Epilepsy Research (2015) 114, 13—22

jo ur nal ho me p ag e: www.elsev ier .com/ locate /ep i lepsyres

Intravenous levetiracetam treatment instatus epilepticus: A prospective study

Murat Mert Atmaca ∗, Elif Kocasoy Orhan,Nerses Bebek, Candan Gurses

Department of Neurology, Istanbul University, Istanbul Medical Faculty, Istanbul, Turkey

Received 27 November 2014; received in revised form 24 March 2015; accepted 8 April 2015Available online 17 April 2015

KEYWORDSStatus epilepticus;Intravenouslevetiracetam;Prospective;Efficacy;Systemic disease

SummaryObjective: To assess the efficacy of intravenous (IV) levetiracetam (LEV) in the treatment ofstatus epilepticus (SE) and treatment outcomes.Methods: This study was conducted on patients, who were classified according to the clinicalcharacteristics of their seizures, in the emergency department, neurology, and other servicesof our hospital. Patients were administrated IV LEV for the treatment of their SE after failingto respond to IV diazepam.Results: We prospectively investigated 30 patients, 16 females and 14 males whose ages rangedbetween 17 and 90 years (55.6 ± 19.6). Fourteen patients had convulsive SE (CSE), 11 had non-convulsive SE (NCSE), and 5 had epilepsia partialis continua (EPC). The patients were given IVLEV with dosages ranging between 1000 and 4000 mg/day. Twenty-nine of the patients continuedto receive LEV orally as maintenance treatment. The most common etiologies were cerebrovas-cular diseases (n = 7) and brain tumors (n = 6). SE was terminated in 23 (76.6%) patients. In the12 months that followed SE, 9 of our patients (30%) died and 4 patients could not be contacted.Fifteen patients reported having no adverse effects, whereas three had mild adverse effects.No major adverse effects or complications causing disability were observed in twelve patientswho were unconscious.Conclusion: Treatment with IV LEV is well-tolerated and effective both in focal and generalizedSE. IV LEV has the combined advantage of efficacy, safety, and ease of use, which qualifies

it to be the first choice after benzodiazepines (BZD) in the treatment of SE. This is the firstprospective study of IV LEV treatment in status epilepticus and has the longest follow-up period,one year.© 2015 Elsevier B.V. All rights reserved.

∗ Corresponding author. Tel.: +90 5332764868.E-mail address: drmuratmertatmaca@hotmail.com (M.M. Atmaca).

http://dx.doi.org/10.1016/j.eplepsyres.2015.04.0030920-1211/© 2015 Elsevier B.V. All rights reserved.

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ntroduction

tatus epilepticus is a neurologic disorder with a significantorbidity and mortality rate between 3% and 39% (Claassen

t al., 2002; Rossetti et al., 2006) and requires immediatereatment to prevent irreversible neuronal damage (Holmes,002; Tsuchida et al., 2007). Treatment invariably startsith BZD. How treatment should proceed when BZD proves

neffective remains controversial. A large number of studiesave documented the use of phenytoin (PHT) and phenobar-ital over the years. However, the standard treatment of SEith these drugs proves inefficient especially due to their

ystemic adverse effects and difficulty of use in patientsho are old and with complications. The new IV forms ofntiepileptic drugs such as valproic acid (VPA), LEV andacosamide have been on the market for some time now butre not licensed as drugs for SE (Shorvon et al., 2008).

The pharmacologic features of LEV including its low pro-ein binding and low interactions with other drugs makest a low-adverse effect drug with a high safety profile.ence, LEV has been widely used since 1999; its IV formas approved by the Food and Drug Administration in thenited States in 2006 (Crepeau and Treiman, 2010; Trinkand Dobesberger, 2009). In Turkey, the oral form of LEV haseen used since 2005 and its IV form was introduced in 2010.n addition to good reports about the efficacy of IV LEV on SEMisra et al., 2012), there are opposing results in the liter-ture. The lowest efficacy of LEV has been reported in onebservational (Eue et al., 2009) and one prospective (Ugest al., 2009) study, the results in which may be explained inelation to the elderly patient populations that were stud-ed. Our aim in this study was to prospectively analyze theutcomes of IV LEV treatment in SE.

ethods

e prospectively investigated 30 patients with SE who failedo respond to BZD and were treated with IV LEV fromugust 2010 through August 2013, at the Istanbul Facultyf Medicine, Istanbul University.

