ClinicalReview&Education JAMA | Review New ... · Focal seizure May start with an aura followed by...
12
Copyright 2016 American Medical Association. All rights reserved. New-Onset Seizure in Adults and Adolescents A Review Jay R. Gavvala, MD, MSCI; Stephan U. Schuele, MD, MPH A pproximately 8% to 10% of the population will experi- ence a seizure during their lifetime. Only about 2% to 3% go on to develop epilepsy. 1 Patients presenting with a sus- pected first-time unprovoked seizure should undergo an orderly evaluation. 2,3 The first step is to distinguish the presenting episode from other paroxysmal events that can mimic seizures, which can include migraine, transient ischemic attack, and syncope (Table 1). 2 The second step is to assess for provocative factors such as acute systemic disturbances or acute insults to the brain that would pre- dispose a patient to acute symptomatic seizures. 4 In the absence of such triggers, a comprehensive workup after a first seizure is re- quired to establish risk of recurrence and necessity of antiepileptic treatment. The previous definition of epilepsy was based on a patient hav- ing at least 2 unprovoked seizures more than 24 hours apart; how- ever, the current definition includes patients with “one unpro- voked seizure and a probability of further seizures similar to the general recurrence risk after two unprovoked seizures (at least 60%) occurring over the next 10 years.” 5 This definition applies to pa- tients with evidence of an epilepsy syndrome on an electroencepha- logram or a significant symptomatic etiology on magnetic reso- nance imaging (MRI) of the brain, 5,6 emphasizing the importance of access to and quality of additional testing. This review will focus on the evaluation of new-onset seizure in adults and adolescents, which includes history and physical ex- amination, the differential diagnosis, characteristic features of each etiology, and features of a rational diagnostic workup. The choice of treatment includes discussion of the consideration of efficacy, ad- verse effects, dosing, and patient counseling. Methods The literature published through November 2016 was reviewed by searching PubMed. The following keywords were used: epilepsy, first time seizure, unprovoked seizures, first time unprovoked seizure, acute symptomatic seizure, antiepileptic treatment, seizure epidemiology, epi- lepsy epidemiology, women with epilepsy, epilepsy in the elderly, sud- den unexplained death in epilepsy, and refractory epilepsy. No lan- guage restriction was applied. Review articles, primary literature, and meta-analysis were included in this review. Articles were reviewed if they were published between 1976 and 2016. Articles were rated using IMPORTANCE Approximately 8% to 10% of the population will experience a seizure during their lifetime. Only about 2% to 3% of patients go on to develop epilepsy. Understanding the underlying etiology leading to an accurate diagnosis is necessary to ensure appropriate treatment and that patients with low risk for recurrence are not treated unnecessarily. OBSERVATIONS Patients can present with new-onset seizure for a variety of reasons such as acute symptomatic seizures due to acute brain injury or metabolic derangements, or unprovoked seizures that are the initial manifestation of epilepsy. A patient history and physical examination may identify features more consistent with an epileptic event and laboratory studies and brain imaging can identify an acute insult contributing to the presentation. Patients diagnosed with first-time unprovoked seizure require electroencephalography and epilepsy protocol–specific magnetic resonance imaging of the brain, which includes thin-cut coronal slices to determine risk of recurrence and the need for long-term treatment. In patients who meet the criteria for diagnosis of epilepsy, a carefully selected antiepileptic medication with consideration of comorbidities, adverse effect profile, and type of epilepsy is essential along with appropriate counseling. CONCLUSIONS AND RELEVANCE Approximately 3% of the population will develop epilepsy but 2 to 3 times as many patients will experience a single seizure or seizure-like event. A diagnosis of epilepsy has significant medical, social, and emotional consequences. A careful patient history and physical examination, electroencephalography, and brain imaging are necessary to separate patients with acute symptomatic seizures, single unprovoked seizures, and nonepileptic events from those with new-onset epilepsy. JAMA. 2016;316(24):2657-2668. doi:10.1001/jama.2016.18625 Author Audio Interview JAMA Patient Page page 2686 Supplemental content CME Quiz at jamanetworkcme.com Related article at jamaneurology.com Author Affiliations: Department of Neurology, Baylor College of Medicine, Houston, Texas (Gavvala); Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois (Schuele). Corresponding Author: Jay R. Gavvala, MD, MSCI, Department of Neurology, Baylor College of Medicine, 7200 Cambridge 9A, Houston, TX 77030 (jay.gavvala @bcm.edu). Section Editors: Edward Livingston, MD, Deputy Editor, and Mary McGrae McDermott, MD, Senior Editor. Clinical Review & Education JAMA | Review jama.com (Reprinted) JAMA December 27, 2016 Volume 316, Number 24 2657 Copyright 2016 American Medical Association. All rights reserved. Downloaded From: http://jamanetwork.com/ by a UAMS Library User on 09/02/2017
Transcript of ClinicalReview&Education JAMA | Review New ... · Focal seizure May start with an aura followed by...
Copyright 2016 American Medical Association. All rights reserved.
New-Onset Seizure in Adults and AdolescentsA ReviewJay R. Gavvala, MD, MSCI; Stephan U. Schuele, MD, MPH
A pproximately 8% to 10% of the population will experi-ence a seizure during their lifetime. Only about 2% to 3%go on to develop epilepsy.1 Patients presenting with a sus-
pected first-time unprovoked seizure should undergo an orderlyevaluation.2,3 The first step is to distinguish the presenting episodefrom other paroxysmal events that can mimic seizures, which caninclude migraine, transient ischemic attack, and syncope (Table 1).2
The second step is to assess for provocative factors such as acutesystemic disturbances or acute insults to the brain that would pre-dispose a patient to acute symptomatic seizures.4 In the absenceof such triggers, a comprehensive workup after a first seizure is re-quired to establish risk of recurrence and necessity of antiepileptictreatment.
The previous definition of epilepsy was based on a patient hav-ing at least 2 unprovoked seizures more than 24 hours apart; how-ever, the current definition includes patients with “one unpro-voked seizure and a probability of further seizures similar to thegeneral recurrence risk after two unprovoked seizures (at least 60%)occurring over the next 10 years.”5 This definition applies to pa-tients with evidence of an epilepsy syndrome on an electroencepha-logram or a significant symptomatic etiology on magnetic reso-
nance imaging (MRI) of the brain,5,6 emphasizing the importance ofaccess to and quality of additional testing.
This review will focus on the evaluation of new-onset seizurein adults and adolescents, which includes history and physical ex-amination, the differential diagnosis, characteristic features of eachetiology, and features of a rational diagnostic workup. The choiceof treatment includes discussion of the consideration of efficacy, ad-verse effects, dosing, and patient counseling.
MethodsThe literature published through November 2016 was reviewed bysearching PubMed. The following keywords were used: epilepsy, firsttime seizure, unprovoked seizures, first time unprovoked seizure, acutesymptomaticseizure,antiepileptictreatment,seizureepidemiology,epi-lepsy epidemiology, women with epilepsy, epilepsy in the elderly, sud-den unexplained death in epilepsy, and refractory epilepsy. No lan-guage restriction was applied. Review articles, primary literature, andmeta-analysis were included in this review. Articles were reviewed ifthey were published between 1976 and 2016. Articles were rated using
IMPORTANCE Approximately 8% to 10% of the population will experience a seizure duringtheir lifetime. Only about 2% to 3% of patients go on to develop epilepsy. Understanding theunderlying etiology leading to an accurate diagnosis is necessary to ensure appropriatetreatment and that patients with low risk for recurrence are not treated unnecessarily.
OBSERVATIONS Patients can present with new-onset seizure for a variety of reasons such asacute symptomatic seizures due to acute brain injury or metabolic derangements, orunprovoked seizures that are the initial manifestation of epilepsy. A patient history andphysical examination may identify features more consistent with an epileptic event andlaboratory studies and brain imaging can identify an acute insult contributing to thepresentation. Patients diagnosed with first-time unprovoked seizure requireelectroencephalography and epilepsy protocol–specific magnetic resonance imaging of thebrain, which includes thin-cut coronal slices to determine risk of recurrence and the need forlong-term treatment. In patients who meet the criteria for diagnosis of epilepsy, a carefullyselected antiepileptic medication with consideration of comorbidities, adverse effect profile,and type of epilepsy is essential along with appropriate counseling.
CONCLUSIONS AND RELEVANCE Approximately 3% of the population will develop epilepsy but2 to 3 times as many patients will experience a single seizure or seizure-like event. A diagnosisof epilepsy has significant medical, social, and emotional consequences. A careful patienthistory and physical examination, electroencephalography, and brain imaging are necessaryto separate patients with acute symptomatic seizures, single unprovoked seizures, andnonepileptic events from those with new-onset epilepsy.
JAMA. 2016;316(24):2657-2668. doi:10.1001/jama.2016.18625
Author Audio Interview
JAMA Patient Page page 2686
Supplemental content
CME Quiz atjamanetworkcme.com
Related article atjamaneurology.com
Author Affiliations: Department ofNeurology, Baylor College ofMedicine, Houston, Texas (Gavvala);Department of Neurology,Northwestern University FeinbergSchool of Medicine, Chicago, Illinois(Schuele).
Corresponding Author: Jay R.Gavvala, MD, MSCI, Department ofNeurology, Baylor College ofMedicine, 7200 Cambridge 9A,Houston, TX 77030 ([email protected]).
Section Editors: Edward Livingston,MD, Deputy Editor, and Mary McGraeMcDermott, MD, Senior Editor.
Clinical Review & Education
JAMA | Review
jama.com (Reprinted) JAMA December 27, 2016 Volume 316, Number 24 2657
Copyright 2016 American Medical Association. All rights reserved.
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Copyright 2016 American Medical Association. All rights reserved.
the Oxford Centre for Evidence-based Medicine 2009 levels of evi-dence and grading scale recommendations for clinical practice (Box).7
A total of 99 articles were included in this review.
