Initial Management of Seizure in Adults - BINASSS

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 385;3 nejm.org July 15, 2021 251

Clinical Practice

From the Department of Neurology, Uni-versity Hospital of Wales, Cardiff, United Kingdom. Address reprint requests to Dr. Smith at the Alan Richens Epilepsy Unit, Department of Neurology, University Hos-pital of Wales, Heath Park, Cardiff, CF14 4XW, United Kingdom, or at smithpe@ cf . ac . uk.

N Engl J Med 2021;385:251-63.DOI: 10.1056/NEJMcp2024526Copyright © 2021 Massachusetts Medical Society.

An 18-year-old woman is brought to the emergency department after having had a seizure. She was up late with friends the night before and drank some alcohol. Shortly after waking this morning, she collapsed without warning, injuring her face. Her boyfriend witnessed her having a generalized tonic–clonic seizure with cyanosis during which she bit the side of her tongue. Her first memory was waking in the ambulance. She has had no previous seizures; specifically, she has not had any invol-untary jerks of the arms and legs on awakening, blank spells, or sensitivity to flash-ing lights (e.g., sunlight flashing through trees, as seen while riding in a car). How should this patient be further evaluated and treated?

The Clinic a l Problem

The incidence rate of a single unprovoked seizure among adults is 23 to 61 cases per 100,000 person-years.1 A seizure may substantially af-fect a person’s social interactions, employment, and driving eligibility. After

a first unprovoked seizure, the overall risk of recurrence may be as high as 60% (Fig. S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org), and this risk is highest within the first 2 years.2 Epilepsy affects 0.65% of adults worldwide,3 and this incidence is highest in developing countries. Epilepsy is diagnosed after two unprovoked seizures that occur more than 24 hours apart or after a single event that occurs in a person who is considered to have a high risk of recurrence (>60% risk in a 10-year period).4 Abnormal findings on electroencephalography (EEG), an abnormal neurologic status, and a second sei-zure all increase the probability of seizure recurrence.5 These three factors allow clinicians to stratify low, medium, and high risks (Table 1) and help in guiding decisions about the initiation of antiseizure medication.

Occasionally, serial seizures or status epilepticus will manifest as a first sei-zure, and these conditions may be life-threatening. The management of these conditions is described elsewhere.6

S tr ategies a nd E v idence

Diagnosis and Evaluation

Expert history taking is essential in the diagnosis of an epileptic seizure. Tele-phoning an eyewitness is often invaluable, and home video recordings of patients with frequent seizures can help in the diagnosis. Table 2 summarizes the main differential diagnoses of a first generalized tonic–clonic seizure and provides in-formation on the history taking, examination, and initial investigations. Careful

Caren G. Solomon, M.D., M.P.H., Editor

Initial Management of Seizure in AdultsPhil E.M. Smith, M.D.

This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist.

The article ends with the author’s clinical recommendations.

An audio version of this article is available at NEJM.org

The New England Journal of Medicine Downloaded from nejm.org at CCSS CAJA COSTARRICENSE DE SEGURO SOCIAL BINASSS on July 15, 2021. For personal use only. No other uses without permission.

Copyright © 2021 Massachusetts Medical Society. All rights reserved.

n engl j med 385;3 nejm.org July 15, 2021252


252

history taking can usually distinguish the three main causes of transient loss of consciousness: epileptic seizure (provoked or unprovoked), syn-cope (reflex, orthostatic, or cardiac), and psycho-genic nonepileptic seizure (which mimics a seizure but is caused by psychological distress rather than abnormal electrical activity in the brain).

Provoked seizures might follow transient cere-bral insults such as alcohol withdrawal, the use of illicit drugs such as cocaine and methamphet-amine, and metabolic disturbances (e.g., hypo-glycemia or hyponatremia). They also may sug-gest a structural cause such as hemorrhagic stroke, encephalitis, venous sinus thrombosis, or tumor.

Seizures and epilepsy are classified according to seizure type (generalized, focal, or unknown8), epilepsy type, and epilepsy syndrome.9 Table 3 and Table S1 provide common examples of each.