Patients with one of the following clinical presentationsere included in the study: A duration of ≥5 min CSE, a dura-

ion of ≥30 min of other forms of SE (simple and complexocal, nonconvulsive and myoclonic), or EPC (Thomas et al.,977). Although, there are various definitions of EPC, weetermined one hour as the minimum duration of a conditionith regular or irregular muscular twitches that affected

limited part of the body and recurred at intervals notbove 10 s (Thomas et al., 1977) as our chosen criterion.lthough no maximum intervals were included in the defini-ion (Cockerell et al., 1996; Obeso et al., 1985), there is auggestion for a shorter minimum duration (30 min) (Wiesernd Chauvel, 2008) in the literature.

We divided the patients into three groups: CSE, NCSE andPC. Electroencephalography (EEG) is used to diagnose NCSEKaplan, 2006). Patients whose seizures were not controlledy BZD were given IV LEV, administered in 0.9% saline. The

ose application time of a previous pharmacokinetic studyas not exceeded (1000 mg in 5 min) (Ramael et al., 2006).

For CSE and EPC, cessation of clinical seizures, and forCSE, cessation of seizure activity on EEG or, if EEG was not

gdct

M.M. Atmaca et al.

vailable, return to baseline neurologic state were accepteds good response to therapy.

Tolerability of IV LEV was clinically evaluated on the basisf adverse reactions.

All patients were evaluated according to new neurologiceficits, cessation of seizures, and drug efficacy. We used thetatus Epilepticus Severity Score (STESS), a prognostic scorehat evaluates patients’ four outcome predictors includingge, history of seizures, seizure type, and extent of con-ciousness impairment on a scale of 0—6 points (Rossettit al., 2008). In the 12th month following SE, all patientsho received IV LEV were contacted to inquire about theirutcomes (Table 1).

The Ethics Committee of Istanbul Faculty of Medicinepproved the study, and written informed consent wasbtained from all subjects prior to the study.

esults

he median age of the thirty patients who were enrollednto the study was 55.6 years (range, 17—90 years). Fourteenatients were male and 16 were female. In terms of their SEemiology, 36.6% (n = 11) of the patients were NCSE, 46.7%n = 14) were CSE, and 16.7% (n = 5) were EPC.

The patients were given IV LEV within the dosage rangef 1000—4000 mg/day. One patient was given 5000 mg IV LEVn 120 h and another 6000 mg in 48 h. A dose of 5—40 mgZD was administered to 24 patients and midazolam wasiven to 3 patients on the intensive care unit (ICU) doctor’sdvice prior to IV LEV administration. Three of the patientsere given IV LEV directly without prior BZD due to their

espiratory insufficiency. Three patients also took PHT afterZD before IV LEV. Fifty percent (n = 15) of the patients hadeen on antiepileptic drug (AED) therapy before SE including1 patients who had already been treated either only withral LEV or its combinations.

The most frequent etiology was cerebrovascular diseaseCVD) (23.3%; n = 7; 5 of them acute, and 2 remote). Thetiology was unknown in 16.6% of patients (n = 5) whereasn 10% (n = 3) the etiology was AED withdrawal (one wasight hemiparetic due to meningoencephalitis; one had leftrontal encephalomalasia due to brain injury, and one had arontal tumor). The clinical features and treatment resultsith prognosis are shown in Table 1.

Five patients with EPC were fully conscious, 16 were con-used or somnolent, and 9 had stupor or coma. In caseshere seizures continued, coma-induction therapy was cho-

en in 6 patients.Twenty-three patients responded to IV LEV and its effi-

acy on SE was 76.6%. Of the seven patients who receivedreatment in addition to IV LEV (patient numbers: 3, 4, 7,3, 15, 23 and 29), those who did not respond to IV LEVere given other treatments (PHT loading, coma induction).hree of these 7 patients were aged over 60 years. In total,2 patients were aged over 60 years, which is a risk factoror SE. It was not possible to determine the etiology in fouratients. The efficacy of IV LEV treatment was 75% in this

roup of patients. Two of the four patients with systemiciseases who had SE during their treatment in the intensiveare unit responded well. Hence, the efficacy of IV LEV inhis group was 50%.