ResultsClinical PresentationThe diagnosis of an epileptic seizure or epilepsy is largely based onclinical history. The clinical features of seizures vary according to theunderlying neuroanatomy.8 The goal of obtaining a patient’s sei-zure history is to determine if the event was likely epileptic, and ifso, to distinguish between seizures with a focal and generalized on-set. Based on their presumed clinical and electrographic onset pat-tern, seizures are classified as generalized (involving bilateral neu-ral networks) or focal (involving neural networks present in 1 lobeor hemisphere) (Table 1).6 Although many events may in fact be sei-zures, the differential diagnosis for paroxysmal neurological disor-ders, particularly if the initial event is unwitnessed, can be broad andincludes migraine, syncope, transient ischemic attack, psycho-genic nonepileptic seizures, movement disorders, sleep disorders,and panic attacks (Table 1).2,9
EpidemiologyPopulation-based studies from the 1980s and 1990s suggested thatthere was a lifetime risk of 8% to 10% for unprovoked or acute symp-tomatic seizures and a 2% to 3% chance of actually developingepilepsy.10,11 More recent studies have shown an incidence of acutesymptomatic seizures of 29 to 39 per 100 000 per year, an inci-dence of a single unprovoked seizure of 23 to 61 per 100 000 per year,and an incidence of epilepsy worldwide of 50.4 per 100 000 peryear.1,12 In 2011, this resulted in an estimated 1.6 million emergency de-partment (ED) visits for evaluation of seizures and approximately400 000 patients with new-onset seizures presenting to the ED.13
Risk Factors for EpilepsyPatient age at onset and a family history of epilepsy are helpful tonarrow in on a likely etiology and epilepsy syndrome. Excessive sleepdeprivation and use of alcohol and illicit drugs can be precipitatingfactors for a seizure. Furthermore, certain medications (clozapine,cephalosporins, fluoroquinolones, bupropion, and tramadol) havebeen shown to reduce the seizure threshold; therefore, a patient’smedication list should be carefully screened for these medications.Metabolic derangements, altered homeostasis due to organ fail-ure, and toxin exposure are also common provoking factors forseizures.3,14 Review of medical and surgical histories are pertinentin the search for acute symptomatic causes and other possible eti-ologies. Questions about the patient’s childhood development suchas complications during delivery, history of central nervous systeminfections, head injuries (particularly those with loss of conscious-ness), and history of central nervous system disease or prior neu-rological surgeries are important in characterizing a patient’s risk forfuture seizures.
Assessment and DiagnosisAdditional testing is necessary for a patient with new-onset seizureto (1) assess if the patient likely had an acute symptomatic seizure,(2) support the clinical suspicion that the event was epileptic and
estimate the risk of recurrence, and (3) determine the type of sei-zure and the most appropriate choice for treatment. In the followingsubsections, the utility and appropriateness of several commonlyordered tests for patients with new-onset seizures are discussed.
History and Physical ExaminationThe diagnosis of epilepsy and epileptic seizures largely remains a clini-cal one that is highly dependent on the patient history and physicalexamination. The initial focus of the history should be the patient’sexperience, recollection, and awareness of the event. Subjectivesymptoms at the onset of a seizure are considered auras, which aretypically seen in patients with focal seizures, and provide the mostlocalizing information of where in the brain seizures might arise. Itis necessary for clinicians to ask patients about prior events that mayrepresent seizure symptoms. A large number of patients who ex-perience a first convulsive seizure may also have had prior staringspells, myoclonic jerks out of wakefulness, or stereotypic events(such as auras) and would meet the criteria for the diagnosis of epi-lepsy or even a specific epilepsy syndrome.
In many cases, the patient has impaired awareness during theevent and witness accounts are crucial. It is important to evaluateand document patient and witness accounts separately. Doing so en-hances the accuracy of the report, and is often the basis of distin-guishing physiological impairment from nonphysiological events(such as when a patient claims awareness of bilateral shaking move-ments that hardly occur during epileptic seizures without amnesiaand unresponsiveness, raising concern of a nonepileptic etiology).
A description of all relevant physical examination findings is be-yond the scope of this article. A thorough physical examination isimportant. Examination of the oral mucosa may reveal lateral tonguebites. In pooled studies, lateral tongue bites are seen in about 22%of patients with all types of epileptic seizures, whereas these bitesare not seen in patients with psychogenic nonepileptic seizures.15
Bruises or scrapes over the body may be seen after falls, and backpain may indicate a vertebral compression fracture. Evidence of nu-chal rigidity or asterixis suggests an underlying systemic disorder thatmay have caused an acute symptomatic seizure. Transient or per-sistent focal weakness or asymmetry on examination suggests areas
DefinitionsSeizure: A transient occurrence of signs and symptoms due toabnormal excessive or synchronous neuronal activity in the brain.
Unprovoked Seizure: Occurring in the absence of precipitatingfactors and may be caused by a static or progressive injury.
Acute Symptomatic Seizure: In close temporal association witha transient central nervous system or systemic insult presumedto be an acute manifestation of the insult.
Focal Seizure: Initial onset originates within 1 part of a cerebralhemisphere.
Generalized Seizure: Initial activity is consistent with rapidlyengaging networks distributing in bilateral cerebral hemispheres.
Epilepsy: Disorder of the brain characterized by an enduringpredisposition to generate epileptic seizures. Has been definedas 2 or more unprovoked seizures occurring more than 24 hoursapart or 1 unprovoked seizure and a high risk (at least 60%)of recurrent unprovoked seizures over the next 10 years.
Clinical Review & Education Review New-Onset Seizure in Adults and Adolescents
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Tabl
e1.
Diff
eren
tialD
iagn
osis
ofN
ew-O
nset
Seiz
ure
Clin
ical
Entit
yCl
inic
alFe
atur
esTo
olsf
orDi
agno
sis
Patie
ntAc
coun
tBy
stan
derA
ccou
ntTr
ansi
enti
sche
mic
atta
ckRe
sults
from
tem
pora
ryin
terr
uptio
nof
bloo
dsu
pply
inth
edi
strib
utio
nof
ace
rebr
alve
ssel
.Thi
spro
duce
srap
idon
seto
fne
gativ
esy
mpt
omss
uch
asnu
mbn
ess,
wea
knes
s,an
dap
hasi
a,an
dis
typi
cally
nota
ssoc
iate
dw
ithst
iffne
ssor
jerk
ing.
Occ
asio
nally
atr
ansi
enti
sche
mic
atta
ckm
aypr
esen
twith
ast
utte
ring
cour
se.
Risk
fact
orsf
orce
rebr
ovas
cula
rdis
ease
.Bra
inm
agne
ticre
sona
nce
imag
ing
and
mag
netic
reso
nanc
ean
giog
ram
look
ing
atbl
ood
vess
elso
fth
ehe
adan
dne
ck.
Fully
awar
eof
defic
itsan
dty
pica
llyon
lyis
limite
din
hiso
rher
abili
tyto
repo
rtth
epr
esen
tatio
ndu
eto
lang
uage
impa
irmen
t.
Sam
eas
patie
ntac
coun
tunl
esst
hepa
tient
hasl
angu
age
impa
irmen
tpr
even
ting
accu
rate
repo
rtin
g.
Mig
rain
eAu
rapr
esen
twith
visu
alau
ra,u
nila
tera
lpul
satin
ghe
adac
he,
naus
ea,a
ndvo
miti
ng.H
owev
er,a
typi
calm
igra
ines
can
pres
ent
with
isol
ated
neur
olog
ical
sym
ptom
sorw
ithou
tass
ocia
ted
head
ache
.The
dura
tion
and
inte
nsity
ofm
igra
ines
typi
cally
last
hour
sto
days
with
asl
owpr
ogre
ssio
nof
aura
and
neur
olog
ical
defic
its.
Ahi
stor
yof
mig
rain
esan
dfa
mily
hist
ory
ofm
igra
ines
may
behe
lpfu
l.Do
esno
tlos
eaw
aren
essd
urin
ga
mig
rain
ean
dca
nac
cura
tely
repo
rthi
sorh
erpr
esen
tatio
n.H
owev
er,
conf
usio
nala
ndba
sila
rmig
rain
esca
nre
sult
inin
atte
ntio
nan
dde
crea
sed
leve
lsof
cons
ciou
snes
s.
Sim
ilart
opa
tient
acco
untu
nles
sthe
reis
asso
ciat
edco
nfus
ion
orin
atte
ntio
nas
can
bese
enin
basi
laro
rcon
fusi
onal
mig
rain
es.
Sync
ope
Atr
ansi
entl
osso
fcon
scio
usne
ssw
ithco
mpl
ete
retu
rnto
pree
xist
ing
neur
olog
ical
func
tion.
Vaso
vaga
lsyn
cope
typi
cally
hasa
situ
atio
nalt
rigge
rsuc
has
fear
,pai
n,m
edic
alpr
oced
ures
,co
ughi
ng,m
ictu
ritio
n,de
feca
tion,
orVa
lsal
vam
aneu
ver.
Ort
host
asis
can
aggr
avat
ea
vaso
vaga
lrea
ctio
nor
brin
gou
ta
sync
ope
from
hypo
vole
mia
orst
ruct
ural
hear
tdis
ease
.
Elec
troc
ardi
ogra
phy,
card
iac
tele
met
ry,a
ndec
hoca
rdio
grap
hyar
ere
com
men
ded
toex
clud
eca
rdia
cet
iolo
gies
.Tilt
tabl
ete
stin
gm
ayhe
lpre
prod
uce
typi
cale
vent
s.
Typi
cally
ispr
eced
edby
feel
ings
ofdi
zzin
ess,
fulln
essi
nea
rs,n
ause
a,an
dbl
urry
visi
on.P
atie
ntsa
reus
ually
pale
and
have
cold
and
clam
my
skin
and
flacc
idm
uscl
eto
ne.P
atie
ntsw
illno
tha
vere
colle
ctio
nof
even
tsth
atoc
cur
afte
rlos
sofc
onsc
ious
ness
,alth
ough
this
perio
dis
brie
f.Th
ere
isty
pica
llyno
post
icta
lsta
te.
May
notic
ebr
iefm
yocl
onic
jerk
sort
onic
post
urin
gat
the
end
ofth
eev
ent.
This
may
bede
scrib
edby
witn
esse
sas
“con
vuls
ive”
activ
ity.