The presentation of a seizure depends on its site of onset (generalized or focal) and pattern of spread. Seizures can occur at any age and in any situation. In some cases, a lack of warning suggests a generalized onset, although a lack of warning is also compatible with focal-onset sei-zures, especially in the frontal lobe. In other cases (usually focal-onset seizures), there is a specific but often “indescribable” aura — such as déjà vu, an epigastric “rising” sensation, or tastes or smells — usually followed by transient altered awareness.

A convulsive seizure typically has a tonic (stiff-ening) phase and then a clonic (convulsing) phase.

Together these phases last 1 to 3 minutes, typi-cally while the patient has open eyes, apnea, and cyanosis. Patients awaken many minutes later feeling tired and achy, and they sometimes have a lateral tongue bite.

Physical examination may reveal findings that point to a cause other than seizure or a condi-tion predisposing to seizure. Attention should be paid to the skin (e.g., to detect facial angiofibro-mas, hypomelanotic macules suggestive of tuber-ous sclerosis, or scars from self-harm that are often associated with psychogenic nonepileptic seizures), the cardiovascular system (an aortic ejection murmur may indicate cardiac syncope, and postural blood-pressure changes may indi-cate orthostatic hypotension), and findings on funduscopic examination (e.g., elevated intracra-nial pressure).

Basic blood tests to measure levels of electro-lytes, glucose, calcium, and magnesium may help to identify potential causes of seizure or coexist-ing conditions. An evaluation with 12-lead electro-cardiography (ECG) is indicated in all patients (especially older adults) who have had a first seizure or unexplained blackout spell to look for evidence of previous myocardial infarction be-cause of the risk of ventricular tachycardia or of rare but potentially fatal (and often familial) disorders, including hypertrophic cardiomyopa-thy and long QT syndromes.10

Brain Imaging

Urgent brain imaging is warranted in patients who present with a first epileptic seizure. Com-

Key Clinical Points

Initial Management of Seizure in Adults

• The clinical diagnosis of an epileptic seizure requires a detailed history taking and, ideally, an eyewitness account of the seizure.

• Evaluation with 12-lead electrocardiography is essential in a patient who has had a first seizure or an unexplained blackout spell.

• In children and teenagers, interictal electroencephalography, ideally within 24 hours after a first seizure, is particularly important.

• All patients who have had a suspected focal-onset seizure should undergo detailed magnetic resonance imaging of the head.

• Patients who have had an epileptic seizure should be informed about factors that may provoke seizures (e.g., sleep deprivation and alcohol use), the risk of a seizure occurring while driving or engaging in solitary activities, and the risks of harm from further seizures.

• Data from long-term pragmatic trials suggest that the first-line medication for patients with focal-onset seizures is either lamotrigine or levetiracetam, although other reasonable options are available; for patients with generalized-onset seizures, the first choice is sodium valproate, except for women of childbearing potential, in whom the first-line medication is usually levetiracetam.




Clinical Pr actice

puted tomography is useful and widely available. However, in most adults with a first seizure (especially a focal-onset seizure) or early epilepsy, detailed magnetic resonance imaging (MRI; ideally 3-T MRI with <3-mm slice thickness on T2-weighted imaging and fluid-attenuated inver-sion recovery11) is warranted to identify more subtle underlying causes such as hippocampal sclerosis, focal cortical dysplasia, or tumor that may be treated surgically.

Electroencephalography

Interictal EEG that is performed in a patient who has had a first seizure is unlikely to capture another seizure, although the procedure may provoke psychogenic nonepileptic seizures. EEG is most informative in patients younger than 25 years of age because these patients are most likely to have subclinical interictal generalized activity that may confirm a generalized seizure tendency and that strongly predicts further sei-zures (70% positive predictive value).12,13

EEG that is performed soon after a patient has had a first seizure identifies more epilepti-form abnormalities than later EEG; one study involving 300 consecutive adults and children identified abnormalities in 51% of those who underwent EEG within 24 hours and in 34% of those who underwent EEG later.14 EEG that is performed in ambulatory or sleep-deprived pa-tients further increases the diagnostic yield in patients in whom an epileptic seizure is likely even though the routine interictal EEG findings

are normal.15 The presence of interictal epilepti-form discharges in either of these investigations increases the 1-year risk of seizure recurrence by a factor of 1.5.16

M a nagemen t

Antiseizure Medications

The medical management of epilepsy predomi-nantly involves seizure suppression with the long-term use of oral medication (Table 4 and Table S2). Antiseizure medication is primarily indicated when the risk of further spontaneous seizures is judged to exceed 60% over the next 10 years.