Intravenous levetiracetam

treatment

in status

epilepticus

15

Table 1 Clinical features and treatment results of patients who were administrated IV LEV.

Patientno

Age,sex Medicalhistory

Type of SE Etiology CurrentAEDs

BZD dose IV LEV dose Oral main-tenancetreatment

Extratreatment

Result STESS 12 monthprognosis

1 52,M Operatedcranialepidermoidcyst (11years ago)

CSE Remotestructural-metabolic(operatedbrain tumor)

None 5 mg 3000 mg LEV1000 mg/d

No Seizurecontrol

2 Return tobaseline

2 38,F Meningitiswhen 4years old,JME

CSE(myoclonic)

Geneticgeneralizedepilepsy

LEV2500 mg/d

15 mg 3000 mg LEV2500 mg/d

No Seizurecontrol

0 Return tobaseline

3 50,F Operatedfrontaltumor (4years ago)

CSE Acutestructural-metabolic(Brain tumorrelapse)

LEV2000 mg/d

30 mg 2000 mg LEV3000 mg/d,PHT300 mg/d

Comainduction

Seizurecontrol

1 Return tobaseline butshe had 5more SEepisodes.She tookcranialradiothe-rapy. Shewas righthemipareticdue totumor

4 67,F MS CSE MS? None 20 mg 2000 mg LEV2000 mg/d,TPM200 mg/d

Comainduction

Seizurecontrol

5 Ex due topneumoniaand sepsisat 4 month

5 72,F HT, IHD,meningitis(30 yearsago)

NCSE ? None 10 mg 1500 mg LEV1500 mg/d

No Seizurecontrol

3 Return tobaseline

6 17,M Chronicepilepsy

CSE Geneticgeneralizedepilepsy

LEV2000 mg/d,VPA2000 mg/d,LTG12.5 mg/d

No 2000 mg Same doseswith currenttreatment

No Seizurecontrol

1 Return tobaseline

16

M.M

. Atm

aca et

al.

Table 1 (Continued)

Patientno

Age,sex Medicalhistory

Type of SE Etiology CurrentAEDs

BZD dose IV LEV dose Oral main-tenancetreatment

Extratreatment

Result STESS 12 monthprognosis

7 35,M Hypoxiaafter beingstabbed

CSE(postanoxicgeneralizedmyoclonia)

Hypoxicischemicencephalopa-thy

None Midazolaminfusion

4000 mg(dividedinto twodoses in oneday)

LEV2000 mg/d,TPM200 mg/d,CLZ 15drops/d

Comainduction

Seizurecontrol

3 Oftenmyoclonia,needs carefor living

8 65,M MCA infarct(6 yearsago)

EPC Remotestructural-metabolic(CVD)

None 10 mg 3000 mg LEV1000 mg/d

No Seizurecontrol

3 Return tobaseline buthe had onemore EPCbecause ofAEDwithdrawal

9 35,M AMLdiagnosisandischemicCVD (1 yearago)

CSE Acutestructural-metabolic(hemor-rhage dueto CVD)

None 25 mg 2000 mg LEV1000 mg/d

No Seizurecontrol

2 Ex due tohemorrhagecaused byCVD after 3days

10 45,M DVT (7monthsago), DM,HT, acuteCVT

CSE Acutestructural-metabolic(CVT)

None 10 mg 2000 mg LEV1000 mg/d

No Seizurecontrol

1 Lefthemipareticat dischargeand died 3monthslater (loss ofconscious-ness, deadatadmission)

11 64,M HT, sleepapnea,abdominalaorticaneurysm,hemorrhagedue to CVD(3 yearsago)

CSE Hyper-natremia(159 mEq/L)

LEV1000 mg/d,CBZ400 mg/d

No 1000 mg Same doseswith currenttreatment

Metabolicarrange-ment

Seizurecontrol

2 Return tobaseline

Intravenous levetiracetam

treatment

in status

epilepticus

17

12 27,F MS (for 7years) andepilepsy (for3 years)

