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Levetiracetam: safety and efficacy in neonatal seizures

e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 0 ) 1 e7 Official Journal of the European Paediatric Neurology Society Levetiracetam: Safety and efficacy in neonatal seizures Georgia Ramantani a,b,*, Chrysanthy Ikonomidou a,c, Beate Walter a, Dietz Rating d,Juergen Dinger e a Department of Pediatric Neurology, University Children’s Hospital Dresden, Fetscherstrasse 74, 01307 Dresden, Germanyb Epilepsy Center, University of Freiburg, Breisacher Strasse 64, 79106 Freiburg, Germanyc University of Wisconcin, Department of Neurology, H6/574 CSC Box 5132, 600 Highland Avenue, Madison, WI 53792, USAd Department of Pediatric Neurology, University Children’s Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germanye Department of Neonatology and Pediatric Intensive Care, University Children’s Hospital Dresden, Fetscherstrasse 74,01307 Dresden, Germany Purpose: Neonatal seizures are common, especially in prematurity. Phenobarbital (PB) currently represents the antiepileptic drug (AED) of choice, despite being related to increased neuronal apoptosis in animal models and cognitive impairment in human subjects. Levetiracetam (LEV) may have a more favorable profile since it does not cause neuronal apoptosis in infant rodents.
Methods: In a prospective feasibility study, LEV was applied as first-line treatment in 38 newborns with EEG-confirmed seizures, after ruling out hypoglycemia, hypocalcaemia, hypomagnesaemia and pyridoxin dependency. Initial intravenous doses of 10 mg/kg LEV were gradually increased to 30 mg/kg over 3 days with a further titration to 45e60 mg/kg at the end of the week. Acute intervention with up to 2 intravenous doses of PB 20 mg/kg was tolerated during LEV titration. LEV was switched to oral as soon as the infants’ condition allowed. Based on clinical observation, EEG tracings (aEEG/routine EEGs), and lab data, drugsafety and anticonvulsant efficacy were assessed over 12 months.
Results: In 19 newborns a single PB dose of 20 mg/kg was administered, while 3 newbornsreceived 2 PB doses. 30 infants were seizure free under LEV at the end of the first week and27 remained seizure free at four weeks, while EEGs markedly improved in 24 patients at 4weeks. In 19 cases, LEV was discontinued after 2e4 weeks, while 7 infants received LEV upto 3 months. No severe adverse effects were observed.
Conclusions: These results illustrate the safety of LEV treatment in neonatal seizures,including prematurity and suggest LEV anticonvulsant efficacy. Additional PB treatmentadmittedly constitutes a methodological shortcoming due to the prolonged anticonvulsiveefficacy of PB. Double blind prospective controlled studies and long-term evaluation ofcognitive outcome are called for.
ª 2010 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights * Corresponding author. Epilepsy Center, University of Freiburg, Breisacher Str. 64, 79106 Freiburg im Breisgau, Germany. Tel.: þ49 720 E-mail address: (G. Ramantani).
1090-3798/$ e see front matter ª 2010 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.ejpn.2010.10.003 Please cite this article in press as: Ramantani G, et al., Levetiracetam: Safety and efficacy in neonatal seizures, European Journalof Paediatric Neurology (2010), doi:10.1016/j.ejpn.2010.10.003 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 0 ) 1 e7 2004e200623encouraged us to further develop this protocol and initiate a prospective feasibility study in our institution.
This study analyses the results regarding anticonvulsant Neonatal seizures are the most frequent clinical manifesta- efficacy and treatment safety obtained using LEV in neonates tion of central nervous system dysfunction in the newborn, with electroclinical and electrographic-only seizures. Our with an incidence of 1.5e3.5/1000 in term newborns and objectives were to evaluate 1) control of seizures, both clini- 10-130/1000 in preterm newborns.1 Seizures in the newborn cally and electroencephalographically and 2) adverse effects frequently signal significant brain pathology, such as hypoxic- associated with the intravenous or oral administration of LEV.