The aim of management is no seizures and minimal adverse effects of treatment. However, if these goals prove to be impossible, then the priority is complete control of major convulsive seizures, which are potentially dangerous because they may increase the risk of sudden unexpected death in epilepsy (SUDEP) above the estimated absolute risk among patients with epilepsy over-all (1.2 cases per 1000 patient-years).23

The initiation of long-term use of antiseizure medication is a major decision that is made by the patient and the clinician. This decision re-quires reasonable certainty of an epilepsy diag-nosis; the use of medication for a trial period in patients in whom the diagnosis is uncertain should be avoided.

The Medical Research Council Multicentre Trial for Early Epilepsy and Single Seizures24 showed that the risk of seizure recurrence was

Table 1. Probability of Another Seizure after a Single Seizure or Early Epilepsy and Recommendations for Use of Antiseizure Medications.*

Level of Risk and No. of Seizures

Neurologic Disorder or Abnormal EEG Probability of Another Seizure

Usual Recommendation for Antiseizure

Medication

By 1 yr By 3 yr By 5 yr

Low risk: 1 seizure Neither 0.19 0.28 0.30 No

Medium risk

1 Seizure Either 0.35 0.50 0.56 Consider

2–3 Seizures Neither 0.35 0.50 0.56 Consider

High risk

1 seizure Both 0.59 0.67 0.73 Yes

2–3 seizures Either 0.59 0.67 0.73 Yes

>3 seizures Neither 0.59 0.67 0.73 Yes

* Adapted from Kim et al.5 EEG denotes electroencephalogram.





Tabl

e 2.

Diff

eren

tial D

iagn

osis

of G

ener

aliz

ed T

onic

–Clo

nic

Seiz

ure

in A

dults

.*

Var

iabl

e

Gen

eral

ized

To

nic–

Clo

nic

Seiz

ure

Foca

l to

Bila

tera

l To

nic–

Clo

nic

Seiz

ure

Fron

tal-L

obe

Seiz

ure

Ref

lex

(Vas

ovag

al)

Sync

ope

Ort

host

atic

Sy

ncop

eC

ardi

ac S

ynco

pe

Psyc

hoge

nic

Non

epile

ptic

Se

izur

ePa

nic

Att

ack

Non

-REM

Pa

raso

mni

a†

Typi

cal d

emo-

grap

hic

char

-ac

teri

stic

s

Youn

g (<

25 y

r);

ofte

n no

sei

-zu

re h

isto

ry

repo

rted

(a

lthou

gh

on d

irec

t qu

estio

ning

, pa

tient

may

de

scri

be

abse

nces

, m

yocl

onus

, ph

otos

ensi

-tiv

ity, o

r al

l th

ese

sym

p-to

ms)

Any

age

; oft

en

with

pre

vi-

ousl

y un

rec-

ogni

zed

epi-

sode

s of

déj

à vu

, epi

gast

ric

“ris

ing”

sen

-sa

tion,

bla

nk

spel

ls w

ith

auto

mat

ism

(e

.g.,

lip

smac

king

and

pi

ckin

g at

cl

othe

s), a

nd

tong

ue b

iting

on

wak

ing

Any

age

, alth

ough

pa

tient

s ar

e of

ten

child

ren

(med

ian

onse

t, 14

yr)

; po

ssib

le fa

m-

ily h

isto

ry o

f fr

onta

l-lob

e se

izur

e (a

uto-

som

al d

omi-

nant

)

