epilepsy should be treated.
      Several factors have been associated with the occurrence of late epileptic seizures in stroke patients: age, stroke severity, stroke localisation or cortical syndrome, stroke type, and the occurrence of early seizures.
      • Cheung C.M.
      • Tsoi T.H.
      • Au-Yeung M.
      • Tang A.S.
      Epileptic seizure after stroke in Chinese patients.
      • Lossius M.I.
      • Ronning O.M.
      • Slapo G.D.
      • Mowinckel P.
      • Gjerstad L.
      Poststroke epilepsy: occurrence and predictors-a long-term prospective controlled study (Akershus stroke study).
      • Paolucci S.
      • Silvestri G.
      • Lubich S.
      • Pratesi L.
      • Traballesi M.
      • Gigli G.L.
      Poststroke late seizures and their role in rehabilitation of inpatients.
      • So E.L.
      • Annegers J.F.
      • Hauser W.A.
      • O’Brien P.C.
      • Whisnant J.P.
      Population-based study of seizure disorders after cerebral infarction.
      • Lossius M.I.
      • Ronning O.M.
      • Mowinckel P.
      • Gjerstad L.
      Incidence and predictors for post-stroke epilepsy. A prospective controlled trial. The Akershus stroke study.
      • De Reuck J.
      • Goethals M.
      • Vonck K.
      • Van Maele G.
      Clinical predictors of late-onset seizures and epilepsy in patients with cerebrovascular disease.
      • Lancman M.E.
      • Golimstok A.
      • Norscini J.
      • Granillo R.
      Risk factors for developing seizures after a stroke.
      • Passero S.
      • Rocchi R.
      • Rossi S.
      • Ulivelli M.
      • Vatti G.
      Seizures after spontaneous supratentorial intracerebral hemorrhage.
      • Kammersgaard L.P.
      • Olsen T.S.
      Poststroke epilepsy in the Copenhagen stroke study: incidence and predictors.
      • Leone M.A.
      • Tonini M.C.
      • Bogliun G.
      • Gionco M.
      • Tassinari T.
      • Bottacchi E.
      • et al.
      Risk factors for a first epileptic seizure after stroke: a case control study.
      • Olsen T.S.
      • Hogenhaven H.
      • Thage O.
      Epilepsy after stroke.
      • Berges S.
      • Moulin T.
      • Berger E.
      • Tatu L.
      • Sablot D.
      • Challier B.
      • et al.
      Seizures and epilepsy following strokes: recurrence factors.
      Nonetheless, there is still debate about which factors have a significant contribution to the risk of developing poststroke epileptic seizures. In our centre Heuts-van Raak

      Heuts-van Raak L. Seizures following a first cerebral infarct: risk factors and prognosis. Thesis, University of Maastricht, Maastricht; 1996.

      performed a prospective study in poststroke patients. They reported a percentage of 13% late onset seizures in patients with an ischemic stroke, clinically a cortical syndrome and a mRS ≥ 3. The mRS is an outcome scale. It is more rational to use a stroke severity scale when selecting patients eligible for a trial. Therefore, we decided to use both the mRS and the NIHSS, a frequently used stroke severity scale, as inclusion criterion. A NIHSS ≥ 6 was chosen because, in our opinion this represented a stroke severity with mRS ≥ 3 best.
      • Tanne D.
      • Gorman M.J.
      • Bates V.E.
      • Kasner S.E.
      • Scott P.
      • Verro P.
      • et al.
      Intravenous tissue plasminogen activator for acute ischemic stroke in patients aged 80 years and older: the tPA stroke survey experience.

