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Use of Levetiracetam in Hospitalized Patients: LEV IN HOSPITALIZED PATIENTS

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Summary: Purpose: The objective of the study was to analyze the short-term efficacy and safety of levetiracetam (LEV) to treat repetitive seizures in hospitalized patients.Methods: During admission to a tertiary hospital, we retrospectively
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   Epilepsia,  47 (12):2186–2188, 2006Blackwell Publishing, Inc. C  2006 International League Against Epilepsy Use of Levetiracetam in Hospitalized Patients Merc`e Falip, Mar Carre˜no, Sergio Amaro, Antonio Donaire, Raquel Delgado, Manuel Toledo,and Iratxe Maestro  Department of Neurology, Hospital Cl´ ınic, Barcelona, Spain Summary:  Purpose:  The objective of the study was to analyzetheshort-termefficacyandsafetyoflevetiracetam(LEV)totreatrepetitive seizures in hospitalized patients.  Methods:  During admission to a tertiary hospital, we retro-spectively identified patients with repetitive seizures who weretreated for the first time with LEV during a hospital stay. LEVwas considered effective if seizure cessation or   > 75% seizurereductionoccurredinthe24hafterstartingLEV(comparedwiththeprevious48h),requiringnofurtherantiepilepticdrug(AED)treatment.  Results:  Thirty patients (12 men, 18 women) were included.Mean age was 59.7 years. Most frequent seizure type was focalmotor in 12 (40%) of 30 patients. Most frequent etiology wasstroke: nine (30%) of 30 patients. Relevant medical conditionsincluded atrial fibrillation (three) and hepatic disease (three).Concomitant medications included oral anticoagulants (seven),corticosteroids (two), and chemotherapy (two). Four patients re-ceived LEV as the only AED. Six patients with focal SE and20 (66.6%) patients with clusters of seizures but not in SE re-ceived LEV as add-on treatment after lack of response to first-line AEDs. Mean LEV dose during first day was 1,119 mg.Mean daily maintenance dose was 1,724 mg. LEV was effec-tive in 24 (80%) patients, all four patients who received it asthe only AED, four of six patients with focal SE, and 16 of 20patients with clusters of seizures. Three (10%) elderly patientswith seizures secondary to stroke and chronic obstructive pul-monary disease (COPD) reported moderate/severe somnolenceand dizziness, leading to treatment discontinuation in one. Ondischarge, 20 (66.7%) patients continued on LEV, nine (30%) asthe only AED. Conclusions:  LEV is effective and safe to treat repetitiveseizures in hospitalized patients, including patients in focal SE. Key Words:  Levetiracetam—Epilepsy—Hospitalized—Statusepilepticus—Interactions. Levetiracetam (LEV) is a broad-spectrum (Grunewald,2005),safe,andeffective(Shorvonetal.,2000)antiepilep-tic drug (AED) that seems potentially useful in statusepilepticus (SE) (Mazarati et al., 2004; Patel et al., 2006).LEV has no known pharmacologic interactions, as ithasnoeffectonmixed-functionoxidaseliverenzymesandhas no protein-binding properties (Patsalos, 2000). It canbe initiated at therapeutic doses and has shown efficacy inthefirstdayoftreatment(FrenchandArrigo,2005).Thesefeatures are especially important in hospitalized patientswhoneedAEDtreatment,asmanyhaveconcomitantmed-ical conditions and receive multiple medications.Theobjectiveofthestudywastoanalyzetheshort-termefficacyandsafetyofLEVwhenadministeredforthefirsttime to hospitalized patients with acute repetitive seizuresin a tertiary center. Accepted April 22, 2006.Address correspondence and reprint requests to Dr. M. Carre˜no atEpilepsy Unit, Department of Neurology, Hospital Cl´ınic, c/Villarroel,170, 08036 Barcelona, Spain. E-mail: mcarreno@clinic.ub.esdoi: 10.1111/j.1528-1167.2006.00850.x PATIENTS AND METHODS Patients with a reliable diagnosis of repetitive seizuresduring admission to the Hospital Clinic of Barcelona(Spain) from January 2004 to