Youn

g; o

ften

he

alth

y, w

ith

hist

ory

of

fain

ting

Old

er a

ge, e

spe-

cial

ly in

pa-

tient

s w

ith a

u-to

nom

ic fa

il-ur

e (d

iabe

tes

or a

uton

omic

ne

urop

athy

) or

use

of v

aso-

dila

tor

med

i-ca

tions

Old

er a

ge, w

ith

vasc

ular

ris

k fa

ctor

s (e

spe-

cial

ly p

revi

ous

myo

card

ial

infa

rctio

n)

Any

age

; of-

ten

with

co

exis

ting

depr

essi

on,

pani

c di

s-or

der,

dru

g or

alc

ohol

de

pend

ence

, se

lf-ha

rm,

or a

dver

se

child

hood

ev

ents

Any

age

; pos

-si

bly

with

co

exis

ting

depr

essi

on,

anxi

ety,

dr

ug o

r al

coho

l de-

pend

ence

, se

lf-ha

rm,

or a

dver

se

child

hood

ev

ents

Youn

g; u

sual

ly

with

ons

et

in c

hild

hood

an

d re

mit-

tanc

e in

ad

oles

cenc

e;

ofte

n a

fam

-ily

his

tory

of

para

som

nia

Occ

urre

nce

in

spec

ific

situ

a-tio

ns

Usu

ally

occ

urs

with

in 1

hr

afte

r w

akin

g

May

occ

ur a

t any

tim

e, in

clud

-in

g du

ring

sl

eep

Usu

ally

occ

urs

duri

ng s

leep

Com

mon

ly s

itu-

atio

nal (

e.g.

, m

ay o

ccur

in

bath

room

or

rest

aura

nt)

and

ofte

n pr

o-vo

ked

(e.g

., w

hile

sta

nd-

ing,

with

the

sigh

t of b

lood

, af

ter

exer

tion)

May

occ

ur w

ith

stan

ding

aft

er

lyin

g do

wn

Rar

ely

situ

atio

nal,

occa

sion

ally

oc

curs

dur

ing

exer

tion

Com

mon

ly

situ

atio

nal,

espe

cial

ly

whe

n pa

tient

is

aw

ake

and

not a

lone

; of

ten

occu

rs

with

str

ess-

ful s

itua-

tions

, but

pa

tient

may

re

port

no

trig

ger

Com

mon

ly

occu

rs in

st

ress

ful

situ

atio

ns

Alw

ays

occu

rs

duri

ng s

leep

, es

peci

ally

du

ring

firs

t th

ird

of th

e ni

ght;

wor

se

with

sle

ep

depr

ivat

ion,

al

coho

l use

, an

d st

ress

War

ning

p

rodr

ome

Unc

omm

onC

omm

on, o

ccur

s w

ith p

rece

d-in

g m

inor

sei

-zu

re (

aura

)

Non

e; o

ccur

s w

hen

patie

nt

is a

slee

p

Com

mon

; pre

ced-

ing

naus

ea

is s

tron

gly

sugg

estiv

e;

occu

rs in

hot

en

viro

nmen

t, w

ith li

ghth

ead-

edne

ss, v

isua

l bl

acko

ut, o

r bo

th

Com

mon

; occ

urs

with

ligh

thea

d-ed

ness

, vis

ual

blac

kout

, or

both

Unc

omm

onC

omm

on; o

c-cu

rs w

ith

fear

, pan

ic,

and

alte

red

men

tal s

tate

, or

pat

ient

m

ay r

epor

t no

war

ning

Alm

ost i

nvar

i-ab

le; o

ccur

s w

ith fe

ar,

pani

c, a

nd

alte

red

men

-ta

l sta

te

Non

e; o

ccur

s w

hen

patie

nt

is a

slee

p




Clinical Pr actice

Var

iabl

e

Gen

eral

ized

To

nic–

Clo

nic

Seiz

ure

Foca

l to

Bila

tera

l To

nic–

Clo

nic

Seiz

ure

Fron

tal-L

obe

Seiz

ure

Ref

lex

(Vas

ovag

al)