Psyc
hoge
nic
none
pile
ptic
seiz
ures
Typi
cally
are
asso
ciat
edw
ithem
otio
nale
vent
sors
tres
sors
,la
stlo
nger
than
epile
ptic
seiz
ures
,and
ofte
nha
vea
wax
ing
and
wan
ing
qual
ity.C
linic
alfe
atur
essu
chas
eye
clos
ure,
pelv
icth
rust
ing,
voca
lstu
tter
ing,
and
part
iala
war
enes
sdu
ring
who
le-b
ody
mot
orm
ovem
ents
are
typi
cal.
Cont
inuo
usel
ectr
oenc
epha
logr
aphi
cm
onito
ring
isre
com
men
ded
toca
ptur
eev
ents
inqu
estio
nan
den
sure
noep
ilept
icch
ange
sare
seen
.
May
clai
maw
aren
esso
fbila
tera
lsha
king
mov
emen
ts,w
hich
inep
ilept
icse
izur
esar
ety
pica
llyas
soci
ated
with
amne
sia
and
unre
spon
sive
ness
.
May
repo
rtcl
inic
alfe
atur
esof
the
even
tsu
chas
thos
em
ostt
ypic
alfo
rps
ycho
geni
cno
nepi
lept
icse
izur
es(e
yecl
osur
e,pe
lvic
thru
stin
g,w
axin
gan
dw
anin
gof
mot
orm
ovem
ents
).Fo
cals
eizu
reM
ayst
artw
ithan
aura
follo
wed
bylo
ssof
awar
enes
s,un
ilate
rals
ensa
tions
,orm
otor
activ
ity.T
hism
aypr
ogre
ssto
age
nera
lized
toni
c-cl
onic
seiz
ure
inso
me
case
s(ev
olvi
ngto
bila
tera
lcon
vuls
ive
activ
ity).
This
prog
ress
ion
isfa
ster
than
seen
with
mig
rain
e.
Anel
ectr
oenc
epha
logr
amm
aysh
owfo
cal
epile
ptifo
rmdi
scha
rges
.Bra
inm
agne
ticre
sona
nce
imag
ing
shou
ldbe
perf
orm
edto
look
fors
truc
tura
labn
orm
aliti
es.
May
repo
rtan
aura
(déj
àvu
oran
epig
astr
icau
raw
ithte
mpo
rall
obe
epile
psy)
,con
tral
ater
alpa
rest
hesi
ain
parie
tall
obe
seiz
ures
,and
visu
aldi
stor
tions
inoc
cipi
tall
obe
seiz
ures
.If
awar
enes
sisn
otaf
fect
ed,h
eor
she
may
repo
rtpr
ogre
ssio
nof
sym
ptom
sto
unila
tera
lmot
oror
sens
ory
sym
ptom
s.If
loss
ofaw
aren
esso
rgen
eral
ized
toni
c-cl
onic
activ
ity,w
illno
tbe
able
tore
port
even
t.
Repo
rtpr
obab
lym
ore
relia
ble
and
may
incl
ude
patie
ntst
arin
g,fr
eque
ntey
ebl
inki
ng,s
emip
urpo
sefu
lmov
emen
tsof
hand
sand
feet
,and
char
acte
ristic
sof
toni
c-cl
onic
seiz
ure
activ
ity.M
ayal
sore
port
open
eyes
,urin
ary
inco
ntin
ence
,fo
calo
rwho
le-b
ody
stiff
enin
g,po
stev
entl
etha
rgy
orco
nfus
ion,
and
ast
ereo
type
dpr
ogre
ssio
nw
ithre
curr
ente
vent
s.
Gene
raliz
edse
izur
eTy
pica
llyno
war
ning
.Sei
zure
scha
ract
eriz
edby
brie
fsta
ring
spel
ls,g
ener
aliz
edto
nic-
clon
icac
tivity
,myo
clon
icje
rks.
Anel
ectr
oenc
epha
logr
amm
aysh
owge
nera
lized
epile
ptifo
rmdi
scha
rges
and
conf
irma
spec
ific
epile
psy
synd
rom
e.
Freq
uent
lyha
veno
awar
enes
sofe
vent
,ex
cept
form
yocl
onic
jerk
s,bu
tmay
repo
rtpo
stic
talf
indi
ngss
uch
asto
ngue
bite
orin
cont
inen
ce(if
gene
raliz
edto
nic-
clon
icse
izur
es).
Cruc
ialt
oun
ders
tand
the
clin
ical
pres
enta
tion.
New-Onset Seizure in Adults and Adolescents Review Clinical Review & Education
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Copyright 2016 American Medical Association. All rights reserved.
of brain dysfunction that could predispose a patient to have sei-zures, which should be confirmed with brain imaging. Examinationof the skin may reveal signs of a neurocutaneous syndrome associ-ated with epilepsy such as neurofibromatosis, tuberous sclerosis, andSturge-Weber syndrome.16,17
Brain ImagingPatients with a first seizure should have neuroimaging; however,uncertainty remains regarding the appropriate timing and type ofimaging (grade B).18,19 Earlier literature suggested approximately10% of patients with new-onset seizures had abnormalitiesrevealed by imaging that were believed to be clinically relevant;however, most of these studies exclusively used computed tomog-raphy (CT).18 With greater use of MRI, the detection rate of abnor-malities believed to contribute to a patient’s occurrence of seizureswas closer to 30%.20 Emergency neuroimaging is recommendedwhen a serious structural brain lesion is suspected as well as fornew neurological deficits, persistent altered mental status, recenttrauma, and prolonged headache.19
Computed tomography is the usual first imaging modality dueto its ease of access and should be considered for patients with new-onset seizures seen in the ED. However, CT scans may miss certain
lesions such as low-grade gliomas, hippocampal sclerosis, cavern-ous malformations, and malformations of cortical development(eg, cortical dysplasia or periventricular heterotopias).21,22 If thereis sufficient concern for a focal abnormality based on the progres-sion of clinical signs and symptoms (seizure semiology) or physicalexamination, further imaging with an MRI is warranted. In patientswho return to baseline after a first unprovoked seizure, have a nor-mal examination in the ED, and normal emergency brain imaging(CT, emergency MRI, or both) results, further imaging with an epi-lepsy protocol–specific brain MRI should be performed in conjunc-tion with evaluation by a neurologist or epileptologist.
An epilepsy protocol–specific brain MRI differs from a typical MRIin that it includes thin 1- to 3-mm slices and coronal fluid–attenuatedinversion recovery sequences that offer additional sensitivity overstandard protocol MRIs for the detection of subtle lesions, particu-larly focal cortical dysplasia and hippocampal sclerosis.23-25 The pres-ence of those often subtle abnormalities signifies a risk for seizure re-currence of greater than 60% and establishes a diagnosis of epilepsy.6
Use of an epilepsy protocol–specific MRI and review of the imagingresults by an expert neuroradiologist can increase the sensitivity in de-tecting abnormalities.25
ElectroencephalographyMost patients with new-onset seizure who do not return to base-line neurological function within 30 to 60 minutes after the end ofa seizure, have a waxing and waning level of consciousness, or havefocal dysfunction unexplained by a structural lesion should be con-sidered for hospital admission and continuous electroencephalo-graphic monitoring. Continuous electroencephalographic monitor-ing has been increasingly used with growing recognition forpatients with seizures that have subtle or no clinical signs. Inpatients with subclinical seizures, less than 50% are detected byroutine 30-minute electroencephalographic monitoring but theyield increases to greater than 90% with 24- to 36-hour continu-ous electroencephalographic monitoring in patients with an acutebrain injury and mental status change.26 However, even amongpatients who return to baseline neurological function, almost one-quarter admitted to the hospital after new-onset seizure had addi-tional risk factors identified during the hospitalization that sug-gested a high likelihood of seizure recurrence.27
Standard 30-minute electroencephalographic monitoring af-ter new-onset seizure is helpful to determine the likely seizure type(focal vs generalized) and to determine the risk of recurrenceafter a first event (grade B).28-30 In patients with new-onset sei-zure, 29% of patients will have epileptiform abnormalities on theirfirst electroencephalogram.18 There does appear to be a slightlyhigher yield of epileptiform abnormalities on electroencephalo-grams performed in patients within 24 to 48 hours of new-onsetseizure.31-33
In a patient who has fully recovered and is considered for dis-charge, electroencephalography can be safely delayed if the treat-ment does not depend on the electroencephalographic result. A re-cent study that assessed 20-year outcomes found an increase inmortality and recurrence following a first generalized tonic-clonicseizure in patients with a known structural etiology.34 However, inpatients without a structural abnormality, recognizing an underly-ing epileptogenic focus or the electroencephalographic pattern ofa particular epilepsy syndrome may be easier and more expertly
Box. Levels of Evidence and Grading ScaleUsed for Article Ratinga
Levels of EvidenceLevel 1A: Systematic review with homogeneity of randomizedclinical trials
B: Individual randomized clinical trial with a narrowconfidence interval
C: All or none case studies (ie, those in which a series of peoplewith the risk factors all experience the outcome or those in whichall do not experience the outcome)
Level 2A: Systematic review with homogeneity of cohort studies
B: Individual cohort study
C: Outcomes research
Level 3A: Systematic review with homogeneity of case-control studies
B: Individual case-control study
Level 4Case series
Level 5Expert opinion
Grading Scale RecommendationsGrade A: Consistent level 1 evidence studies
Grade B: Consistent level 2 or 3 evidence studies or extrapolationsfrom level 1 studies
Grade C: Level 4 studies or extrapolations from level 2 or 3evidence studies
Grade D: Level 5 evidence studies or troublingly inconsistentor inconclusive studies of any level
a Defined by the Oxford Centre for Evidence-based Medicine.7
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done while the patient is an outpatient. This may also reduce theconfounding factors of an inpatient admission, such as medicationeffects or acute postictal electroencephalographic changes, and pro-vide a more accurate representation of a patient’s inherent risk forseizure recurrence.