CSE MS LEV2000 mg/d

No 2000 mg LEV2000 mg/d,CBZ400 mg/d

No Seizurecontrol

1 Return tobaseline butshe has oneSE episodeevery month

13 90,F Nothing EPC ? None 40 mg 2500 mg LEV2000 mg/d

Comainduction

No seizurecontrol

3 Exitus duetorespiratoryfailure nextday

14 52,M Righthemiplegicdue tomeningitisat age 2.Epilepsyfrom age 18

CSE AEDwithdrawal

PHT300 mg/d,LEV1000 mg/d

5 mg 3000 mg Same doseswith currenttreatment

No Seizurecontrol

1 Return tobaseline

15 88,F DM, CHF,DLB,delirium for1 month,subacutePCA infarct

NCSE SubacuteCVD, DLB,UTI,pneumonia

None 10 mg 5000 mg (in120 h)

LEV1000 mg/d,CBZ400 mg/d

PHT 750 mg No seizurecontrol

6 Ex due tohypotensiveshockbecause ofsepsis

16 42,F Geneticgeneralizedepilepsy

NCSE (Eyelidmyocloniawithabsence SE)

Geneticgeneralizedepilepsy

VPA500 mg/d,LTG37.5 mg/d

20 mg 3000 mg VPA1000 mg/d,LEV2000 mg/d

No Seizurecontrol

0 Return tobaseline butshe had 2more SEepisodes in2 months

17 25,F Epilepsy(from age6), febrileconvulsionat age 1.5

NCSE(complexpartial SE)

Doublecortex

CBZ800 mg/d

20 mg 3000 mg CBZ800 mg/d,LEV1000 mg/d

No Seizurecontrol

0 Return tobaseline buther complexpartialseizurescontinue

18

M.M

. Atm

aca et

al.

Table 1 (Continued)

Patientno

Age,sex Medical history Type ofSE

Etiology CurrentAEDs

BZD dose IV LEV dose Oral main-tenancetreatment

Extratreatment

Result STESS 12 monthprognosis

18 60,F Cholangiocarcinomaand she had righthepatectomy andhepaticojejunos-tomy 1 weekago

NCSE ? None 1 mgMidazolam

1500 mg LEV2000 mg/d

No Seizurecontrol

4 Return tobaseline but exdue to portalvein thrombosisand renalfailure 1 monthlater

19 67,M CVD 4 years ago andhe had 3 SEepisodes before

CSE Remotestructural-metabolic(CVD)

LEV1000 mg/d,CBZ800 mg/d,CLZ 2 mg/d

30 mg 2000 mg LEV1500 mg/d,CBZ800 mg/d,CLZ 2 mg/d

PHT1600 mg *

Seizurecontrol

4 Return tobaseline but hehad two moreSE episodes

20 77,F Cholangiocarcinoma,adrenal glandmetastasis

NCSE ? None 20 mg 2000 mg LEV2000 mg/d

PHT1400 mg *

Seizurecontrol

5 Seizure controlin EEG but shedidn’t return tobaselineclinically anddied because ofcardiac failure,hepatic failureand varicoseveinhemorrhage

21 88,F Hypotiroidism,essentialthrombocytosis, HT,CAD and she hadherpes encephalitis1 year ago

NCSE Remotestructural-metabolic(herpesencephali-tis)

LEV2000 mg/d

20 mg 6000 mg(4000 mg)two equaldoses on thesame daywith 3 hintervals,followed bysingle2000 mgdose nextday

LEV2500 mg/d,CBZ800 mg/d

PHT1000 mg*

Seizurecontrol

2 After SE ishemiplegic andshe has severecognitiveimpairment,needs care forliving, she hadSE 5 monthslater

Intravenous levetiracetam

treatment

in status

epilepticus

19

22 53,M Left frontalencephalo-malacia inMRI due tobeing shotby gun, HT,MI

CSE AEDwithdrawal

OXC1200 mg/d,LEV500 mg/d,TPM50 mg/d

** 3000 mg Same doseswith currenttreatment

No Seizurecontrol

2 Return tobaseline

23 56,M SAH, ACoarteryaneurysm

EPC Acutestructural-metabolic(SAH)