Sync

ope

Ort

host

atic

Sy

ncop

eC

ardi

ac S

ynco

pe

Psyc

hoge

nic

Non

epile

ptic

Se

izur

ePa

nic

Att

ack

Non

-REM

Pa

raso

mni

a†

Ons

et a

nd s

igns

Sudd

en o

nset

; hi

ghly

st

ereo

typi

-ca

l: to

nic

(stif

feni

ng)

phas

e,

then

clo

nic

(con

vuls

-in

g) p

hase

, to

geth

er

last

ing

1–3

min

, typ

i-ca

lly w

ith

eyes

ope

n,

apne

a, a

nd

cyan

osis

Gra

dual

or

sud-

den

onse

t; st

ereo

typi

cal:

aura

or

fo-

cal s

eizu

re

may

pre

cede

co

nvul

sion

; in

toni

c ph

ase,

hea

d an

d ga

ze d

e-vi

atio

n to

the

side

con

tra-

late

ral t

o se

i-zu

re fo

cus,

or

“sig

n of

four

” (o

ne a

rm

exte

nded

, the

ot

her

flexe

d)

Sudd

en o

nset

; va

riab

le a

l-th

ough

hig

hly

ster

eoty

pica

l w

ithin

an

indi

vidu

al

patie

nt (

e.g.

, dr

amat

ic p

re-

sent

atio

n w

ith

scre

amin

g,

sem

ipur

pose

-fu

l mot

or

auto

mat

ism

, in

clud

ing

run-

ning

, or

asym

-m

etri

c to

nic

post

urin

g w

ith k

icki

ng

and

cycl

ing)

Gra

dual

ons

et;

brie

f los

s of

co

nsci

ous-

ness

(<1

m

in),

pal

lor,

so

met

imes

lim

b je

rks

and

post

urin

g

Gra

dual

or

sud-

den

onse

t; br

ief l

oss

of

cons

ciou

s-ne

ss (

<1

min

), p

allo

r,

som

etim

es

limb

jerk

s an

d po

stur

ing

Sudd

en o

nset

; us

ually

bri

ef

but o

ccas

ion-

ally

pro

long

ed

loss

of c

on-

scio

usne

ss,

pallo

r, a

nd

swea

ting;

so

met

imes

lim

b je

rks

and

post

urin

g

Gra

dual

ons

et;

ofte

n pr

o-lo

nged

(>2

m

in)

with

ey

es c

lose

d,

brea

thin

g an

d co

lor

mai

ntai

ned,

ra

pid

shak

-in

g (e

spe-

cial

ly h

ead

and

arm

s),

back

arc

h-in

g; fl

uctu

at-

ing

seve

rity

Gra

dual

ons

et;

vari

able

du-

ratio

n, w

ith

eyes

clo

sed,

br

eath

ing

mai

ntai

ned

or r

apid

, an

d co

lor

mai

ntai

ned

Ons

et d

ur-

ing

slee

p;

vari

able

co

mpl

exity

, no

t hig

hly

ster

eoty

pi-

cal,

last

ing

seco

nds

to 3

0 m

in;

conf

usio

nal

arou

sals

; sl

eepw

alki

ng

with

sem

i-pu

rpos

eful

be

havi

or

(e.g

., dr

ess-

ing

or e

at-

ing)