ischemic injury, stroke, intracranial infection, hypoglycemia,inborn errors of metabolism, or brain malformations. Etiologysignificantly influences outcome. Newborn seizures correlate with higher mortality as well as motor or cognitive disabilityin survivors.2,3 Furthermore, an association could be estab- In 2006, following availability of intravenous LEV, consecu- lished between the amount of EEG seizure activity and tively admitted newborns with EEG-confirmed seizures, subsequent mortality and morbidity in infants.4 In this light, including premature and extremely premature infants treated effective therapeutic interventions addressing both clinical at the Department of Neonatology and Pediatric Intensive seizures and EEG seizure activity might significantly improve Care of the University Hospital Carl Gustav Carus Dresden, neurocognitive development as well as reduce morbidity and Germany, were considered for this study. Infants presenting with clinical seizures that were confirmed as such through There are currently no evidence-based guidelines for a clear correlation with pathologic EEG findings were subse- evaluation and management of neonatal seizures. Available quently treated with levetiracetam as a first-line AED.
data indicate that phenobarbital (PB) remains the first-line Parents of newborns enrolled gave written informed treatment for neonatal seizures.5 Yet, a recent Cochrane consent for the study. In 15 cases, parents refused participa- Review concluded that “there is little evidence to support the tion or enrollment was impracticable because of time limita- use of any of the anticonvulsants currently used in the tions. In further 2 cases an underlying disease of complex neonatal period”.6 Conventional treatment (phenobarbital genetic/metabolic origin was presumed that led to exclusion.
and phenytoin) only achieves clinical control in 50%e80% of These newborns were lost to the study and consequently cases and is even less effective in controlling most neonatal electroencephalographic seizures.7 On the other hand, there is Neonatal seizures were defined according to Volpe’s clas- increasing concern over the long time adverse effects of sification as subtle, focal clonic, multifocal clonic, focal tonic, phenobarbital, since it was shown to increase neuronal generalized tonic and myoclonic. Infants that presented with apoptosis in animal models8 and induce cognitive impairment subtle seizures, especially in the form of apneas, posed a major diagnostic challenge in prematurity. However, most of Levetiracetam (LEV) is an effective and well-tolerated these patients showed multiple seizure types that altogether antiepileptic drug currently licensed as adjunctive therapy in clinically confirmed the classification of events as epileptic.
the treatment of partial onset seizures with and without The EEG recordings were performed bedside in the secondary generalization in adults, children and infants with neonatal/intensive care unit; 10 or 21 cerebral electrodes, epilepsy starting from 1 month of age (in oral application) and depending on the infant’s head size (21 being applicable only already licensed in children aged !4 years at study initia- to full-term eutrophic newborns), were applied according to tion.10 Retrospective series in children including patients the 10e20 International System, and EKG, EOG, chin EMG younger than 4 years showed comparable responder rates and activity, abdominal respiration were the other parameters side-effect profiles of add-on LEV treatment.11,12 Prospective most frequently monitored. Tests were continued until studies with small patient groups in infants and very young a complete cycle of awake, quiet and active sleep states were children reported similar results.13,14 There are hardly any recorded. EEG was monitored online and whenever state reports of severe, life threatening side effects, while most changes were not clearly distinguishable, recording was per- frequently observed adverse effects included somnolence and formed for at least 60 min. The EEG recording was routinely behavioral problems.15 Furthermore, LEV presents a favorable performed within 1e2 h from the clinical episode and reported profile regarding neuronal apoptosis: in contrast to most other by an experienced neonatologist/pediatric neurologist. EEGs established antiepileptic drugs it was not found to increase were scored with an emphasis on age-dependent background apoptosis in the developing rodent brain16 or interfere with activity24: 1. Normal/Mild abnormalities: normal pattern for neuroprotective up-regulation of hypoxia inducible tran- gestational age, including slightly abnormal activity, e.g. mild scription factor 1 (HIF-1a)17 and it was shown to decrease asymmetry, mild voltage depression; moderate abnormalities: neurodegeneration in rodent models of hypoxia/ischemia18 or discontinuous activity with interburst interval too long for GA, clear asymmetry or asynchrony, absence of age-appropriate To date, ten patients with neonatal seizures who were EEG features; 2. Major abnormalities: severe discontinuity in successfully treated with LEV in the neonatal period have EEG for gestational age, burst suppression pattern, no appro- been reported in detail,21e23 while one of these patients priate wakeesleep cycle for gestational age, multifocal sharp received LEV intravenously.21 The preliminary data on waves; 3. Severe abnormalities: severe discontinuity in EEG safety and anticonvulsive efficacy in the pilot study carried for gestational age, burst suppression pattern, no appropriate through at the University Hospital of Heidelberg in the years wakeesleep cycle for gestational age, multifocal sharp waves.