Even in patients with apparent acute symptomatic seizures, itis important to not overlook the importance of electroencephalog-raphy or brain imaging. Older data suggest that up to 30% of pa-tients with suspected alcohol withdrawal seizures had a potentiallyepileptogenic structural abnormality related to a traumatic injury.35
Conversely, a large number of adult patients with a first acute symp-tomatic seizure are found to have electroencephalographic abnor-malities suggestive of a genetic predisposition for generalized sei-zures, which may have only manifested with additional triggers.36
Emergency electroencephalography is indicated when a pa-tient does not return to baseline neurological function within 30 to60 minutes after the end of a seizure, has a waxing and waning levelof consciousness, or has focal neurological dysfunction that is un-explained by a structural lesion. In all other cases, nonemergent elec-troencephalography is recommended, ideally within 24 to 48 hoursof the new-onset seizure.
Chemistry PanelRoutine screening of patients after new-onset seizure for hypogly-cemia, uremia, drug intoxication, and hyponatremia has been pro-posed (grade D). These recommendations are largely based on pa-tients seeking care in the ED with a higher frequency of acutesymptomatic seizures.37,38 In the one prospective study evaluatingpatients with new-onset seizures, only 4% of patients had relevantlaboratory findings of hyperglycemia and hyponatremia.38 In out-patient clinic–based studies, laboratory findings were of limited util-ity and no significant results were seen.39
Prolactin LevelElevated serum prolactin level has been measured in patients afterthe seizure event. If the pretest probability of a patient having anepileptic seizure is 50% or greater, prolactin level has a positive pre-dictive value of greater than 93% in differentiating generalized orfocal seizures with impaired consciousness from psychogenic non-epileptic seizures if a patient’s prolactin level is measured 10 to 20minutes after a suspected event (grade B). However, prolactin levelmeasured after the seizure event has to be compared with the pa-tient’s baseline prolactin level measured at least 6 hours prior to thesuspected event, which is rarely done, making prolactin level analy-sis generally impractical for clinical use. Furthermore, prolactin el-evations can also be seen with a syncopal event and thus cannot dif-ferentiate between an epileptic seizure and syncope (grade B).40
It is also important to note the low sensitivity and low negativepredictive value of prolactin level analysis, making it insufficient in di-agnosing patients with psychogenic nonepileptic seizures or for ex-cluding patients with epileptic seizures with impairment of conscious-ness (grade A).40 Prolactin level analysis can be effective indistinguishing between patients with seizures that involve impair-ment of consciousness and psychogenic nonepileptic seizures, butonly if prolactin level is measured 10 to 20 minutes after a suspectedevent and is compared with a baseline prolactin level measured at least6 hours prior to the suspected event. Serum prolactin level analysisis not an effective test to distinguish seizure from syncope.
Lumbar PunctureLumbar puncture should be considered in cases with concern for men-ingitis, encephalitis, or subarachnoid hemorrhage. No study has ex-amined the systematic use of lumbar puncture in patients present-ing with new-onset seizures (grade D). In studies from the ED in whichclinical reasoning guided the use of lumbar puncture, up to 8% of pa-tients were found to have clinically significant findings.18 Even thoughthese findings were almost always found in patients with high clini-cal suspicion of central nervous system infection, in rare cases immu-nocompromised patients (such as those with human immunodefi-ciency virus) had abnormal lumbar puncture results without overtclinical evidence of central nervous system infection.41
Risk of Seizure RecurrenceUnprovoked SeizuresA recent American Academy of Neurology practice guideline sum-marized the current data on prognosis and therapy after new-onsetseizure.42 There is an approximately 35% chance of a seizure recur-rence within 5 years following new-onset seizure in adults.11,43-45 How-ever, in persons who have had a second seizure, the risk of a recur-rent seizure increases to 75% during the following 5 years.44,46
Patients with an abnormal neurological examination, abnormal brainimaging (grade B), an electroencephalogram with epileptiform ab-normalities (grade A), nocturnal seizure (grade B), or seizures attrib-uted to a prior brain injury (grade A) consistently have a much higherrisk of seizure recurrence.11,18,42,43,46 Individual studies were high-lighted in the American Academy of Neurology practice guideline asrepresentative examples of the increased risk of seizure recurrence.Patients with seizures attributed to a prior brain injury had 2.55 (95%CI, 1.44-4.51) times the rate of seizure recurrence based on 5-year re-currence rates increasing from 29% to 48% compared with patientswith seizures not attributed to a clear cause.42,47
Patients with abnormal brain imaging results had 2.44 (95% CI,1.09-5.44) times the risk for seizure recurrence during the subse-quent 4 years (from 47% to 89%) compared with those with nor-mal imaging results.42,48 Patients with generalized spike wave epi-leptiform abnormalities on an electroencephalogram were 2.16 (95%CI, 1.0-4.3) times more likely to have seizure recurrence during thefollowing 5 years based on recurrence rates increasing from 26% to58% compared with those without epileptiform abnormalities.42,47
Patients who experienced seizures at night were 2.1 (95% CI, 1.0-4.3) times more likely to have seizure recurrence based on 3-yearrecurrence rates of 33% increasing to 54% compared with patientswho experienced seizures during wakefulness.42,49 Other factorssuch as the patient’s age, type of seizure, and family history of sei-zures have not been consistently validated and are of uncertain prac-tical significance.43
Acute Symptomatic SeizuresThe qualities of provoked seizures (acute symptomatic seizures) arenot as well characterized but clearly portend a lower risk in pa-tients for subsequent unprovoked seizures. Patients with seizuresresulting from acute brain insults have a recurrence risk for sei-zures of 10% to 20%. This includes patients with seizures resultingfrom a severe closed head injury, acute hemorrhagic and ischemicstroke, subarachnoid hemorrhage, brain surgery, and central ner-vous system infections.50 An electroencephalogram obtained dur-ing the acute period showing epileptiform activity increases the
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likelihood in patients for recurrent acute symptomatic seizures, butis not predictive for future unprovoked seizures.50
TreatmentA seizure can be a terrifying experience with significant medical, emo-tional, and social consequences. There is a natural desire by pa-tients, families, and clinicians to prevent another seizure by empiri-cally starting antiepileptic medications even though two-thirds ofpatients with new-onset seizures do not warrant treatment. Whenconsidering treatment, clinicians need to have an understanding ofthe risk of seizure recurrence, seizure type and etiology, suitablechoice of antiepileptic medication, and anticipated duration of treat-ment. A suggested algorithm for treatment of new-onset seizure isoutlined in Figure 1 and for new-onset epilepsy in Figure 2.
Choice of Antiepileptic MedicationThe ideal first prescribed antiepileptic medication should be effica-cious, well tolerated, and easy for clinicians to prescribe and pa-tients to take. There are many available antiepileptic medications thatcan be considered for first-line monotherapy in adults with epilepsy,51
each with its advantages and limitations (Table 2).The choice of antiepileptic medication is primarily based on the
presumed type of epilepsy.51,52 Antiepileptic medications can be di-vided into broad-spectrum and narrow-spectrum agents. Narrow-spectrum agents are typically effective in patients with all forms offocal seizures regardless of alteration of consciousness or second-ary generalization. However, some narrow-spectrum agents may
worsen myoclonic and absence seizures in patients with genetic gen-eralized epilepsies, such as absence epilepsy and juvenile myo-clonic epilepsy.53 Broad-spectrum agents improve seizures in pa-tients with focal epilepsy and most generalized epilepsies, but oftenwith variable efficacy directed at specific seizure types.16,51,52 La-motrigine has been reported to worsen myoclonic seizures, topira-mate has not been shown to be effective against absence seizures,and zonisamide has limited evidence supporting its effectiveness inmyoclonic or absence seizures.52,54 Use of a broad-spectrum agentis recommended for patients if there is insufficient evidence point-ing to a focal onset.55
Another important consideration when making an antiepilep-tic medication choice is the time to therapeutic onset. This is par-ticularly important (1) in the inpatient setting in patients found tohave frequent seizures that warrant rapid antiepileptic medicationadministration and (2) in the ED if the goal is to get a patient to atherapeutic dose prior to discharge. Medications considered for first-line monotherapy and available in intravenous preparation includefosphenytoin, valproate, levetiracetam, and lacosamide (only la-beled for adjunctive use in Europe).
Special ConsiderationsThe choice of antiepileptic medication should account for the pa-tient’s comorbidities, other medication use, age, sex, and the costof the medication. Older antiepileptic medications such as phenytoinand carbamazepine are potent inducers of the cytochrome P450 sys-tem and valproate is an inhibitor, resulting in possible drug-drug
Figure 1. Suggested Systematic Approach to Patients With New-Onset Seizure
Yes
No
No
Yes
No
Yes
Yes
No
Is the event description and witnessreport suggestive of a seizure?
Is there evidence of fever, focal deficit, or mental status change?
Is there evidence of provoking factors (sleep deprivation, alcoholuse, medications, or drugs)?
Are the test results abnormal and consistent with etiologic findings in epilepsy?
Individual with a possible new-onset seizure
Obtain history and perform physical examination
Perform EEG and epilepsy protocol MRI
Evaluate for other diagnoses,including migraine, TIA, syncope(see Table 1)
Urgent evaluation for acute symptomatic seizureWorkup
Laboratory testingUrgent CT and/or MRIUrgent EEG and/or cEEG
ManagementInpatient admission
Probable unprovoked seizure
Nonurgent evaluation for acute symptomatic seizureWorkup
Laboratory testingBrain CTOutpatient EEG
ManagementLifestyle modificationsDefer antiepileptic medication
EpilepsyChoose first-line antiepilepticmedication (see Table 2 and Figure 2)
First unprovoked seizureMay defer antiepileptic medication
This algorithm presents the keyclinical questions and workup neededin the evaluation of a patientsuspected of having new-onsetseizure. This approach is a suggestionfor how to evaluate patients based onthe authors’ experience and has notbeen validated. This is meant asa general recommendation foran evaluation of a patient withnew-onset seizure; however,individual cases may deviate fromthis algorithm. CT indicatescomputed tomography; cEEG,continuous electroencephalography;EEG, electroencephalography;MRI, magnetic resonance imaging;TIA, transient ischemic attack.A checklist version of this algorithmappears in eAppendix 1 in theSupplement.