or

slee

p te

rror

s

Con

scio

usne

ss

and

resp

on-

sive

ness

Not

dur

ing

epi-

sode

Part

ial d

urin

g w

arni

ng

(aur

a) b

ut

not d

urin

g ep

isod

e

May

be

at le

ast

part

ially

re-

tain

ed

Not

dur

ing

epi-

sode

Not

dur

ing

epi-

sode

Not

dur

ing

epi-

sode

Var

iabl

e, e

ven

with

in e

pi-

sode

; stim

u-la

tion

can

term

inat

e ep

isod

e

Var

iabl

e; p

atie

nt

may

be

re-

spon

sive

Patie

nt p

oorl

y re

spon

sive

du

ring

epi

-so

de

Inco

ntin

ence

Com

mon

Com

mon

Com

mon

Occ

asio

nal

Occ

asio

nal

Occ

asio

nal

Occ

asio

nal

Rar

eR

are

Inju

ryC

omm

on, i

n-cl

udin

g la

t-er

al to

ngue

bi

ting,

faci

al

inju

ry, o

r po

ster

ior

shou

lder

di

sloc

atio

n

Com

mon

, inc

lud-

ing

late

ral

tong

ue b

it-in

g; w

arni

ng

limits

ris

k of

in

jury

Com

mon

, de-

spite

ret

aine

d aw

aren

ess

Occ

asio

nal m

inor

, ra

re to

ngue

bi

ting

Unc

omm

on (

with

w

arni

ng)

Com

mon

, inc

lud-

ing

tong

ue

bitin

g

Occ

asio

nal

tong

ue a

nd

chee

k bi

ting,

w

rist

inju

ry,

carp

et b

urn;

oc

casi

onal

di

rect

ed v

io-

lenc

e

Occ

asio

nal m

i-no

r to

ngue

an

d ch

eek

bitin

g

Unc

omm

on

Rec

over

ySl

ow; p

atie

nt is

dr

owsy

, con

-fu

sed,

and

ha

s m

uscl

e ac

hes

Slow

; pat

ient

is

dro

wsy

, co

nfus

ed, a

nd

has

mus

cle

ache

s

Rap

idR

apid

reg

aini

ng

of c

onsc

ious

-ne

ss, b

ut

patie

nt o

ften

fa

tigue

d

Oft

en r

apid

, un-

less

pat

ient

re

mai

ns in

up

righ

t pos

i-tio

n du

ring

ep

isod

e

Oft

en r

apid

Oft

en s

low

Usu

ally

rap

idPa

tient

typi

cally

re

turn

s to

sl

eep





Var

iabl

e

Gen

eral

ized

To

nic–

Clo

nic

Seiz

ure

Foca

l to

Bila

tera

l To

nic–

Clo

nic

Seiz

ure

Fron

tal-L

obe

Seiz

ure

Ref

lex

(Vas

ovag

al)

Sync

ope

Ort

host

atic

Sy

ncop

eC

ardi

ac S

ynco

pe

Psyc

hoge

nic

Non

epile

ptic

Se

izur

ePa

nic

Att

ack

Non

-REM

Pa

raso

mni

a†

Find

ings

on

exa

min

atio

n an

d in

itial

te

sts

Late

ral t

ongu

e bi

ting,

fa-

cial

inju

ry;

inte

rict

al

EEG

sho

ws

spik

e–po

lysp

ike-

and-

wav

e pa

tter

ns;

MR

I of h

ead

norm

al,

indi

cate

d pa

rtic

ular

ly

for

atyp

ical

fe

atur

es

(inc

ludi

ng

pers

iste

nce

of s

eizu

res

desp

ite u

se

of a

ntis

ei-

zure

med

i-ca

tion)

; 12

-lead

EC

G u

sed

to e

xclu

de

prop

ensi

ty

for

card

iac

arrh

ythm

ia

mim

icki

ng

seiz

ure

Late

ral t

ongu

e bi

ting,

cra

nial

sc

ars

from

pr

evio

us in

ju-

ry o

r su

rger

y,

hem

iatr

ophy

(s

ugge

stin

g m

ild c

ereb

ral

pals

y); M

RI

of h

ead

may

sh

ow u

nder

ly-

ing

stru

ctur

al

caus

e; in

-te

rict

al E

EG

may

sho

w

foca

l sha

rp,

spik

e, a

nd

slow

wav

es;

12-le

ad

ECG

use

d to

exc

lude

pr

open

sity

fo

r ca

rdia

c ar

rhyt

hmia

m

imic

king

se

izur

e

Cra

nial

sca

rs

from

pre

vi-

ous

inju

ry o

r su

rger

y; M

RI

of h

ead

may

sh

ow u

nder

ly-

ing

stru

ctur

al

caus

e; E

EG

may

sho

w

foca

l sha

rp,

spik

e, a

nd

slow

wav

es o

r m

uscl

e ar

ti-fa

ct o

nly,

eve

n du

ring

sei

-zu

res

(dee

p fo

cus)