None Midazolaminfusion

1500 mg LEV2000 mg/d

Midazolaminfusion

Seizurecontrol

1 Return tobaseline

24 70,F Frontaltumor

NCSE Frontaltumor

CBZ2000 mg/d

** 3500 mg CBZ2000 mg/d,LEV1000 mg/d

No Seizurecontrol

5 Patient notcontacted

25 60,F EndometriumCa, aplasticanemia,hyperam-monemia

NCSE Acutestructural-metabolic(Frontaltumor)

None ** 1000 mg LEV1000 mg/d

No Seizurecontrol

4 Patient notcontacted

26 23,M Frontaltumor,epilepsy

EPC AEDwithdrawal

VPA500 mg/d,CBZ800 mg/d

** 1500 mg VPA500 mg/d,CBZ800 mg/d,LEV2000 mg/d

No Seizurecontrol

0 Return tobaselineAfter VNS hehas fewerseizures

27 78,F Earlieroperationfor GBM

NCSE Earlieroperationfor GBM

CBZ200 mg/d,PHT300 mg/d,LEV1000 mg/d

** 3000 mg CBZ200 mg/d,PHT300 mg/d,LEV3000 mg/d

No Seizurecontrol

4 Ex due toGBM

28 48,M IschemicCVD 2 daysago,multiplemyeloma

CSE Acutestructural-metabolic(CVD)

None ** 2000 mg LEV1000 mg/d

No Seizurecontrol

2 Ex due tomyeloma 3monthslater

20

Tabl

e

1

(Con

tinu

ed)

Pati

ent

noAg

e,se

x

Med

ical

hist

ory

Type

of

SE

Etio

logy

Curr

ent

AED

sBZ

D

dose

IV

LEV

dose

Ora

l mai

n-te

nanc

etr

eatm

ent

Extr

atr

eatm

ent

Resu

lt

STES

S

12

mon

thpr

ogno

sis

29

60,M

Righ

t

PCA

infa

rct,

oper

atio

nfo

rdu

oden

umtu

mor

NCS

E

Acut

est

ruct

ural

-m

etab

olic

(CVD

)

LEV

1000

mg/

d**

2000

mg

?

Com

ain

duct

ion

Seiz

ure

cont

rol

3 Pa

tien

t

not

cont

acte

d

30

63,F

DM

EPC

Fron

tal

tum

orN

one

**

1000

mg

LEV,

CBZ

No

Seiz

ure

cont

rol

1

Pati

ent

not

cont

acte

d

SE:

stat

us

epile

ptic

us,

EPC:

epile

psia

part

ialis

cont

inua

,

LEV:

leve

tira

ceta

m,

CBZ:

carb

amaz

epin

e,

VPA:

valp

roic

acid

,

TPM

:

topi

ram

ate,

CLZ:

clon

azep

am,

PHT:

diph

enyl

hyda

ntoi

n,CV

D:

cere

brov

ascu

lary

dise

ase,

AED

:

anti

-epi

lept

ic

drug

,

GBM

:

glio

blas

tom

e

mul

tifo

rme,

VNS:

vaga

l

nerv

e

stim

ulat

ion,

CSE:

conv

ulsi

ve

stat

us

epile

ptic

us,

NCS

E:

non-

conv

ulsi

ve

stat

usep

ilept

icus

,

EPC:

epile

psia

part

ialis

cont

inua

,

LEV:

leve

tira

ceta

m,

CBZ:

carb

amaz

epin

e,

OXC

:

oxca

rbaz

epin

e,

VPA:

valp

roic

acid

,

TPM

: to

pira

mat

e,

CLZ:

clon

azep

am,

LTG

:

lam

otri

gine

,BZ

D:

benz

odia

zepi

n,

PHT:

diph

enyl

hyda

ntoi

n,

CVD

:

cere

brov

ascu

lary

dise

ase,

SAH

:

suba

rach

noid

hem

orrh

age,

AED

:

anti

-epi

lept

ic

drug

,

HT:

hype

rten

sion

,

DM

:

diab

etes

mel

litus

,

MI:

miy

ocar

dial

infa

rcti

on,

MS:

mul

tipl

e

scle

rosi

s,

AML:

acut

e

mye

lodi

spla

stic

leuk

emia

,

CAD

:

coro

nary

arte

ry

dise

ase,

GBM

:

glio

blas

tom

e m

ulti

form

e,

CVT:

cere

bral

vein

trom

bosi

s,

DVT

:

deep

vein

trom

bosi

s,

MCA

:

mid

dle

cere

bral

arte

ry,

PCA:

post

erio

r

cere

bral

arte

ry,

ACo

arte

ry:

ante

rior

com

mun

ican

arte

ry,

UTI

:

urin

ary

trac

t

infe

ctio

n,

DLB

:

Dem

enti

a

of

Lew

y

bodi

es,

CHF:

conj

esti

ve

hear

t

failu

re,

IHD

:

isch

emic

hear

t

dise

ase,

JME:

juve

nile

myo

clon

ic

epile

psy,

STES

S:

stat

us

epile

ptic

us

seve

rity

scor

e,

*:

PHT

was

give

n

befo

re

LEV,

**:

BZD

was

give

n

befo

re

LEV

but

dosa

ge

was

not

note

d,

?:

not

know

n.

cplhr8sIata

otsttd(pldl1ont

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D

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asiaea

o(

M.M. Atmaca et al.

No major adverse effects or complications that couldause disability were seen in any of our patients. Threeatients had mild adverse effects: patient-5 was somno-ent; patient-16 suffered from headaches, and patient-27ad spasms in the face and neck. We were not able toetrieve information on adverse effects from 12 patients,

of whom had died and 4 were taken care of in the inten-ive care unit. Twelve patients who where under care in theCU and were unconscious were not reported to have hadny observable adverse effects such as physical (skin erup-ion, etc.) or systemic (fever, hypo/hypertension, cardiacrrhythmias) abnormalities by their relatives or ICU staff.

Fifty-eight percent of patients (n = 17) survived and 46.6%f patients (n = 14) had a good prognosis 12 months afterheir SE episode (they returned to their baseline neurologictate). Four patients could not be contacted 12 months afterhe SE episode. Thirty percent of patients (n = 9) died duringhe 12 months after SE. Eight patients died of underlyingisease or their later complications and only one patientpatient no 13) died due to systemic complications of SE. Twoatients (patient no: 7 and 3) needed help to go on with theirives at their 12th month follow-up because of underlyingiseases. One patient (patient no: 21) developed permanenteft hemiplegia and cognitive impairment due to SE. In the2 months that followed the first SE, 6 patients developedther SE episodes. Of the 5 patients whose etiology couldot be determined, 4 died indicating the worst prognosis inhis group.

The STESS of 13 patients was 3 or above, which indi-ates poor prognosis. Six of these patients died, 1 needsupport to continue life functions, three returned to base-ine values, and 3 could not be contacted. Excluding theatients who could not be contacted, 70% of the patientsan be said to have complied with the expected prognosis.eventeen patients, on the other hand, had STESS values 2r lower. Three of them died, 1 developed permanent neu-ologic deficits due to SE, 1 continued to have SE once aonth, 1 could not be contacted, 1 had hemiplegia due to

umor, and 10 returned to baseline values. Once again, therognosis was correlated with STESS, as expected.

iscussion

he synaptic vesicle protein 2A (SV2A) receptor is the mainarget of LEV (Lynch et al., 2004). It has been suggested thatould LEV be used with BZD, especially in the early phasef SE, when the GABA system is most susceptible becauseEV interacts with GABAergic transmission and potentiatesZD efficacy, both in human and animal studies (Dudra-astrzebska et al., 2009; Mazarati et al., 2004; Rigo et al.,002).

It is crucial to evaluate the response to first-line ther-py, the duration of SE before treatment, the etiology ofeizures, the age of patients, and dosage and rate of drugnfusion in order to adopt the right course of treatment. Asn observational study, our aim was to combine LEV with thestablished SE management protocol without a comparative

pproach to demonstrate LEV efficacy as opposed to BZD.

IV LEV is recommended for the treatment of SE becauseral use of LEV has had promising results in individual casesRossetti and Bromfield, 2005; Rupprecht et al., 2007). IV

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Intravenous levetiracetam treatment in status epilepticus

LEV can be used on patients who are taking various drugs forsystemic diseases and elderly patients because it generallyhas only mild adverse effects (Stefan and Feuerstein, 2007).LEV provides a good balance between safety and tolerabilitywhen used intravenously (Uges et al., 2009).