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interactions. In patients with multiple comorbidities, or taking med-ications such as warfarin or chemotherapeutic agents, use of newerantiepileptic medications such as levetiracetam, lamotrigine, orlacosamide with limited drug interactions is favored. Anotherimportant consideration is if the patient has liver or renal dysfunc-tion that would result in impaired elimination of an antiepilepticmedication.51,55
Generic FormulationsWith the rising costs among health care systems, there has been in-creasing use of generic formulations. Although the US Food and DrugAdministration requires manufacturers of generic formulations to havebioequivalence to the original brand-name product with the same ac-tive ingredients, prior retrospective studies and case reports have sug-gested that seizure control and rates of adverse effects change aftersubstitution with a generic antiepileptic medication.56,57 Even thoughthe generic formulation has bioequivalence to the brand-name prod-uct, the differences between generic formulations may have greaterthan expected differences in plasma drug concentrations.58 How-ever, 3 recently completed studies (2 of which were prospective ran-domized clinical trials) showed no difference in bioequivalence whenswitching from a brand-name product to a generic product or be-tween multiple generic products.59-61
Comparative TrialsComparative efficacy of the available antiepileptic medications is lim-ited. An earlier study comparing older antiepileptic medicationsfound that phenytoin and carbamazepine offered the highest treat-ment success in patients with focal epilepsy, although phenytoin hadmore adverse effects (grade A).62 Valproate and carbamazepinewere found to have similar effectiveness in the treatment of pa-tients with focal seizures evolving into bilateral convulsive sei-zures; however, carbamazepine was found to have better controlof focal seizures with fewer adverse effects (grade A).63 Subse-quent studies showed similar efficacy of lamotrigine, oxcarbaz-epine, and carbamazepine in patients with newly diagnosed focalepilepsy, although lamotrigine was better tolerated (grade A).64 Inpatients with generalized epilepsies, valproate was found to be moreefficacious than lamotrigine and better tolerated than topiramate(grade A).65 More recent studies have shown levetiracetam and zon-isamide to be both efficacious and well tolerated in the treatmentof patients with focal and generalized epilepsy (grade A).66,67
Adverse EffectsIn patients taking their first antiepileptic medication after new-onset seizure, adverse effects were seen in 7% to 31% of allpatients.42 In patients with epilepsy, especially those receiving poly-therapy, the number of adverse effects is significantly higher and wasup to 88% according to 1 study.68 It is important for clinicians to askabout adverse effects at each office visit because patients are lesslikely to report them unless directly asked.29,69,70 Most commonly,patients experience somnolence, dizziness, blurry vision, and diffi-culties with concentration and memory.69 Typically these are dose-dependent adverse effects and are most prominent during the firstfew days of therapy. Slower dose escalations or giving lower sched-uled doses but more frequently timed (eg, 100 mg of phenytoin3 times/day vs 150 mg of phenytoin twice daily) may be beneficialin alleviating these effects.
All antiepileptic medications can cause a rash, ranging from amild erythematous maculopapular rash to severe reactions such asStevens-Johnson syndrome or toxic epidermal necrolysis.69 Anti-epileptic medications most commonly associated with develop-ment of a rash are phenytoin, carbamazepine, and lamotrigine.Approximately 1 to 10 per 10 000 patients newly taking antiepilep-tic medications will develop severe cutaneous reactions such asStevens-Johnson syndrome or toxic epidermal necrolysis.69 Morethan 90% of all patients who develop toxic epidermal necrolysis andStevens-Johnson syndrome developed symptoms within the first60 days of therapy so clinicians should be especially vigilant duringthis period and advise patients and families of warning signs.71
Recent studies have highlighted the effect of genetic polymor-phisms in the development of cutaneous adverse drug reactions, inparticular the association of HLA-B*15:02 alleles with the develop-ment of Stevens-Johnson syndrome or toxic epidermal necrolysis
Figure 2. Suggested Treatment Algorithm in Patients WithNew-Onset Epilepsy
No YesIs the patient still having seizures?
No YesDo the seizures persist?
Individual with new-onset epilepsy1 seizure and abnormal EEG and/or MRIor2 seizures
Focal epilepsyBegin antiepileptic medication
Narrow-spectrum medicationCarbamazepineOxcarbazepinePhenytoinLacosamide
orBroad-spectrum medication
LamotrigineLevetiracetamTopiramateValproateZonisamide
Generalized epilepsy or unknown epilepsy typeBegin broad-spectrum antiepileptic medication(choice dependent on seizure type)
LamotrigineLevetiracetamTopiramateValproateZonisamide
Titrate to therapeutic dose
Continue current treatment until seizure-free for at least 2 y
Continue treatment (either as monotherapy or dual therapy) until seizure-free for at least 2 y
Revisit diagnosis for seizures that persist for >1 yConsider epilepsy monitoring unit admission
Add a second medication (dual therapy) or taper, then discontinue first medication while adding a second medication
This algorithm is a suggested approach to treatment and has not been validated.This is meant as a general recommendation; however, individual cases maydeviate from this algorithm. Further information on the specific antiepilepticmedications appears in the Table 2. Unknown epilepsy type refers to a type ofepilepsy for which the data are inconclusive as to whether the seizures were focalor generalized in origin. EEG indicates electroencephalography; MRI, magneticresonance imaging. A checklist version of this algorithm appears in eAppendix 2in the Supplement.
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Tabl
e2.
Firs
t-Li
neAn
tiepi
lept
icM
edic
atio
ns
Nam
eof
Med
icat
iona
Initi
alTi
trat
ion
Inst
ruct
ions
Targ
etM
aint
enan
ceDo
se,m
g/db
Type
ofSe
izur
eQ
uick
Ons
et?c
Adva
ntag
esDi
sadv
anta
ges
Nar
row
-Spe
ctru
mM
edic
atio
nsd
Carb
amaz
epin
eTw
ice
daily
incr
ease
of20
0m
gto
targ
etdo
seov
er1-
4w
k80
0-12
00Fo
cal
No
Larg
eam
ount
ofhi
gh-q
ualit
yev
iden
cede
mon
stra
ting
itsef
fect
iven
ess,
low
cost
,has
moo
dst
abili
zer
prop
ertie
s
Enzy
me
indu
cer,
can
wor
sen
gene
raliz
edep
ileps
ies
(par
ticul
arly
myo
clon
ican
dab
senc
ese
izur
es),
risk
ofsk
inhy
pers
ensi
tivity
,hyp
onat
rem
ia,a
gran
uloc
ytos
isEs
licar
baze
pine
Onc
eda
ilydo
seof
400
mg,
incr
ease
by40
0-60
0m
gea
chw
eek
800-
1200
Foca
lN
oUn
ique
mec
hani
smof
actio
nco
mpa
red
with
othe
rag
ents
,eas
ytit
ratio
n,on
ceda
ilydo
sing
Hyp
onat
rem
ia
Gaba
pent
ine
Star
twith
300-
900
mg
perd
ay,
incr
ease
over
1-2
wk
900-
1800
Foca
lN
oN
ohe
pato
toxi
city
,wel
ltol
erat
edin
olde
rpat
ient
s(a
ged
≥65
year
s),n
onen
zym
ein
duce
r,ef
fect
ive
for
neur
opat
hic
pain
,low
risk
ofsk
inhy
pers
ensi
tivity
reac
tions
Wei
ghtg
ain,
limite
dev
iden
ceof
effic
acy
(exc
epti
nol
der
patie
ntsa
ged
≥65
year
s)
Laco
sam
idef
Star
twith
100
mg
twic
eda
ily,
incr
ease
by10
0m
gto
tal
ever
yw
eek
300-
400
Foca
lYe
sIn
trav
enou
sfor
mul
atio
n,no
hepa
toto
xici
tyLi
mite
dev
iden
ceof
effic
acy,
dizz
ines
s,ar
rhyt
hmia
s
Oxc
arba
zepi
neTw
ice
daily
dose
of30
0m
g,in
crea
seto
targ
etdo
seov
er1-
2w
k
1200
Foca
lN
oLo
wer
pote
ntia
lofe
nzym
ein
duct
ion,
low
erris
kof
rash
than
carb
amaz
epin
eH
ighe
rris
kof
hypo
natr
emia
than
carb
amaz
epin
e,ca
nw
orse
nge
nera
lized
epile
psie
s(su
chas
myo
clon
ican
dab
senc
ese
izur
es)
Phen
ytoi
nDo
seof
100
mg
3tim
espe
rday
,in
crea
seto
targ
etev
ery
3-5
d30
0-60
0Fo
cal
Yes
Stro
ngev
iden
ceof
effic
acy,
low
cost
,rap
idtit
ratio
n,in
trav
enou
sfor
mul
atio
nEn
zym
ein
duce
r,hi
ghin
tera
ctio
nra
te,g
ingi
val
hype
rpla
sia,
leuk
open
iaBr
oad-
Spec
trum
Med
icat
ions
g
Lam
otrig
ine
Daily
dose
of25
mg
daily
for
2w
k,50
mg
daily
for2
wk,
100
mg
daily
for2
wk,
then
can
incr
ease
by50
mg
ever
y1-
2w
kh
250-
350
Foca
l,m
ost
gene
raliz
edN
oN
onen
zym
ein
duce
r,no
sign
ifica
ntin
tera
ctio
ns,
effe
ctiv
efo
rbip
olar
depr
essi
on,e
ffic
acio
usin
olde
rpa
tient
s(ag
ed≥6
5ye
ars)
Slow
titra
tion,
inte
ract
ions
with
valp
roat
ean
des
trog
en-c
onta
inin
gco
mpo
unds
,has
been
repo
rted
tow
orse
nm
yocl
onic
seiz
ures
,ris
kof
rash
,Ste
ven-
John
son
synd
rom
eLe
vetir
acet
amSt
artw
ith50
0m
gtw
ice
daily
,in
crea
seby
500
mg
ever
y1-
2w
kto
targ
etdo
se
1000
-200
0Fo
cal,
mos
tge
nera
lized
Yes
Non
enzy
me
indu
cer,
nosi
gnifi
cant
inte
ract
ions
,ra
pid
titra
tion,
intr
aven
ousf
orm
ulat
ion
avai
labl
eRi
skof
psyc
hiat
ricad
vers
eef
fect
s
Topi
ram
ate
Dose
of25
mg
twic
eda
ily,
incr
ease
by25
-50
mg
ever
yw
eek
200-
400
Foca
l,m
ost
gene
raliz
edN
oLo
wen
zym
ein
duct
ion
pote
ntia
l,ef
fect
ive
inm
igra
ine
prop
hyla
xis
Slow
titra
tion,
can
caus
em
etab
olic
acid
osis
,ren
alst
ones
,pa
rest
hesi
as,c
ogni
tive
adve
rse
effe
cts,
tera
toge
nic
effe
cts,
inef
fect
ive
agai
nsta
bsen
cese
izur
esVa
lpro
ate
Dose
of25
0m
gtw
ice
daily
or3
times
perd
ay,i
ncre
ase
dose
by25
0-50
0ev
ery
wee
k
500-
1500
Foca
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associated with carbamazepine or phenytoin in patients of Asiandescent.72,73 In fact, the Food and Drug Administration mandatesscreening for HLA-B*15:02 in all persons of Asian descent prior to ini-tiation of carbamazepine therapy. Patients should be advised topromptly report development of a rash and consideration should begiven for a hospital admission or urgent dermatologic evaluation. Of-fending antiepileptic medications should be promptly withdrawn toprevent progression of an adverse effect.69
Antiepileptic Medication Use in FemalesIn women of childbearing age, it is necessary to consider the anti-epileptic medication’s potential for teratogenic effects and interac-tions with contraception. Several antiepileptic medications, most no-tably P450 inducers, have been shown to increase the clearance oforal contraceptives, possibly resulting in unplanned pregnancies. Fur-thermore, oral contraceptives have been shown to decrease theplasma concentrations of lamotrigine, leading to fluctuations of la-motrigine levels during a women’s ovulatory cycle.74 It is importantfor patients to choose alternative methods of contraception or usecontinuous oral contraceptives without placebo dosing. Intrauter-ine devices seem to be the best method for contraception in thispopulation because they are the most effective form of contracep-tion and use of these devices enables avoidance of the drug-druginteractions seen between hormonal contraception and manyantiepileptic medications.75