September 2005, who re-ceivedLEVforthefirsttimeduringthehospitalstay,wereincluded in the study. Efficacy was defined as completeseizure cessation (as documented in the patient’s chart)or  > 75% reduction in seizure frequency in the 24 h after starting LEV (compared with the previous 48 h), with noneed for further AED treatment during hospital stay. RESULTS Thirty patients (12 men, 18 women) were included inthe study. Mean age was 59.7 years (range, 17–89 years;SD, 20.3). Most frequent seizure type was focal motor seizures, in 12 (40%) of 30 patients. The epilepsy waslocalization related in all patients, and the most frequentetiology was stroke, in nine (30%) of 30 patients, fol-lowedbybraintumor(primaryormetastatic),insix(20%).Concomitant medical conditions included liver disease(three patients) and atrial fibrillation (three patients).  2186    LEV IN HOSPITALIZED PATIENTS 2187  Seven patients received oral anticoagulants, two, corti-costeroids, and two, chemotherapeutic agents.Six (20%) patients with focal SE and 20 (66.6%) pa-tients with clusters of seizures, but not in status, receivedLEV as add-on treatment after lack of response to first-line AEDs [phenytoin (PHT) and valproic acid (VPA)];four (13.3%) patients received LEV as the only AED,to avoid interactions with concomitant medications (an-ticoagulant drugs, three patients, and chemotherapy, onepatient). Mean LEV dose administered during the firstday was 1,119 mg (SD, 269.5). Depending on the age of thepatientandconcomitantdiseases,first, “ loading ” doseranged between 500 and 1,000 mg, being 1,000 mg inall patients with focal SE. The mean daily maintenancedose of LEV was 1,724 mg (SD, 600.3); patients with fo-cal SE received higher mean doses than did patients inthe monotherapy group (2,250 mg vs. 1,375 mg) or withclusters of seizures (2,250 mg vs. 1,631 mg).LEV was effective to control seizures during admis-sionin24(80%)patients.Infive(16.7%)patients,seizurefrequency was unchanged, and one (3.3%) patient expe-rienced worsening of seizures. Treatment with LEV waseffective in all four patients who received LEV monother-apy, in four of six patients with focal SE (Table 1), and in16 of 20 patients with clusters of seizures.LEVdidnotproducesignificantchangesinbiochemicalor hematologic parameters. Three (10%) elderly patientswith seizures secondary to stroke and chronic obstruc-tivepulmonarydisease(COPD)reportedmoderate/severesomnolence and dizziness. Somnolence was severe in onepatient, leading to treatment discontinuation.Two of the patients in this series died. One patient,with seizures secondary to ischemic stroke and COPD,who reported moderate somnolence after LEV, developedpneumonia and died several weeks later. Another patient,diagnosed with glioblastoma multiforme, died because of tumoral progression.At the moment of discharge, 20 (66.7%) patients con-tinued to take LEV, with LEV as the only AED in nine(30%). The other 11 (36.7%) continued to take LEV asadjunctive AED therapy, mainly combined with PHT or VPA. DISCUSSION LEV has become a widely used drug as add-on therapyin patients with different epileptic syndromes (Karceskiet al., 2005). LEV is mainly prescribed in outpatientepilepsyorneurologyclinics.However,itsfavorablephar-macokinetic profile, lack of known pharmacologic inter-actions, good tolerability, and possibility of fast titrationsuggest that it may be a very useful drug to use in hos-pitalized patients. This retrospective study confirms itsshort-term safety and effectiveness to control seizures inthese patients.       T      A      B      L      E      1  .     G   e   n   e   r   a    l   c    h   a   r   a   c    t   e   r    i   s    t    i   c   s   o    f    t    h   e   g   r   o   u   p   o    f   p   a    t    i   e   n    t   s   w    i    t    h    f   o   c   a    l    S    E   w    h   o   w   e   r   e    t   r   e   a    t   e    d   w    i    t    h    L    E    V   a   s   a    d    d  -   o   n    t    h   e   r   a   p   y     T   y   p   e    M   a    i   n    t   e   n   a   n   c   e    A   g   e   o    f    S    t   a   r    t    i   n   g    d   a    i    l   y    A    E    D   s   u   s   e    d    N   o .    