; vid

eo

may

cap

ture

ty

pica

l eve

nt

if fr

eque

nt

Low

blo

od p

res-

sure

; bed

side

po

stur

al

bloo

d-pr

es-

sure

rea

ding

us

ually

not

ne

cess

ary

or

help

ful;

12-

lead

EC

G u

sed

to e

xclu

de

prop

ensi

ty

for

card

iac

ar-

rhyt

hmia

; he

ad-u

p til

t-ta

ble

test

(if

doub

t rem

ains

af

ter

hist

ory,

ex

amin

atio

n,

and

ECG

) m

ay

show

abr

upt

brad

ycar

dia

and

hypo

ten-

sion

aft

er

15–3

0 m

in

Bed

side

blo

od

pres

sure

de-

crea

ses

over

a

peri

od o

f a fe

w

min

utes

whi

le

patie

nt is

in

upri

ght p

osi-

tion,

with

out

com

pens

ator

y ta

chyc

ardi

a;

12-le

ad E

CG

us

ed to

ex-

clud

e pr

open

-si

ty fo

r ca

rdia

c ar

rhyt

hmia

; am

bula

tory

bl

ood-

pres

-su

re m

onito

r-in

g if

doub

t re

mai

ns

Sign

s of

con

ges-

tive

card

iac

failu

re, e

jec-

tion

syst

olic

m

urm

ur (

aor-

tic s

teno

sis

or

hype

rtro

phic

ca

rdio

myo

pa-

thy)

, or

both

; 12

-lead

EC

G

used

to id

en-

tify

prop

ensi

ty

for

card

iac

ar-

rhyt

hmia

(e

spec

ially

if

patie

nt h

as

had

prev

ious

m

yoca

rdia

l in

farc

tion)

; tr

anst

hora

cic

echo

card

io-

grap

hy u

sed

to

iden

tify

unde

r-ly

ing

stru

ctur

al

card

iac

caus

e;

cons

ider

ur

gent

car

diol

-og

y re

ferr

al

Scar

s fr

om s

elf-

harm

; car

pet

burn

s; v

ideo

of

eve

nts

if fr

eque

nt

to lo

ok fo

r gr

adua

l on

set,

long

du

ratio

n;

patie

nt h

as

eyes

clo

sed,

ra

pid

brea

th-

ing,

abs

ence

of

cya

nosi

s,

limb

thra

sh-

ing,

bac

k ar

chin

g; E

EG

may

cap

ture

ty

pica

l eve

nt

(esp

ecia

lly

with

pho

tic

stim

ulat

ion)

w

ith o

nly

icta

l mov

e-m

ent a

rtifa

ct

Patie

nt a

ppea

rs

anxi

ous;

vid

-eo

of e

vent

s if

freq

uent

to

look

for

grad

ual

onse

t, lo

ng

dura

tion;

pa

tient

ha

s pa

rtia

l aw

aren

ess,

an

xiou

s ex

pres

sion

, ey

es c

lose

d,

rapi

d br

eath

ing;

EE

G m

ay

capt

ure

typi

cal e

vent

(e

spec

ially

w

ith p

hotic

st

imul

a-tio

n) w

ith

only

icta

l m

ovem

ent

artif

act

Nor

mal

ex-

amin

atio

n;

vide

o of

ev

ents

use

d to

dis

tin-

guis

h fr

om

fron

tal-l

obe

epile

psy;

EE

G w

hile

pa

tient

is

asle

ep m

ay

capt

ure

typi

-ca

l eve

nt

* EC

G d

enot

es e

lect

roca

rdio

grap

hy, M

RI

mag

netic

res

onan

ce im

agin

g, a

nd R

EM r

apid

eye

mov

emen

t.†

Dat

a ar

e fr

om D

erry

.7

Tabl

e 2.

(Con

tinue

d.)