Valproate is well known for its potential teratogenic effects withan estimated 10% risk for major congenital malformations.76-78
Recent studies have also demonstrated that children of women tak-ing valproate during pregnancy have lower IQs, memory, and ver-bal function.79 Major congenital malformations also have beenshown with use of phenobarbital, topiramate, phenytoin, andcarbamazepine.77,78 Females taking levetiracetam and lamotriginehave a risk of major congenital malformations similar to the generalpopulation.76-78 Few articles in the literature have commented onincidence of minor congenital malformations or obstetric compli-cations. The frequency of these malformations and complicationsseem to be increased with use of antiepileptic medications basedon older literature.80 There is limited evidence of the potential tera-togenicity with use of newer antiepileptic medications such aslacosamide and oxcarbazepine.76-78
Antiepileptic Medication Use in Older PatientsChanges in pharmacokinetics, concurrent medical illnesses, andlower tolerability of antiepileptic medications pose challengesto prescribing antiepileptic medications in older patients (aged�65 years). The limited literature available found lamotrigine andgabapentin to have fewer adverse reactions and have goodefficacy.51,81,82 Levetiracetam also has been recommended for usedue to its lower adverse effect profile and higher 1-year retentionrate than carbamazepine or valproic acid.82,83
Response RatesInitial studies suggested early initiation of antiepileptic therapy mayalter the natural history of epilepsy and improve seizure control. How-ever, 2 large randomized clinical trials looking at immediate vs de-layed initiation of antiepileptic therapy after patients experiencednew-onset seizure found that while immediate treatment delayedthe time to another seizure, long-term prognosis was not affected
by delayed initiation of therapy (grade A).42,45,84 In patients diag-nosed with epilepsy after 2 or more unprovoked seizures, approxi-mately 50% will become seizure-free after starting the first appro-priately dosed antiepileptic medication. The likelihood of patientfreedom from seizures declines with increased number of antiepi-leptic medication regimens, with 13% becoming seizure-free afterinitiation of a second antiepileptic medication and 4% after initia-tion of a third antiepileptic medication.85
Patient CounselingThe treatment of a patient after new-onset seizure should includecounseling about the medical and social consequences of seizuresand safety considerations.29 It is important for patients to under-stand the distinction between new-onset seizure and new-onset epi-lepsy as well as their type of seizure, risk of recurrence, and a dis-cussion of underlying etiology if known. Counseling should includefactors that may lower seizure threshold such as sleep deprivation,alcohol intake, drug use, strobe lights, and stress.3 Patients shouldalso be specifically counseled to avoid working at heights and work-ing with heavy machinery. Persons with epilepsy are 15 to 19 timesmore likely to die of drowning compared with the general popula-tion and high-risk activities should be avoided such as scuba div-ing, climbing, unobserved swimming, and taking tub baths (patientsshould be encouraged to take showers instead).3,86
Sudden unexpected death in epilepsy is defined as a suddenunexpected witnessed or unwitnessed mortality in otherwisehealthy patients with epilepsy with or without evidence of a sei-zure, in which postmortem examination does not reveal a cause ofdeath.87 Based on inpatient recordings, sudden unexpected deathin epilepsy appears to result from an early postictal, centrally medi-ated, severe alteration of respiratory and cardiac function inducedby generalized tonic-clonic seizures.88 Sudden death in personswith epilepsy occurs at a rate 20 times higher than in the generalpopulation.87 Although sudden unexpected death is more likely inpatients with epilepsy and large numbers of generalized tonic-clonic seizures, it rarely has occurred in patients with infrequentseizures or after a first seizure.87,89
Driving restrictions vary from state to state. In the majority ofstates, physicians are not required to report patients who have a sei-zure history to the motor vehicle administration.90 In the states inwhich physicians are not obligated to report patients directly to themotor vehicle administration, patient counseling should focus on therisks for driving with a history of seizures and the legal rules and re-sponsibilities for driving, such as the duty to self-report. These dis-cussions should be documented in the patient’s medical record.91
Most states allow noncommercial driving to resume in pa-tients 6 months after an unprovoked seizure and 3 months after anacute symptomatic seizure. Commercial driving after an unpro-voked seizure is usually not permitted until patients are free of sei-zures for at least 2 to 5 years.3
Duration of TherapyAfter a period in which a patient is free from seizures, it is reasonableto consider withdrawal of the antiepileptic medication. In the largeststudy (n = 1013) evaluating withdrawal of antiepileptic medicationsin patients with epilepsy who had been seizure-free for at least 2years, 59% remained seizure-free 2 years after weaning of medica-tions.92 Factors associated with successful remission included being
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seizure-free for more than 2 years while taking antiepileptic medica-tions and a normal neurological examination (grade A).92,93
In a more recent study evaluating adults with focal epilepsy, aseizure-free period of less than 4 years before withdrawal and a lon-ger duration of active epilepsy were independent risk factors for sei-zure relapse following withdrawal of antiepileptic medication. Thehighest risk of relapse appears to be during the first 2 years with lessthan 1% of relapses occurring more than 5 years after withdrawalof antiepileptic medication.94 Persistent electroencephalographicabnormalities and structural lesions are associated with a higher riskof relapse and any weaning of medications in these cases should beapproached more cautiously.95
In patients with acute symptomatic seizures, the likelihood ofunprovoked seizures (ie, the risk of developing epilepsies) is low andany use of antiepileptic medications is for the prevention of addi-tional acute symptomatic seizures. In patients with relatively treat-able and self-limited derangements (or metabolic abnormalities), an-tiepileptic medication use could be limited to 7 days if that amountof time is sufficient to correct the abnormality. In patients with anacute brain insult, the prophylaxis is sometimes extended from 1month to 6 months.4,50
DiscussionMaking the initial diagnosis of epilepsy has significant medical, so-cial, and emotional consequences. Although many patients will ex-perience only a single seizure, a careful patient history and physicalexamination and appropriate use of electroencephalography andneuroimaging will help differentiate patients who have alternativediagnoses from the ones at risk for recurrent seizures. Figure 1 is abroad overview of the treatment approach for patients with new-onset seizure. This can serve as a practical guide; however, it is im-portant to realize that patients are not always easily categorized anddecisions such as whether to start an antiepileptic medication shouldbe individualized with careful consideration of the risks and ben-efits by the patient, family, and treating physician.
Several medical centers have explored the benefits of new-onset seizure clinic that would be staffed by epileptologists as amechanism to bypass long wait times for a neurology evaluation andthe ordering of relevant tests. Early studies from Canada have sug-gested that this model is effective in reducing wait times for ap-pointments, in increasing the speed of diagnostic test completion,and in making an earlier and more accurate diagnosis with approxi-
mately 40% of patients meeting criteria for a diagnosis of epilepsyat the initial visit.96,97 One of these studies found that of childrenreferred to the clinic, one-quarter were incorrectly diagnosed as hav-ing a seizure and the diagnosis of epilepsy was missed in more thanone-third.97 Further data, particularly in the adult population, areneeded to validate whether this approach is an effective model toemulate on a larger scale.
The American Academy of Neurology recently published a prac-tice guideline summarizing the prognosis and therapy after pa-tients experience new-onset seizure. Patients with an abnormal neu-rological examination, MRI, electroencephalogram, or a nocturnalseizure had a much higher risk of seizure recurrence.42 It must benoted that the guideline included a meta-analysis that pooled casesof both treated and untreated patients with new-onset seizure,which were the basis of some of the recommendations, limiting theguideline’s strength and its applicability. The specific combinationof electroencephalographic and imaging findings necessary to makethe diagnosis of epilepsy after new-onset seizure is unclear. It wouldbe overly simplistic to assume that a single seizure plus a lesion or asingle seizure plus epileptiform spikes on an electroencephalo-gram automatically satisfy the criteria for diagnosis of epilepsy. Con-flicting evidence from prior studies on seizure recurrence rates inthe presence of epileptiform electroencephalographic patternsshows risks both above and below the 60% threshold.98,99
High-quality data demonstrating the risk of recurrent seizuresin patients with specific types of imaging abnormalities are lackingand very few studies evaluate patients who have both structuralimaging and electroencephalographic abnormalities. Future re-search should focus on the use of predictive models to better char-acterize the potential additive effects and timing of clinical vari-ables such as seizure etiology, electroencephalographic findings, andbrain imaging as it pertains to seizure recurrence.