G   e   n    d   e   r    (   y   r    )   s   e    i   z   u   r   e    d   o   s   e   o    f    L    E    V    d   o   s   e   o    f    L    E    V    b   e    f   o   r   e    L    E    V    E    f    f    i   c   a   c   y    E    t    i   o    l   o   g   y    A    d   v   e   r   s   e   e   v   e   n    t   s    E    E    G   p   r   e    L    E    V    E    E    G   p   o   s    t    L    E    V    1    M   a    l   e    7    7    F .   m   o    t   o   r    1 ,    0    0    0    2 ,    0    0    0    V    P    A    Y   e   s    H   e   m   o   r   r    h   a   g    i   c   s    t   r   o    k   e    S   o   m   n   o    l   e   n   c   e ,   e   x    i    t   u   s    F   o   c   a    l   s   z   s    R    F   r   o   n    t   a    l    G   e   n   e   r   a    l    i   z   e    d   s    l   o   w    i   n   g ,   n   o    E    E    G   s   z   s    2    F   e   m   a    l   e    5    9    A   r   m    t   o   n    i   c   s   z   s    1 ,    5    0    0    2 ,    0    0    0    P    H    T      +     P    B      +     T    P    M    Y   e   s    E   n   c   e   p    h   a    l    i    t    i   s    N   o    G   e   n   e   r   a    l    i   z   e    d   e    l   e   c    t   r   o    d   e   c   r   e   m   e   n    t   a    l   p   a    t    t   e   r   n    d   u   r    i   n   g   c    l    i   n    i   c   a    l   s   z   s    G   e   n   e   r   a    l    i   z   e    d   s    l   o   w    i   n   g ,   n   o    E    E    G   s   z   s    3    F   e   m   a    l   e    6    8    F .   m   o    t   o   r    1 ,    5    0    0    3 ,    0    0    0    P    H    T      +     V    P    A      +     B    Z    D    Y   e   s    H   e   m   o   r   r    h   a   g    i   c   s    t   r   o    k   e    S   o   m   n   o    l   e   n   c   e    F .   s   z   s ,    L    F   r   o   n    t   o    t   e   m   p   o   r   a    l    G   e   n   e   r   a    l    i   z   e    d   s    l   o   w    i   n   g ,    L    h   e   m    i   s   p    h   e   r   e    P    L    E    D    S ,   n   o    E    E    G   s   z   s    4    F   e   m   a    l   e    4    6    C   o   m   p    l   e   x   p   a   r    t    i   a    l    1 ,    0    0    0    3 ,    0    0    0    P    H    T      +     V    P    A      +     B    Z    D    N   o    (   n   e   e    d   e    d    i   v   p   r   o   p   o    f   o    l    )    C   r   y   p    t   o   g   e   n    i   c    N   o    L    t   e   m   p   o   r   a    l   s   z   s    L    t   e   m   p   o   r   a    l   s   z   s    5    F   e   m   a    l   e    2    1    V    i   s   u   a    l   a   u   r   a   s    (   a   m   a   u   r   o    t    i   c   s    t   a    t   u   s    )    2 ,    0    0    0    2 ,    0    0    0    P    H    T    Y   e   s    C   e   r   e    b   r   a    l   a    b   s   c   e   s   s    d   u   e    t   o   s   e   p    t    i   c   e   m    b   o    l    i   s   m    N   o    R   p   a   r    i   e    t   o   o   c   c    i   p    i    t   a    l   s   z   s    F   o   c   a    l   s    l   o   w    i   n   g ,    R   p   a   r    i   e    t   o   o   c   c    i   p    i    t   a    l    6    M   a    l   e    3    8    R    h   a   n    d    t   o   n    i   c   s   z  -   c   o   m   p    l   e   x   p   a   r    t    i   a    l    1 ,    0    0    0    2 ,    0    0    0    P    H    T      +     B    Z    D    N   o    V   a   s   c   u    l   a   r   m   a    l    f   o   r   m   a    t    i   o   n    N   o    L   p   a   r    i   e    t   o   o   c   c    i   p    i    t   a    l   s   z   s    L   p   a   r    i   e    t   o   o   c   c    i   p    i    t   a    l   s   z   s    F ,    f   o   c   a    l   ;    S   z   s ,   s   e    i   z   u   r   e   s   ;    L ,    l   e    f    t   ;    R ,   r    i   g    h    t .  