      2.4.2 Trial medication

      LEV is assumed to have anti-epileptogenic properties. When we started this study, this effect had been tested in several animal models, e.g. amygdala kindled rats,
      • Loscher W.
      • Honack D.
      • Rundfeldt C.
      Antiepileptogenic effects of the novel anticonvulsant levetiracetam (ucb L059) in the kindling model of temporal lobe epilepsy.
      corneally kindled mice,
      • Matagne A.
      • Klitgaard H.
      Validation of corneally kindled mice: a sensitive screening model for partial epilepsy in man.
      and spontaneous epileptic rats.
      • Yan H.D.
      • Ji-qun C.
      • Ishihara K.
      • Nagayama T.
      • Serikawa T.
      • Sasa M.
      Separation of antiepileptogenic and antiseizure effects of levetiracetam in the spontaneously epileptic rat (SER).
      • Ji-qun C.
      • Ishihara K.
      • Nagayama T.
      • Serikawa T.
      • Sasa M.
      Long-lasting antiepileptic effects of levetiracetam against epileptic seizures in the spontaneously epileptic rat (SER): differentiation of levetiracetam from conventional antiepileptic drugs.
      After initiation of our trial in 2005, more reports have been published about the antiepileptogenic effects of LEV in animal models.
      • Vinogradova L.V.
      • van Rijn C.M.
      Anticonvulsive and antiepileptogenic effects of levetiracetam in the audiogenic kindling model.
      • Sugaya Y.
      • Maru E.
      • Kudo K.
      • Shibasaki T.
      • Kato N.
      Levetiracetam suppresses development of spontaneous EEG seizures and aberrant neurogenesis following kainate-induced status epilepticus.
      • Ohno Y.
      • Ishihara S.
      • Terada R.
      • Serikawa T.
      • Sasa M.
      Antiepileptogenic and anticonvulsive actions of levetiracetam in a pentylenetetrazole kindling model.
      • Russo E.
      • Citraro R.
      • Scicchitano F.
      • De Fazio S.
      • Di Paola E.D.
      • Constanti A.
      • et al.
      Comparison of the antiepileptogenic effects of an early long-term treatment with ethosuximide or levetiracetam in a genetic animal model of absence epilepsy.
      Sugaya et al.
      • Sugaya Y.
      • Maru E.
      • Kudo K.
      • Shibasaki T.
      • Kato N.
      Levetiracetam suppresses development of spontaneous EEG seizures and aberrant neurogenesis following kainate-induced status epilepticus.
      suggested that prophylactic use of LEV for several weeks after a cerebral insult, like cerebral infarction, could provide long-lasting protection in the prevention of the late onset of spontaneous epilepsy.
      Early treatment with LEV in stroke patients does not seem harmful with regard to the effect on ischemic brain tissue.
      • Hanon E.
      • Klitgaard H.
      Neuroprotective properties of the novel antiepileptic drug levetiracetam in the rat middle cerebral artery occlusion model of focal cerebral ischemia.
      Tolerability of LEV in clinical practice is good.
      • Ben-Menachem E.
      • Edrich P.
      • Van Vleymen B.
      • Sander J.W.
      • Schmidt B.
      Evidence for sustained efficacy of levetiracetam as add-on epilepsy therapy.
      • Alsaadi T.M.
      • Shatzel A.
      • Marquez A.V.
      • Jorgensen J.
      • Farias S.
      Clinical experience of levetiracetam monotherapy for adults with epilepsy: 1-year follow-up study.
      • Abou-Khalil B.
      • Schaich L.
      Long-term efficacy of levetiracetam for partial seizures.
      • Cramer J.A.
      • Leppik I.E.
      • Rue K.D.
      • Edrich P.
      • Kramer G.
      Tolerability of levetiracetam in elderly patients with CNS disorders.
      We choose a target LEV dose of two times daily 750 mg, which is a clinically accepted dose with acceptable tolerability and high enough to be effective.

      2.4.3 Start of treatment

      An early start of treatment seemed necessary to allow for the best possible anti-epileptogenic effects, when one considers epileptogenesis as a continuous process which starts immediately following stroke. Due to logistic reasons, such as the need to provide extensive patient information to guarantee compliance for the duration of 12 months, and to give patients and their relatives time to consider inclusion in the trial, initiation of treatment was not started within 48 h. To allow participation of patients who could not give informed consent, e.g. due to somnolence in severe stroke, we extended the inclusion period to 7 days after stroke.

      2.4.4 Treatment duration and follow-up

      The length of the intervention period (12 weeks) was based on calculations from the study by Heuts-van Raak.

      Heuts-van Raak L. Seizures following a first cerebral infarct: risk factors and prognosis. Thesis, University of Maastricht, Maastricht; 1996.