Please cite this article in press as: Ramantani G, et al., Levetiracetam: Safety and efficacy in neonatal seizures, European Journalof Paediatric Neurology (2010), doi:10.1016/j.ejpn.2010.10.003 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 0 ) 1 e7 The neurophysiology technologist performing the recording visits. Additional examinations were performed during rapid noted all behavioral changes or specific clinical correlates.
LEV titration in the first week and later, in the case of seizure In 19 cases, an ictal pattern could be confirmed in the recurrence. Based on the experience gained in older children, conventional EEG recording, while in another 9 cases, aEEG LEV serum levels were not used to decide LEV dosage over 24e48 h presented typical seizure patterns. All other newborns enrolled had overtly pathologic interictal findings Infants with occasional seizures which presented beyond in conventional EEG pointing to a low seizure threshold. EEG the neonatal period (44 completed weeks post-conceptional recordings were not strictly classified according to the age), persisted beyond the third month corrected age and amount of epileptiform activity i.e. according to the relative correlated with the presence of epileptic spikes/sharps waves density of spikes in a set period, due to the nature of in routine EEG were considered to have developed post- newborn EEG; physiological background varies from burst neonatal epilepsy. Also infants for whom it was not indicated suppression patterns to temporal spiking, according to to taper the antiepileptic therapy because of recurrent gestational age. In this light, we chose to classify EEG data seizures were considered to suffer from post-neonatal based on the deviation from the gestational-age appropriate epilepsy. On the other hand, the classification of patients as norm. On the other hand, aEEG recordings were not included seizure free was based on clinical observation (lack of suspi- in this classification, since they were not applied routinely to cious clinical events) and conventional EEG recordings. In case every patient but rather used as a low-resolution longitudinal of doubt a long-term conventional EEG recording or aEEG observation in order to clarify the nature of an event or series registration were further implemented. A formal statistical evaluation was not performed due to the small number of In EEG-confirmed newborn seizures, metabolic derange- ments (hypoglycemia, hypocalcaemia, hypomagnesaemia)were swiftly ruled out (glucose, electrolyte and blood gasscreening available directly at the ward) and Vitamin B6 (100 mg i.v. up to a cumulative dosage of 300 mg i.v.) wasadministered. In case of ongoing seizures, LEV was adminis- In the period between 2006 and 2008, following availability of tered as the first AED within the first 8 h from seizure mani- intravenous LEV, a total of 38 newborns with EEG-confirmed festation, in some cases even as an acute intervention during seizures, including 19 extremely premature infants at gesta- a prolonged clinical seizure/EEG ictal pattern.
tional age <28 þ 0 weeks, birth weight 410e1330 g, 6 prema- LEV initial dosage was 10 mg/kg intravenously adminis- ture infants with gestational age >28 to 36 þ 6 weeks, birth tered twice daily increasing by 10 mg/kg over 3 days up to weight 1250e1890 g, and 13 term newborns were evaluated in 30 mg/kg, while a further increase up to 45e60 mg/kg was this study. Clinical data of all infants included in the study are performed at the end of the first week of treatment in case of summarized in Table 1, while response to treatment is pre- persistent seizures or grave EEG pathology suggesting a low seizure threshold. Two single intravenous doses of PB 20 mg/kg Seven newborns were affected by status epilepticus, with were tolerated during LEV titration to treat seizures that were a frequency equally distributed between groups of different prolonged or recurrent (duration of over 5 min or over 2 gestational age. All other newborns presented repetitive episodes in 15 min) and called for acute intervention. This seizures, while isolated seizures prompted close surveillance, additional PB administration admittedly constitutes a meth- but no pharmacotherapy. In 11 out of 19 cases where seizure odological shortcoming due to the prolonged anticonvulsive patterns were recognized in EEG newborns were treated with levetiracetam in the context of an acute intervention.