ConclusionsApproximately 3% of the population will develop epilepsy but 2 to3 times as many patients will experience a single seizure or seizure-like event. A new diagnosis of epilepsy has significant medical, so-cial, and emotional consequences. A careful patient history and physi-cal examination, electroencephalography, and brain imaging arenecessary to separate patients with acute symptomatic seizures,single unprovoked seizures, and nonepileptic events from those withnew-onset epilepsy.
ARTICLE INFORMATION
Author Contributions: Dr Gavvala had full accessto all of the data in the study and takesresponsibility for the integrity of the data and theaccuracy of the data analysis.Concept and design: Both authors.Acquisition, analysis, or interpretation of data: Bothauthors.Drafting of the manuscript: Both authors.Critical revision of the manuscript for importantintellectual content: Both authors.Administrative, technical, or material support:Schuele.Supervision: Schuele.
Conflict of Interest Disclosures: The authors havecompleted and submitted the ICMJE Form forDisclosure of Potential Conflicts of Interest.Dr Gavvala reported receiving support from aresearch fellowship grant from the American BrainFoundation and the American Academy ofNeurology. Dr Schuele reported receiving researchsupport from the National Institute of NeurologicalDisorders and Stroke, the National Institute onDeafness and Other Communication Disorders, andthe Danny Did Foundation; and receiving speaker’sfees from Sunovion and Eisai.
Submissions: We encourage authors to submitpapers for consideration as a Review. Pleasecontact Edward Livingston, MD, at Edward
[email protected] or Mary McGraeMcDermott, MD, at [email protected].
REFERENCES
1. Hauser WA, Beghi E. First seizure definitions andworldwide incidence and mortality. Epilepsia.2008;49(suppl 1):8-12.
2. Cornes SB, Shih T. Evaluation of the patient withspells. Continuum (Minneap Minn). 2011;17(5neurologic consultation in the hospital):984-1009.
3. Pohlmann-Eden B, Legg KT. Treatment of firstseizure in adults. Epileptology. 2013;1(1):61-67.
4. Beleza P. Acute symptomatic seizures. Neurologist.2012;18(3):109-119.
Clinical Review & Education Review New-Onset Seizure in Adults and Adolescents
2666 JAMA December 27, 2016 Volume 316, Number 24 (Reprinted) jama.com
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: http://jamanetwork.com/ by a UAMS Library User on 09/02/2017
Copyright 2016 American Medical Association. All rights reserved.
5. Fisher RS, Acevedo C, Arzimanoglou A, et al.ILAE official report: a practical clinical definition ofepilepsy. Epilepsia. 2014;55(4):475-482.
6. Berg AT, Berkovic SF, Brodie MJ, et al. Revisedterminology and concepts for organization ofseizures and epilepsies. Epilepsia. 2010;51(4):676-685.
7. Oxford Centre for Evidence-based Medicine.2009 Levels of evidence. http://www.cebm.net.Accessed November 17, 2016.
8. Blume WT, Lüders HO, Mizrahi E, et al. Glossaryof descriptive terminology for ictal semiology.Epilepsia. 2001;42(9):1212-1218.
9. Sheldon R, Rose S, Ritchie D, et al. Historicalcriteria that distinguish syncope from seizures. J AmColl Cardiol. 2002;40(1):142-148.
10. Hauser WA, Annegers JF, Kurland LT. Incidenceof epilepsy and unprovoked seizures in Rochester,Minnesota. Epilepsia. 1993;34(3):453-468.
11. Berg AT, Shinnar S. The risk of seizurerecurrence following a first unprovoked seizure.Neurology. 1991;41(7):965-972.
12. Ngugi AK, Kariuki SM, Bottomley C, et al.Incidence of epilepsy. Neurology. 2011;77(10):1005-1012.
13. Wyman AJ, Mayes BN, Hernandez-Nino J, et al.The First-Time Seizure Emergency DepartmentElectroencephalogram Study. Ann Emerg Med.2016;0(0):622-628.
14. Delanty N, Vaughan CJ, French JA. Medicalcauses of seizures. Lancet. 1998;352(9125):383-390.
15. Brigo F, Storti M, Lochner P, et al. Tongue bitingin epileptic seizures and psychogenic events.Epilepsy Behav. 2012;25(2):251-255.
16. Browne TR, Holmes GL. Epilepsy. N Engl J Med.2001;344(15):1145-1151.
17. Ahmed SN, Spencer SS. An approach to theevaluation of a patient for seizures and epilepsy. WMJ.2004;103(1):49-55.
18. Krumholz A, Wiebe S, Gronseth G, et al.Practice parameter: evaluating an apparentunprovoked first seizure in adults (anevidence-based review): report of the QualityStandards Subcommittee of the American Academyof Neurology and the American Epilepsy Society.Neurology. 2007;69(21):1996-2007.
19. Quality Standards Subcommittee of theAmerican Academy of Neurology in cooperationwith American College of Emergency Physicians,American Association of Neurological Surgeons,and American Society of Neuroradiology. Practiceparameter: neuroimaging in the emergency patientpresenting with seizure—summary statement.Neurology. 1996;47(1):288-291.
20. Ho K, Lawn N, Bynevelt M, Lee J, Dunne J.Neuroimaging of first-ever seizure. Neurol Clin Pr.2013;398-404.
21. Heinz ER, Heinz TR, Radtke R, et al. Efficacy ofMR vs CT in epilepsy. AJR Am J Roentgenol. 1989;152(2):347-352.
22. Pohlmann-Eden B, Newton M. First seizure:EEG and neuroimaging following an epilepticseizure. Epilepsia. 2008;49(suppl 1):19-25.
23. Toledo M, Sarria-Estrada S, Quintana M, et al.3 TESLA MR imaging in adults with focal onsetepilepsy. Clin Neurol Neurosurg. 2013;115(10):2111-2116.
24. Wellmer J, Quesada CM, Rothe L, et al.Proposal for a magnetic resonance imagingprotocol for the detection of epileptogenic lesionsat early outpatient stages. Epilepsia. 2013;54(11):1977-1987.
25. Zijlmans M, de Kort GA, Witkamp TD, et al.3T versus 1.5T phased-array MRI in the presurgicalwork-up of patients with partial epilepsy ofuncertain focus. J Magn Reson Imaging. 2009;30(2):256-262.
26. Herman ST, Abend NS, Bleck TP, et al.Consensus statement on continuous EEG incritically ill adults and children, part I: indications.J Clin Neurophysiol. 2015;32(2):87-95.
27. Goldberg I, Neufeld MY, Auriel E,Gandelman-Marton R. Utility of hospitalizationfollowing a first unprovoked seizure. Acta NeurolScand. 2013;128(1):61-64.
28. Salinsky M, Kanter R, Dasheiff RM.Effectiveness of multiple EEGs in supporting thediagnosis of epilepsy. Epilepsia. 1987;28(4):331-334.
29. Fountain NB, Van Ness PC, Swain-Eng R, et al.Quality improvement in neurology: AAN epilepsyquality measures. Neurology. 2011;76(1):94-99.
30. Pillai J, Sperling MR. Interictal EEG and thediagnosis of epilepsy. Epilepsia. 2006;47(suppl 1):14-22.
31. King MA, Newton MR, Jackson GD, et al.Epileptology of the first-seizure presentation. Lancet.1998;352(9133):1007-1011.
32. Schreiner A, Pohlmann-Eden B. Value of theearly electroencephalogram after a firstunprovoked seizure. Clin Electroencephalogr. 2003;34(3):140-144.
33. Neufeld MY, Chistik V, Vishne TH, Korczyn AD.The diagnostic aid of routine EEG findings inpatients presenting with a presumed first-everunprovoked seizure. Epilepsy Res. 2000;42(2-3):197-202.
34. Leone MA, Vallalta R, Solari A, et al. Treatmentof first tonic-clonic seizure does not affectmortality. J Neurol Neurosurg Psychiatry. 2011;82(8):924-927.
35. Earnest MP, Yarnell PR. Seizure admissions to acity hospital: the role of alcohol. Epilepsia. 1976;17(4):387-393.
36. Cutting S, Lauchheimer A, Barr W, Devinsky O.Adult-onset idiopathic generalized epilepsy. Epilepsia.2001;42(11):1395-1398.
37. Wiebe S, Téllez-Zenteno JF, Shapiro M.An evidence-based approach to the first seizure.Epilepsia. 2008;49(suppl 1):50-57.
38. Sempere AP, Villaverde FJ, Martinez-MenéndezB, et al. First seizure in adults. Acta Neurol Scand.1992;86(2):134-138.
39. Hopkins A, Garman A, Clarke C. The firstseizure in adult life. Lancet. 1988;1(8588):721-726.
40. Chen DK, So YT, Fisher RS. Use of serumprolactin in diagnosing epileptic seizures: report ofthe Therapeutics and Technology AssessmentSubcommittee of the American Academy ofNeurology. Neurology. 2005;65(5):668-675.
41. Holtzman DM, Kaku DA, So YT. New-onsetseizures associated with human immunodeficiencyvirus infection. Am J Med. 1989;87(2):173-177.
42. Krumholz A, Wiebe S, Gronseth GS, et al.Evidence-based guideline: management of an
unprovoked first seizure in adults. Neurology. 2015;84:1705-1713.
43. Berg AT. Risk of recurrence after a firstunprovoked seizure. Epilepsia. 2008;49(suppl 1):13-18.
44. Hauser WA, Rich SS, Lee JR, Annegers JF,Anderson VE. Risk of recurrent seizures after twounprovoked seizures. N Engl J Med. 1998;338(7):429-434.
45. Musicco M, Beghi E, Solari A, et al. Treatmentof first tonic-clonic seizure does not improve theprognosis of epilepsy. Neurology. 1997;49(4):991-998.
46. Kim LG, Johnson TL, Marson AG, et al.Prediction of risk of seizure recurrence after a singleseizure and early epilepsy. Lancet Neurol. 2006;5(4):317-322.
47. Hauser WA, Rich SS, Annegers JF, Anderson VE.Seizure recurrence after a 1st unprovoked seizure:an extended follow-up. Neurology. 1990;40(8):1163-1170.
48. Hui ACF, Tang A, Wong KS, Mok V, Kay R.Recurrence after a first untreated seizure in theHong Kong Chinese population. Epilepsia. 2001;42(1):94-97.