      Within the first year after stroke, the occurrence of late epileptic seizures was evenly distributed without peak periods. The treatment period should be long enough to prevent epileptogenesis. However, longer treatment periods increase the risk that treatment is anti-convulsive instead of anti-epileptogenic, as some patients would have had epileptic seizures if the AED would not have been given. The purpose of this trial was not to study the anti-convulsive effect of LEV, but to test the hypothesis of an anti-epileptogenic or prophylactic effect.
      The length of our follow-up period was based on data indicating that approximately two third of the late epileptic seizures occur within 1 year after stroke.
      • Lossius M.I.
      • Ronning O.M.
      • Slapo G.D.
      • Mowinckel P.
      • Gjerstad L.
      Poststroke epilepsy: occurrence and predictors-a long-term prospective controlled study (Akershus stroke study).
      • So E.L.
      • Annegers J.F.
      • Hauser W.A.
      • O’Brien P.C.
      • Whisnant J.P.
      Population-based study of seizure disorders after cerebral infarction.

      2.4.5 Estimated inclusion rate

      Before starting this trial we tried to estimate the number of patients eligible for inclusion in this trial. In this period yearly about 340 patients were admitted to our hospital with a stroke, of which 62% had an ischemic stroke with a cortical syndrome, and 7% had a lobar intracerebral haemorrhage (resulting in 235 available patients per year). Because in this prophylactic trial only first-ever ischemic stroke patients with a predefined severity were suitable for inclusion, we estimated another 80 patients would not have the required severity of neurological deficit for inclusion or other medical problems preventing inclusion (resulting in 155 available patients per year). Furthermore, we estimated that two third would give informed consent. Hence, we would be able to include 100 patients a year. So, in our centre 2 years would be sufficient to include 200 patients. By inviting a second hospital to include similar numbers of patients, we supposed the necessary 400 patients could be included in 2 years, leading to a trial duration of 3 years, which seemed feasible.

      3. Results

      In the period from August 2005 until December 2006 we included 16 patients from the department of Neurology at the University Hospital Maastricht. No patients were included in the second centre. Therefore, we decided to end the trial prematurely.
      In this period about 500 patients were admitted to our hospital with a stroke. Most patients, however, were not eligible for inclusion. Table 1 gives an overview of the reasons to exclude patients. It illustrates the most crucial problem that we encountered in our trial. The ‘label’ of stroke combines a heterogeneous group of patients with a stroke and many complicating factors. Due to these factors, in addition to exclusion based on stroke type and stroke severity, many patients were ineligible for this prophylactic trial.
      Table 1Reasons for not including stroke patients in the trial.
      ReasonsPercentage (%)
      Non-cortical stroke (brainstem, cerebellar, lacunar)25
      Former history of stroke13
      Deep intracerebral haematoma, cerebellar hematoma, (suspicion of) bleeding in a braintumor, or subdural haematoma13
      Minor neurological deficit (isolated symptoms like hemianopia, central facial palsy)13
      Somnolence (e.g. due to severe stroke or pneumonia) with inability to swallow, or pending death11
      A history of epileptic seizure(s) and/or AED use or acute symptomatic seizures requiring treatment8
      Uncertainty about etiology of neurological deficit (e.g. confusion as presenting symptom, hypodensity on CT scan suspect for lowgrade malignancy, or suspicion of a seizure causing neurological deficit)6
      Admission for minor stroke and progression of neurological deficit several days after admission, or occurrence of symptoms several days before presentation in our hospital preventing inclusion within 7 days following stroke5
      Decreased renal function3
      Severe co-morbidity with a short life-expectancy2
      No informed consent possible (due to, e.g. aphasia or mental retardation, and no family members available to give consent)<1
      Missed due to admission to other ward<1
      History of other brain disease (e.g. pituitary tumor)<1
      Only 31 of the 500 patients were eligible for our trial. Of these, 15 refused, and 16 gave informed consent. Of the 16 included patients, nine patients were randomised to LEV, seven to placebo.
      Reasons for the high refusal rate were fear of side-effects, disapproval of the experimental character of the trial, which meant a 50% chance of treatment with placebo (‘taking pills for nothing’) or relatives thinking that the trial would give too large a burden to the already ill patient. Patients were at a vulnerable phase in their lives, they just suffered a major life event. They did not want to be bothered with scientific investigations.
      Table 2 shows results of the mRS, NIHSS, BI, and VAS score of the EuroQol per group and overall.
      Table 2Patient characteristics by group (LEV vs. placebo) and overall: number of patients; mean values and standard deviation between brackets of age, gender, stroke type, modified Rankin score, NIH stroke scale, Barthel index and quality of life questionnaire VAS score.
      LevetiracetamPlaceboTotal
      Number of patients9716
      Age in years (SD)66.0 (14.1)69.6 (9.9)67.6 (12.2)
      Gender (male/female)3 M/6 F5 M/2 F8 M/8 F
      Ischemic/hemorrhagic stroke7 I/2 H7 I/0 H14 I/2 H
      mRS on inclusion (SD)3.8 (0.4)4.3 (0.5)4.0 (0.5)
      mRS at 1 year (SD)2.9 (1.5)3.6 (0.5)3.2 (1.2)
      NIHSS on inclusion (SD)10.0 (3.6)14.6 (3.7)12.0 (4.2)
      NIHSS at 1 year (SD)5.3 (4.1)10.8 (4.7)7.6 (5.1)
      BI at week 6 (SD)13.9 (5.9)6.8 (8.0)11.2 (7.4)
      BI at week 16 (SD)14.6 (6.4)9.5 (8.1)12.9 (7.1)
      BI at 1 year (SD)13.1 (7.2)7.0 (7.8)10.8 (7.7)
      EuroQol-VAS at week 6 (SD)6.8 (1.5)4.8 (2.4)6.0 (2.0)
      EuroQol-VAS at week 16 (SD)6.5 (1.3)5.5 (3.1)6.1 (2.1)
      EuroQol-VAS at 1 year (SD)7.0 (1.8)4.8 (2.8)6.1 (2.5)
      M = male, F = female, I = ischemic stroke, H = intracranial haemorrhage, mRS = modified Rankin score, NIHSS = NIH stroke severity score, BI = Barthel index, EuroQol-VAS = VAS score on the Euro-QOL.