LEV was switched to oral solution as soon as the infants’ 11 newborns required an additional application of PB 20 mg condition allowed. In most cases, this coincided with the i.v. as an acute measure in the first 8 h after the diagnosis of initiation of oral feeding after an initial period of full paren- newborn seizures and after initiation of LEV treatment, due to seizure recurrence during LEV titration. In further 8 patients Neuropediatric follow-up included daily visits in the first a single dosage of PB 20 mg i.v. was applied in the second day week, weekly visits up to one month after treatment initia- after treatment initiation, while only 3 newborns received tion, and follow-up visits at 3, 6 and 12 months. Patients were the maximal allowed PB dosage of 40 mg additional to LEV clinically examined, and seizure frequency, antiepileptic (Table 2). No other AEDs e.g. benzodiazepines were adminis- medication, and adverse events were documented at every tered concurrently. Out of the 5 term infants with hypoxic- visit. Conventional EEG was performed a week after treatment ischemic insult, three additionally underwent therapeutic initiation, at the end of the first month, at 3, 6 and 12 months.
After the first four weeks, decisions regarding further treat- 30 infants were seizure free under LEV at the end of the ment were considered on an individual basis, especially week, and 27 remained seizure free at four weeks, while EEGs regarding the duration of LEV treatment. Cerebral ultrasound markedly improved in 25 patients at four weeks. Three infants was performed in all infants in the first 48 h, followed by at presented with seizure recurrence after the first week, in one least two further ultrasound screenings in the first two weeks case this led to a change in AED and initiation of a conven- of life and weekly controls up to 40 weeks post-conceptional tional PB therapy (Table 2). There was no significant difference age. Laboratory tests including complete blood count, hepatic between infants that received adjunctive PB and those that and renal function parameters and LEV serum levels were were treated with LEV alone in regards to clinical character- performed weekly during the first four weeks and at all further istics or response to treatment, although a formal statistic is Please cite this article in press as: Ramantani G, et al., Levetiracetam: Safety and efficacy in neonatal seizures, European Journalof Paediatric Neurology (2010), doi:10.1016/j.ejpn.2010.10.003 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 0 ) 1 e7 Table 1 e Clinical characteristics of patients treated with levetiracetam.
a Normal: normal muscle tone, active muscle movements, normal alertness for age; Mildly abnormal: hypertonia, hyperexcitability; Moder-ately abnormal: hypotonia/hypertonia, decreased muscle movements, lethargy; Severely abnormal: flaccid, inactive and coma.
b EEG-scoring according to Holmes and Lombroso.
c Normal: no pathology; Moderately abnormal: IVH I/II, mild ventriculomegaly, periventricular echodensities; Severely abnormal: IVH III/IV,cystic PVL, malformation.
impracticable due to the size of the study population. The switching from intravenous to oral. There was no significant limited number of newborns included further prohibits any variation in LEV plasma levels between newborns that definite conclusions as to the response to LEV in newborn received 1e2 additional doses of PB compared to those where seizures of different etiology. However, there was a trend for this intervention was not necessary.
poor response among patients with extensive intracerebral Follow-up data is available on patients that remained seizure-free under LEV at 4 weeks after treatment initiation .