The inclusion criteria for this study were the require-ment to use IV LEV where patients failed to respond to BZD.The cause for this failure could have been etiology, whichalso plays a vital role in both treatment failure and adverselong-term outcomes with symptomatic seizures (Brevoordet al., 2005; Chen et al., 2009; Ruegg et al., 2008). In thisprospective study, the group with best results was that ofthe patients with epilepsy and the worst results were in thegroup of patients with tumors. In terms of their etiology,among patients with no response to IV LEV, two had epilepsyof unknown cause, 3 had CVD, 1 had anoxia, and 1 had a braintumor. In terms of clinical presentation, among patients withno response to IV LEV, 4 had CSE, 2 had NCSE, and 1 had EPC.Four of the 7 patients with CVD and 4 of the 5 patients withepilepsy of unknown cause, died. With respect to respon-siveness to IV LEV and outcomes, the best were patientswith epilepsy due to genetic etiology (n = 3) and with AEDwithdrawal (n = 3). All of these 6 patients were alive andresponded well to IV LEV. In general, a 76.6% seizure con-trol was achieved with IV LEV. Efficacy of IV LEV was 75%in patients aged over 60 years, and was 50% in patientswith systemic diseases who had SE during their treatmentin the intensive care unit. In the literature, the efficacy ofIV LEV ranges from 44 to 75% in prospective studies (Eueet al., 2009; Misra et al., 2012; Uges et al., 2009), and 52 to94% in retrospective studies (Aiguabella et al., 2011; Alvarezet al., 2011; Berning et al., 2009; Beyenburg et al., 2009;Gamez-Leyva et al., 2009; Knake et al., 2008). Althoughexperience with IV LEV is relatively limited, the drug appearsto have either no significant adverse effects or is well toler-ated in all age groups as well as in those with comorbidities.Double-blind controlled-group studies must be undertakenin larger series, especially on patients in intensive careunits.

It is possible to administer IV LEV in emergencies regard-less of age and without the need to check for cardiac orrespiratory monitoring. Thus, IV LEV is easy to use and iswell tolerated; it has mild or no adverse effects; it yields agood response to SE in all age groups, all of which render IVLEV a favorable and preferable alternative for clinicians.

We administered a maximum dose of 4000 mg/day IV LEVwith no undesirable adverse effects. The maximum dose inliterature is reported as 9000 mg/day (Moddel et al., 2009).

There is no agreement on the relationship betweenseizure type and the outcome of drug effect in the litera-ture (Trinka and Dobesberger, 2009). Similarly, we were notable to observe such a correlation in the various types ofseizures in our groups, perhaps due to the limited numberof patients.

Most adverse effects related to IV LEV are signs- orsymptoms-associated with the central nervous system suchas somnolence, dizziness, headache, and fatigue, which arethe most common but still rare occurrences (Berning et al.,

2009; Beyenburg et al., 2009; Eue et al., 2009). Those whichwere considered as mild adverse effects of IV LEV in ourpatients may have been postictal symptoms rather thanadverse effects of the drug.

C

21

It would be difficult to argue for exact prognosis based onTESS results but larger series could yield more informativeesults. One limitation of this study is the small number ofatients involved.

On the other hand, this was a nonrandomized prospectivetudy, which has the longest follow-up in the literature toate compared with other studies; this study is the first toave a follow-up period of one year.

We found that IV LEV treatment was well tolerated andffective both in focal and generalized SE. It generally showsild adverse effects, if any, which is important for patientsho are taking various drugs for systemic diseases and forlderly patients. Compared with other intravenously-usedntiepileptic drugs, IV LEV has the combined advantage offficacy, safety, and ease of use, which could make it a firsthoice after BZD in the treatment of SE.

onflict of interest

he authors reported no conflict of interest related to thisrticle.

cknowledgement

e thank David Chapman for proofreading; Hakan Yener,evcan Es, Mustafa Pasaoglu, Elif Gulfem Celik, Filiz Barutor their help in EEG recording and technical support; andlso Muhsin Sungur, Ender Bostanci for their help in EEGeports in our electroencephalography laboratory.

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