      3.1 Primary endpoint

      In four patients (4, 9, 12, 16) possible epileptic seizures were reported. One episode was reported the day after the event; the other episodes were only reported at the next follow-up visit.
      In two patients a diagnosis of late epileptic seizures was considered by the treating physician: in patient 9, who was randomised to placebo and in patient 16, who was randomised to LEV. After revision of the chart of patient 9 by one of our experienced neurologists (MdK), the diagnosis poststroke epilepsy was confirmed. This patient received carbamazepine (CBZ) to treat his poststroke seizures and because seizures recurred, LEV was added.
      Patient 16 had absence-like episodes and collapses. She was treated with CBZ because her treating physician considered these episodes to be poststroke epilepsy. After several weeks of CBZ treatment, she had a pacemaker implanted because of a sick sinus syndrome. The collapses then disappeared. After revision of her medical chart the diagnosis of poststroke epilepsy was considered very unlikely by our experienced neurologist (MdK).
      In patients 4 and 12, both randomised to LEV, the episodes were diagnosed as vasovagal collapse and both a vasovagal collapse and a recurrent stroke, respectively.

      3.2 Co-medication with anticonvulsive effects

      Five patients were treated with co-medication which may have influenced the occurrence of epileptic seizures. During follow-up, two patients (9, 16) received AEDs because they were diagnosed as having poststroke seizures (correctly in patient 9, undeserved in patient 16). Two patients (3, 11) received AEDs to treat neuropathic pain due to a thalamic syndrome. Patient 3 was treated with carbamazepine and patient 11 with pregabalin. Two patients (5, 9) used benzodiazepines as sleep medication. Without this co-medication, we would possibly have recorded more epileptic seizures during follow-up.

      3.3 Side effects

      To evaluate the impact of side-effects during the treatment with LEV, the SIDAED questionnaire was recorded. At the first follow-up after inclusion, which is one week after start of the trial medication, 12 patients completed the SIDAED list. Data from four patients are missing: patient 13 died 6 days after inclusion, patient 12 had severe aphasia preventing adequate answers to the questions, patient 7 had behavioural problems (agitation and anxiety) and could not cooperate, and in patient 16 the list was forgotten at this follow-up point. At 6 weeks follow-up 4 patients did not fill out the questionnaire: three died (4, 13, 14), and patient 12 still had severe aphasia. Therefore, the questionnaire was not recorded in 30% of the patients at both weeks 1 and 6. Patient 11 stopped taking the trial medication one week after initiation of the trial and therefore her side-effect list at week 6 can neither be used as a follow-up parameter in the LEV group, nor in the placebo group because she stopped taking her trial medication.
      Fig. 2 shows the percentage of problems per category, which were reported at week 1 and week 6. The number of problems at week 1 is higher in the LEV group than in the placebo group. However, some of these problems were reported to exist several months or longer than 6 months. Therefore, these problems cannot be caused by either stroke or side-effects of the trial medication but must reflect longer existing premorbid problems.
      At week 6 no clear differences in complaints existed between the LEV and placebo group. Because data were not available for all patients at both follow-up points, comparison of the overall results at week 1 and 6 is not possible.