Epilepsia, Vol. 47, No. 12, 2006    2188 M. FALIP ET AL. In monotherapy, it seems especially useful in those pa-tientswithacuterepetitiveseizuresandwhothereforeneeda drug with a rapid onset of action but have medical con-ditions or receive other medications likely to interact withclassic AEDs (Di Bonaventura et al., 2006), for example,in patients with seizures in the context of stroke, brain tu-mors (Wagner et al., 2003), hepatic disease, or immuno-suppression (all four patients in our series became seizurefree during the hospital stay).In patients with clusters of seizures or focal SE notresponding to a first or second AED, LEV can also be ef-fectively used in the hospital environment (Patel et al.,2006). The possibility of irreversible neuronal damageduring prolonged focal SE (Donaire et al., 2006) has tobeweighedagainstthepossiblecomplicationsofsedationrequiring orotracheal intubation and stay at the intensivecare unit, especially in critically ill and elderly patients.LEV seems a good option to try in these patients beforeproceedingtopropofolormidazolam.Inourseries,itcon-trolled ongoing seizures in four of six patients.LEV was well tolerated in our series, in spite of highinitialdoses(patientsoftenreceived1,000mgasthestart-ing dose). The most frequently observed adverse eventwas somnolence. However, both the underlying etiology(stroke) and concomitant medical diseases (COPD) couldhave contributed to the somnolence in these patients.Our study is limited by its retrospective and observational na-ture. Despite these limitations, we believe that the studyreflects accurately everyday clinical practice in a tertiaryhospital and can provide interesting information to neu-rologists and other physicians dealing with patients withrepetitive seizures in a hospital setting.Our study shows that LEV is an easy-to-use, effective,and well-tolerated treatment when used to treat repetitiveseizuresinhospitalizedpatients.Asadd-ontherapy,itmaybe useful to stop seizure activity in patients with focal SEnot responding to first-line intravenous AEDs. REFERENCES Di Bonaventura C, Mari F, Fattouch J, Egeo G, Vaudano AE, Man-fredi M, Prencipe M, Giallonardo AT. (2006) Use of levetiracetamin treating epilepsy associated with other medical conditions.  Acta Neurologica Scandinavica  113:82  –  86.Donaire A, Carre ˜ no M, Gomez B, Fossas P, Bargall ´ o N, Agudo R, FalipM,SetoainX,BogetT,RaspallT,ObachV,RumiaJ.(2006)Corticallaminarnecrosisrelatedtoprolongedfocalstatusepilepticus.  Journalof Neurology, Neurosurgery and Psychiatry  77:104  –  106.French J, Arrigo C. (2005) Rapid onset of action of levetiracetam inrefractory epilepsy patients.  Epilepsia  46:324  –  326.Grunewald R. (2005) Levetiracetam in the treatment of idiopathic gen-eralized epilepsies.  Epilepsia  46(suppl 9):154  –  160.Karceski S, Morrell MJ, Carpenter D. (2005) Treatment of epilepsy inadults: expert opinion, 2005.  Epilepsy and Behavior   7(suppl 1):S1  –  S64; quiz S6-S57.Mazarati AM, Baldwin R, Klitgaard H, Matagne A, Wasterlain CG.(2004) Anticonvulsant effects of levetiracetam and levetiracetam-diazepam combinations in experimental status epilepticus.  Epilepsy Research  58:167  –  174.Patel NC, Landan IR, Levin J, Szaflarski J, Wilner AN. (2006) Theuse of levetiracetam in refractory status epilepticus.  Seizure  15:137  –  141.Patsalos PN. (2000) Pharmacokinetic profile of levetiracetam: towardideal characteristics.  Pharmacological Therapeutics  85:77  –  85.Shorvon SD, Lowenthal A, Janz D, Bielen E, Loiseau PO. (2000)Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partialseizures: European Levetiracetam Study Group.  Epilepsia  41:1179  –  1186.Wagner GL, Wilms EB, Van Donselaar CA, Vecht C. (2003) Levetirac-etam:preliminaryexperienceinpatientswithprimarybraintumours. Seizure  2003;12:585  –  586.  Epilepsia, Vol. 47, No. 12, 2006 
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