In 19/30 cases, LEV was discontinued after 2e4 weeks At 6 months 4/14 premature infants developed post-neonatal seizure freedom. In view of multiple comorbidities especially epilepsy, 7/14 presented developmental delay and 5/14 associated with extreme prematurity, LEV was continued in 7 multiple comorbidities. In the newborn group, 2/12 developed cases up to 3 months after treatment initiation. Drowsiness was epilepsy and 5/12 were diagnosed with developmental delay, the only adverse effect observed in infants during the titration while 1/12 had comorbidities. At 12 months 3/14 extremely period, often concomitant with adjunctive PB therapy.
premature infants had post-neonatal epilepsy and 5/14 pre- LEV plasma levels were in the range of 12,5e55 mg/ml sented with developmental delay compared to 2/12 with post- (reference values 5e65,0 mg/ml) under intravenous adminis- neonatal epilepsy and 3/12 with developmental delay in the tration and remained in the same therapeutic range when Please cite this article in press as: Ramantani G, et al., Levetiracetam: Safety and efficacy in neonatal seizures, European Journalof Paediatric Neurology (2010), doi:10.1016/j.ejpn.2010.10.003 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 0 ) 1 e7 Table 2 e Anticonvulsant efficacy of levetiracetam.
Number of patients initially included in the study PB administration in the first 2 d of titration PB administration > 3 d ¼ excluded from further study Single seizure recurrence, no change in treatment Infants with post-neonatal epilepsy commonly presented studies suggest that neonatal seizures affect the developing symptomatic localization-related epilepsy with focal motor brain with long-term adverse effects on cognition, learning, seizures and secondary generalization regardless of gesta- and seizure threshold,26,27 and when a suspicious event is tional age. None of them presented electro-clinical patterns confirmed electrographically, treatment seems warranted.
consistent with West syndrome. However, there was a strong Repeated seizures may be deleterious to the brain even correlation of post-neonatal epilepsy with developmental without disturbances of ventilation or perfusion by increasing delay ranging from mild retardation to cerebral palsy.
central nervous system metabolic demand and causing therelease of excitatory amino acids such as glutamate.28 The most common anticonvulsant used initially in the newborn period for seizure treatment is intravenous PB29although there are many concerns regarding the short-term The causes of neonatal seizures vary as do the duration and adverse effects of PB as well as long-term effect on neuro- frequency, and the distinction between an epileptic and non- cognitive development. Intravenous phenytoin and benzodi- epileptic event in neonates is often difficult to demonstrate.25 azepines are commonly employed as second-line intravenous On the other hand, current data from animal and human medications in the treatment of neonatal seizures.30 Theadverse effects of phenytoin are well known and includecardiac arrhythmias and hypotension. Fosphenytoin may be Table 3 e Outcome at 6 and 12 months after treatment a safer alternative but is less well studied and is not available in every country. Benzodiazepines have been successfully used to stop status epilepticus, but the long-term use of these medi- cations is not recommended. Midazolam,31 carbamazepine, primidone, lidocaine, and valproate6,32 are other medicationsthat have been used with limited data on success and safety.29 The potentially neurotoxic effects of antiepileptic drugs have been known for decades. Intrauterine exposure to phenobarbital and phenytoin is a risk factor for birth defects, microcephaly, mental retardation, and learning deficits or lower IQ scores that persist to adulthood.33e36 Furthermore, infants and toddlers randomized to prophylactic phenobarbital therapy for febrile seizures had lower IQ scores that outlasted the duration of treatment.37,38 A more recent study showed thatclinically relevant levels of antiepileptic drugs including Infants in which occasional seizures continued after the neonatal phenobarbital, phenytoin, and diazepam led to apoptotic period, considered up to 44 completed weeks’ post-conceptionalage for preterm infants born <37 weeks of GA, and persisted neurodegeneration in the developing rat brain.8 The impact of beyond the third month of corrected age with the presence of therapeutic doses of these agents on neurodevelopmental epileptic spikes/sharps waves in their routine EEG or infants for outcome in newborns with seizures is not known.