      3.4 Adjustment of trial medication dose or discontinuation of trial medication

      Patients 3, 15 and 16 received a lower dose of the trial medication due to renal dysfunction.
      In patient 3 the trial medication was discontinued by his treating nursing home doctor without further consultation with the trial team and without tapering off the trial medication when the patient was transferred to a nursing home 48 days after inclusion in our trial. After unblinding the trial medication proved to be placebo.
      In patient 9 the family requested lowering of the dose because of fear of side-effects (dizziness, cognitive complaints). He appeared to be treated with placebo.
      The family of patient number 11 demanded discontinuation of the trial medication one week after start of the trial medication, because of the occurrence of visual hallucinations. As hallucinations have been reported as a side effect of LEV we tapered off the trial medication and discontinued it 20 days after start of the trial. She had been treated with LEV.

      3.5 Lost to follow-up or died during follow-up

      Three patients died during follow-up (4, 13, 14), two of them received placebo, one received LEV. Patient 4 died in a nursing home. The coroner concluded this was caused by a second intracranial haemorrhage (autopsy was not performed). Patient 13 died 5 days after start of trial medication due to massive lung embolism (confirmed on autopsy). Patient 14 died at home. Paramedics concluded that a cardiac arrest was the cause of death (no autopsy).
      In patient 16 follow-up at 1 year after inclusion was by telephone with a nurse. No visit was allowed due to a bad neurological state.