49. Bora I, Seçkin B, Zarifoglu M, et al. Risk ofrecurrence after first unprovoked tonic-clonicseizure in adults. J Neurol. 1995;242(3):157-163.
50. Leung H, Man CB, Hui AC, Kwan P, Wong KS.Prognosticating acute symptomatic seizures usingtwo different seizure outcomes. Epilepsia. 2010;51(8):1570-1579.
51. Schmidt D, Schachter SC. Drug treatment ofepilepsy in adults. BMJ. 2014;348:g254.
52. Perucca E, Tomson T. The pharmacologicaltreatment of epilepsy in adults. Lancet Neurol. 2011;10(5):446-456.
53. Schmidt D. Drug treatment of epilepsy. EpilepsyBehav. 2009;15(1):56-65.
54. Velizarova R, Crespel A, Genton P, Serafini A,Gelisse P. Zonisamide for refractory juvenileabsence epilepsy. Epilepsy Res. 2014;108(7):1263-1266.
55. Asconapé JJ. The selection of antiepilepticdrugs for the treatment of epilepsy in children andadults. Neurol Clin. 2010;28(4):843-852.
56. Andermann F, Duh MS, Gosselin A, Paradis PE.Compulsory generic switching of antiepilepticdrugs. Epilepsia. 2007;48(3):464-469.
57. Zachry WM III, Doan QD, Clewell JD, Smith BJ.Case-control analysis of ambulance, emergencyroom, or inpatient hospital events for epilepsy andantiepileptic drug formulation changes. Epilepsia.2009;50(3):493-500.
58. Krauss GL, Caffo B, Chang YT, Hendrix CW,Chuang K. Assessing bioequivalence of genericantiepilepsy drugs. Ann Neurol. 2011;70(2):221-228.
59. Ting TY, Jiang W, Lionberger R, et al. Genericlamotrigine versus brand-name Lamictalbioequivalence in patients with epilepsy. Epilepsia.2015;56(9):1415-1424.
60. Privitera MD, Welty TE, Gidal BE, et al.Generic-to-generic lamotrigine switches in peoplewith epilepsy. Lancet Neurol. 2016;15(4):365-372.
New-Onset Seizure in Adults and Adolescents Review Clinical Review & Education
jama.com (Reprinted) JAMA December 27, 2016 Volume 316, Number 24 2667
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: http://jamanetwork.com/ by a UAMS Library User on 09/02/2017
Copyright 2016 American Medical Association. All rights reserved.
61. Kesselheim AS, Bykov K, Gagne JJ, et al.Switching generic antiepileptic drug manufacturernot linked to seizures. Neurology. 2016;87(17):1796-1801.
62. Mattson RH, Cramer JA, Collins JF, et al.Comparison of carbamazepine, phenobarbital,phenytoin, and primidone in partial and secondarilygeneralized tonic-clonic seizures. N Engl J Med.1985;313(3):145-151.
63. Mattson RH, Cramer JA, Collins JF. A comparisonof valproate with carbamazepine for the treatmentof complex partial seizures and secondarilygeneralized tonic-clonic seizures in adults. N Engl JMed. 1992;327(11):765-771.
64. Marson AG, Al-Kharusi AM, Alwaidh M, et al.The SANAD study of effectiveness ofcarbamazepine, gabapentin, lamotrigine,oxcarbazepine, or topiramate for treatment ofpartial epilepsy. Lancet. 2007;369(9566):1000-1015.
65. Marson AG, Al-Kharusi AM, Alwaidh M, et al.The SANAD study of effectiveness of valproate,lamotrigine, or topiramate for generalised andunclassifiable epilepsy. Lancet. 2007;369(9566):1016-1026.
66. Brodie MJ, Perucca E, Ryvlin P, et al. Comparisonof levetiracetam and controlled-releasecarbamazepine in newly diagnosed epilepsy. Neurology.2007;68(6):402-408.
67. Baulac M, Brodie MJ, Patten A, Segieth J,Giorgi L. Efficacy and tolerability of zonisamideversus controlled-release carbamazepine for newlydiagnosed partial epilepsy. Lancet Neurol. 2012;11(7):579-588.
68. Baker GA, Jacoby A, Buck D, et al. Quality of lifeof people with epilepsy. Epilepsia. 1997;38(3):353-362.
69. Toledano R, Gil-Nagel A. Adverse effects ofantiepileptic drugs. Semin Neurol. 2008;28(3):317-327.
70. Gilliam FG, Fessler AJ, Baker G, et al.Systematic screening allows reduction of adverseantiepileptic drug effects. Neurology. 2004;62(1):23-27.
71. Mockenhaupt M, Messenheimer J, Tennis P,Schlingmann J. Risk of Stevens-Johnson syndromeand toxic epidermal necrolysis in new users ofantiepileptics. Neurology. 2005;64(7):1134-1138.
72. Cheung Y-K, Cheng S-H, Chan EJM, et al.HLA-B alleles associated with severe cutaneousreactions to antiepileptic drugs in Han Chinese.Epilepsia. 2013;54(7):1307-1314.
73. Man CBL, Kwan P, Baum L, et al. Associationbetween HLA-B*1502 allele and antiepilepticdrug-induced cutaneous reactions in Han Chinese.Epilepsia. 2007;48(5):1015-1018.
74. Sabers A, Ohman I, Christensen J, Tomson T.Oral contraceptives reduce lamotrigine plasmalevels. Neurology. 2003;61(4):570-571.
75. Gerard EE, Meador KJ. Managing epilepsy inwomen. Continuum (Minneap Minn). 2016;22(1epilepsy):204-226.
76. Harden CL. Pregnancy and epilepsy. Continuum(Minneap Minn). 2014;20(1 neurology ofpregnancy):60-79.
77. Hernández-Díaz S, Smith CR, Shen A, et al.Comparative safety of antiepileptic drugs duringpregnancy. Neurology. 2012;78(21):1692-1699.
78. Tomson T, Battino D, Bonizzoni E, et al.Dose-dependent risk of malformations withantiepileptic drugs. Lancet Neurol. 2011;10(7):609-617.
79. Meador KJ, Baker GA, Browning N, et al. Fetalantiepileptic drug exposure and cognitiveoutcomes at age 6 years (NEAD study). LancetNeurol. 2013;12(3):244-252.
80. Holmes LB, Harvey EA, Coull BA, et al.The teratogenicity of anticonvulsant drugs. N Engl JMed. 2001;344(15):1132-1138.
81. Rowan AJ, Ramsay RE, Collins JF, et al. Newonset geriatric epilepsy. Neurology. 2005;64(11):1868-1873.
82. Werhahn KJ, Trinka E, Dobesberger J, et al.A randomized, double-blind comparison ofantiepileptic drug treatment in the elderly withnew-onset focal epilepsy. Epilepsia. 2015;56(3):450-459.
83. Pohlmann-Eden B, Marson AG, Noack-Rink M,et al. Comparative effectiveness of levetiracetam,valproate and carbamazepine among elderlypatients with newly diagnosed epilepsy. BMC Neurol.2016;16(1):149-153.
84. Marson A, Jacoby A, Johnson A, et al.Immediate versus deferred antiepileptic drugtreatment for early epilepsy and single seizures.Lancet. 2005;365(9476):2007-2013.
85. Brodie MJ, Barry SJ, Bamagous GA, Norrie JD,Kwan P. Patterns of treatment response in newlydiagnosed epilepsy. Neurology. 2012;78(20):1548-1554.
86. Bell GS, Gaitatzis A, Bell CL, Johnson AL,Sander JW. Drowning in people with epilepsy: howgreat is the risk? Neurology. 2008;71(8):578-582.
87. Shorvon S, Tomson T. Sudden unexpecteddeath in epilepsy. Lancet. 2011;378(9808):2028-2038.
88. Ryvlin P, Nashef L, Lhatoo SD, et al. Incidenceand mechanisms of cardiorespiratory arrests inepilepsy monitoring units (MORTEMUS):a retrospective study. Lancet Neurol. 2013;12(10):966-977.
89. Langan Y, Nashef L, Sander JW. Suddenunexpected death in epilepsy: a series of witnesseddeaths. J Neurol Neurosurg Psychiatry. 2000;68(2):211-213.
90. Krumholz A. Driving issues in epilepsy: past,present, and future. Epilepsy Curr. 2009;9(2):31-35.
91. Krumholz A, Hopp JL, Sanchez AM. Counselingepilepsy patients on driving and employment.Neurol Clin. 2016;34(2):427-442, ix.
92. Medical Research Council Antiepileptic DrugWithdrawal Study Group. Randomised study ofantiepileptic drug withdrawal in patients inremission. Lancet. 1991;337(8751):1175-1180.
93. Report of the Quality Standards Subcommitteeof the American Academy of Neurology. Practiceparameter: a guideline for discontinuingantiepileptic drugs in seizure-freepatients—summary statement. Neurology. 1996;47(2):600-602.
94. He R-Q, Zeng Q-Y, Zhu P, Bao Y-X, Zheng R-Y,Xu H-Q. Risk of seizure relapse after antiepilepticdrug withdrawal in adult patients with focalepilepsy. Epilepsy Behav. 2016;64(pt A):233-238.
95. Buna DK. Antiepileptic drug withdrawal—agood idea? Pharmacotherapy. 1998;18(2):235-241.
96. Rizvi S, Hernandez-Ronquillo L, Moien-Afshari F,et al. Evaluating the single seizure clinic model.J Neurol Sci. 2016;367:203-210.
97. Hamiwka LD, Singh N, Niosi J, Wirrell EC.Diagnostic inaccuracy in children referred with firstseizure. Epilepsia. 2007;48(6):1062-1066.
98. Shinnar S, Berg AT, Moshé SL, et al. Risk ofseizure recurrence following a first unprovokedseizure in childhood: a prospective study. Pediatrics.1990;85(6):1076-1085.
99. Stroink H, Brouwer OF, Arts WF, et al. The firstunprovoked, untreated seizure in childhood.J Neurol Neurosurg Psychiatry. 1998;64(5):595-600.
Clinical Review & Education Review New-Onset Seizure in Adults and Adolescents
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