whom it was impracticable to taper the antiepileptic therapy LEV, a novel anticonvulsant drug with a nonconventional because of recurrent seizures were considered as suffering from mechanism of action, is well studied as an adjunctive therapy for partial epilepsy. Given the safety profile of this medication Please cite this article in press as: Ramantani G, et al., Levetiracetam: Safety and efficacy in neonatal seizures, European Journalof Paediatric Neurology (2010), doi:10.1016/j.ejpn.2010.10.003 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 0 ) 1 e7 as well as its linear pharmacokinetics (half-life of 7 h),39 rapid (“electroclinical dissociation”) are a common occurrence in absorption (30 min), nonhepatic elimination, lack of protein neonates with abnormal neurological findings.44,45 We did not binding (<10%), no known interactions with other antiepileptic attempt a further increase of LEV dosage, in accordance with drugs, and favorable efficacy in children,12,40 it is empirically usual dosage of LEV in children and adults ranging from 30 to considered a viable alternative for seizure treatment in all 60 mg/kg/d. However, clearance of LEV is significantly higher in pediatric age groups, including infants and neonates.41 infants46 and doses over 100 mg/kg/d without side effects have Several pediatric studies have reported marked decrease in been reported in very young children.21,13 It is not clear, seizure frequency with the use of LEV, including a recent whether our patients may have had additional benefit from report of six patients that received LEV as a first-line AED, allowing 1e2 additional doses of PB during titration.23 LEV was discontinued at 2e4 weeks in 19 cases, but Furthermore, in a recent survey conducted at the 2007 continued for 9e12 weeks in 7 cases, due to multimorbidity.
Annual Meeting of the Child Neurology Society, seventy-three Although neonatal seizures are an important risk factor for percent (40/55) of pediatric neurologists present recom- childhood epilepsy, the timing of onset of post-neonatal mended treatment of neonatal seizures with one or both of seizures is variable and seizures may recur in spite of LEV and topiramate (TPM); 47% (26/55) recommended LEV; and prophylactic antiepileptic drug therapy, making the value of 55% (30/55) recommended TPM.42 Factors driving LEV use in ongoing therapy uncertain.47,3 Most experts recommend early the intensive care nursery may include a low side-effect cessation of antiepileptic drug therapy due to the high side- profile and its ease of use with either parenteral or liquid effect profile of old AEDs coupled with the fact that neonatal seizures typically abate within days independent of the ther- In our study, we observed the anticonvulsant efficacy and apeutic intervention and have a low risk of early recurrence.48 safety of LEV as a first-line AED in neonatal seizures, after In follow-up, favorable response to treatment with cessa- excluding standard metabolic causes. 30/38 (79%) infants were tion of seizures and EEG normalization was associated with seizure free under LEV at the end of the first week, and 27/30 a favorable neurodevelopmental outcome, as reported in term (90%) remained seizure free at four weeks, while EEGs were neonates.4 At 12 months 3/14 extremely premature infants markedly improved in 25/30 (83%) patients at four weeks.
developed post-neonatal epilepsy and 5/14 presented with Three infants presented with seizure recurrence after the first developmental delay compared to 2/12 with post-neonatal week; in one case this led to a change in AED. LEV was toler- epilepsy and 3/12 with developmental delay in the newborn ated extremely well in our study group, with somnolence group. In our patient group, we observed an association of during titration (at least partially) attributed to adjunctive PB outcome with etiology, as suggested by previous studies,49 therapy. Plasma levels of LEV were in the therapeutic range in although the limited number of patients treated did not all occasions, including when changing administration from intravenous to oral. This observation underlines the safety of The encouraging results obtained in this population illus- LEV administration in an ICU setting and suggests a high trate the safety of LEV treatment in neonatal seizures, including prematurity, and suggest LEV anticonvulsant effi- Our study has various limitations: 1. it was a non- cacy. Double blind prospective controlled studies and long- randomized study with a relatively small sample size and no term evaluation of cognitive outcome is called for, in order to control group; 2. adjunctive PB therapy in some patients was establish a reasonable alternative to PB.
tolerated during LEV titration, thus constituting a methodo-logical shortcoming due to the prolonged anticonvulsive effi- cacy of PB; 3. simultaneous video-EEG monitoring was notperformed. Certain abnormal clinical behavior, even withoutEEG epileptiform manifestation, may represent subcortical 1. Volpe JJ. Neonatal seizures. In: Volpe, editor. Neurology of the seizures. Seizure control under LEV monotherapy cannot be newborn. 5th ed, vol. 2008. Philadelphia: W.B. Saunders; 2008.
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