      4. Discussion

      The need for clinical studies to investigate the benefits of prophylactic treatment to prevent poststroke epilepsy is clear.
      • Kwan J.
      • Wood E.
      Antiepileptic drugs for the primary and secondary prevention of seizures after stroke.
      However, inherent to such a trial is a plethora of difficulties that has also been discussed by Herman.
      • Herman S.T.
      Clinical trials for prevention of epileptogenesis.
      In this paper we discuss the problems we met and which resulted in a premature ending of our trial.
      Only 16 patients (nine treated with LEV, seven with placebo) were included in the trial. One patient in the placebo group developed poststroke epilepsy. The number of included patients is far too low to determine the possible anti-epileptogenic effect of LEV in stroke patients. This paper intends to disclose the problems encountered in order to prevent future prophylactic trial failures.
      The problems and complicating factors can be summarised as follows:
      • 1.
        As shown in the results section selecting sufficient patients eligible for inclusion was difficult. Calculations based on our stroke registry did not give an adequate estimate of the number of patients suitable for inclusion. The majority of the patients either met exclusion criteria or had such co-morbidity that inclusion is impossible for practical reasons. With the present in- and exclusion criteria, each centre will only have a limited number of eligible patients. This means that a large multicentre and probably multinational trial is required to include sufficient patients in an anti-epileptogenesis trial.
      • 2.
        The assessment of seizure like episodes in stroke patients was difficult. The occurrence of epileptic seizures may be missed by the patient itself, health personnel and family members.
        • Blum D.E.
        • Eskola J.
        • Bortz J.J.
        • Fisher R.S.
        Patient awareness of seizures.
        In this trial, most episodes that possibly reflect an epileptic seizure were not mentioned to the examiner immediately. Generally, they were mentioned at the next follow-up visit, either spontaneously or on request, which caused a recall-bias. Some episodes may never have been mentioned. Seizures in stoke patients, in particular complex partial seizures may be difficult to recognize.
        • Cloyd J.
        • Hauser W.
        • Towne A.
        • Ramsay R.
        • Mattson R.
        • Gilliam F.
        • et al.
        Epidemiological and medical aspects of epilepsy in the elderly.
        The differential diagnostic considerations included stroke recurrence, vasovagal collapse, limb shaking TIA, hypoglycaemia or other metabolic disturbances, cardiac arrhythmias with syncope, and hyperventilation.
        • Drury I.
        • Beydoun A.
        Seizure disorders of aging: differential diagnosis and patient management.
        • Pourmand R.
        Seizures and epilepsy in older patients: evaluation and management.
        Therefore, measurement of the primary endpoint, the occurrence of late epileptic seizures, was difficult.
      • 3.
        Furthermore, the use of benzodiazepines and AEDs as co-medication caused a problem in this trial because these drugs have potential anticonvulsive effects. Without this co-medication, we would possibly have recorded more epileptic seizures during follow-up. These drugs were mostly prescribed by other treating physicians (general physician, rehabilitation doctor, nursing home doctor). This is part of good clinical practice, and could not be avoided.
      • 4.
        A further difficulty in our trial was the evaluation of side-effects occurring during the administration of the trial medication. A reliable assessment of side-effects was considered important in order to balance the beneficial effects of preventing poststroke seizures, on the one hand, and the risk and severity of side-effects when using prophylactic medication, on the other hand.
        In this trial, symptoms which occurred during treatment with the trial medication may be related to the stroke, to co-medication which is started at the onset of stroke, to co-medication used prior to the stroke or to the trial medication. Furthermore, aphasia or inability to cooperate otherwise may limit the report of side effects of the trial medication.
        At the first evaluation point at week 1, patients in the LEV group reported more possible side-effects than patients in the placebo group. However, part of these complaints were found to exist already before the trial medication was started and even before the stroke, and therefore could not be ascribed to treatment with the trial medication. At week 6 there were no differences in number of possible side effects. This could point to a disappearance of side-effects of the trial medication or co-medication due to habituation, but also to a neurological recovery from stroke. A third explanation is that complaints which existed before the stroke may disappear to the background due to new complaints as a consequence of stroke and new medication. Evaluation of side-effects in patients with a recent stroke is also difficult because many complaints caused by a stroke are the same as complaints caused by side-effects of AEDs.
      • 5.
        Continuation of trial medication after discharge from the neurological ward is an additional problem. Most stroke patients were admitted to the neurological ward for a limited period of time. After several days or, in some patients, weeks, patients were transferred to a nursing home or rehabilitation centre. Informing other health care workers (nurses, doctors) is crucial but also very difficult. Despite our measures to inform other health care personnel, as described in the methods section, continuation of trial medication after discharge appeared to be difficult. Also continuation of the trial medication when a patient was readmitted to our hospital for a non-neurological reason on another ward was difficult.
      • 6.
        The influence of thrombolytic drugs has to be considered. Hafeez et al.
        • Hafeez F.
        • Razzaq M.A.
        • Levine R.L.
        • Ramirez M.A.
        Reperfusion seizures: a manifestation of cerebral reperfusion injury after administration of recombinant tissue plasminogen activator for acute ischemic stroke.
        reported on a partial status epilepticus following administration of a thrombolytic drug. Rodan et al.
        • Rodan L.H.
        • Aviv R.I.
        • Sahlas D.J.
        • Murray B.J.
        • Gladstone J.P.
        • Gladstone D.J.
        Seizures during stroke thrombolysis heralding dramatic neurologic recovery.
        reported three patients with epileptic seizures following thrombolysis each with very good neurological recovery. A recent report suggests that thrombolysis may partly prevent the occurrence of late-onset seizures, probably by a better reperfusion of the ischemic brain regions.
        • De Reuck J.
        • Van Maele G.
        Acute ischemic stroke treatment and the occurrence of seizures.
        We believe that stroke patients treated with a thrombolytic drug should not be excluded in a trial aimed at preventing poststroke seizures.

      5. Conclusions

      The problems arising in a prophylactic trial aimed at preventing poststroke seizures concern difficulties in assessing the primary endpoint, which is the occurrence of a first late epileptic seizure, a very slow inclusion rate due to few eligible patients, the use of co-medication with anticonvulsive properties, difficulties to maintain patients on their treatment regimen during the trial, and difficulties in evaluating possible side effects of the trial medication.
      In our opinion a prophylactic trial assessing the anti-epileptogenic efficacy of a short AED treatment period to prevent poststroke epilepsy is not feasible.

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