Clinical Pr actice

lower in the first 2 years after the first seizure among patients who received immediate initia-tion of medication (generally carbamazepine or sodium valproate) than among those who re-ceived delayed treatment pending a second sei-zure (32% vs. 39%), but earlier initiation of treat-ment did not affect longer-term seizure remission. Adverse events were significantly more common with immediate treatment than with delayed treatment (in 39% and 31% of the patients), and quality-of-life measures were similar in the two groups. Therefore, clinicians usually advise with-holding medication in patients who have had a single seizure unless the recurrence risk is par-ticularly high.4 Despite a low estimated risk of recurrence, some patients choose to receive med-

ication because they have had a particularly se-vere or injurious first seizure or because they live in areas such as the United Kingdom where a second seizure might extend the driving restric-tion from 6 months to 12 months.

Factors Guiding Medication Choice

The choice of medication should be guided by the type of seizure and epilepsy syndrome (broad-ly, valproate or levetiracetam is used in patients with generalized-onset seizures and lamotrigine or levetiracetam is used in those with focal-onset seizures) as well as by the effectiveness, adverse-event profile, and pharmacodynamic and pharma-cokinetic properties of a given drug. Coexisting conditions must also be considered. For example,

Table 3. Common Types of Seizures in Adolescents and Adults.*

Seizure Type Description and Common Examples

Generalized onset The patient’s symptoms or description of the seizure by a witness do not indi-cate an anatomical localization of the seizure. It is thought to start within and rapidly engage bilaterally distributed cerebral networks.

Motor Myoclonic seizures manifest as involuntary “jumps” of the arms, legs, or head, especially shortly after waking and with sleep deprivation; general-ized tonic–clonic seizures typically occur without warning, although they may follow myoclonic or absence seizures and are most likely to occur within 1 hr after waking and with sleep deprivation.

Nonmotor Typical absences manifest as a brief loss of awareness, with an abrupt onset and offset, provoked by hyperventilation, often with eyelid flickering, and ictal 3-Hz generalized spike-and-wave activity on EEG; atypical absences have a less abrupt onset and offset, with an atypical, generalized spike-and-wave activity on EEG that is slower (<2.5 Hz) than that in typical seizures.

Focal onset Most new-onset seizures in adults, including tonic–clonic seizures, are of focal onset. There is clinical evidence of seizure onset localized to one part of the brain, regardless of whether it subsequently involves the re-mainder of the brain. The site of onset determines the features: temporal lobe (epigastric “rising” sensation, déjà vu, and smell or taste), frontal lobe (features are often sleep-related, with adversive head turn, arm and leg jerking, and speech arrest), occipital lobe (elementary visual halluci-nations in the contralateral visual field), parietal lobe (lateralized sensory symptoms, including pain), or insular cortex (laryngeal constriction, dys-pnea, and contralateral somatosensory symptoms).

Awareness In focal-onset aware (formerly called simple partial) seizures, awareness of the self or environment is retained; in focal-onset impaired awareness (formerly called complex partial) seizures, awareness of the self or envi-ronment is impaired.

Motor features Motor seizures include automatisms (e.g., lip smacking and picking at clothes) and atonic, tonic, clonic, and myoclonic features; nonmotor seizures include autonomic, behavior arrest, cognitive, emotional, and sensory features.

Secondary generalization In focal to bilateral tonic–clonic (formerly called secondarily generalized) sei-zures, the focal seizure develops into a tonic–clonic seizure. Such seizures often first occur during sleep.

Unknown onset The origin of a seizure is often uncertain, especially after only one seizure.

* Data are from Fisher et al.8





Tabl

e 4.

Fir

st-L

ine

Ant

isei

zure

Med

icat

ions

.

Med

icat

ion

and

Indi

catio

nM

echa

nism

and

Ph

arm

acok

inet

ic P

rofil

eD

ose

in A

dults

Adv

erse

Eff

ects

Inte

ract

ions

Com

men

ts

Lam

otri

gine

(La

mic

tal)

fo

r fo

cal-o

nset

sei

-zu

res17

, 18 ;

effe

ctiv

e fo

r ge

nera

lized

-ons

et

toni

c–cl

onic

sei

zure

s bu

t may

exa

cerb

ate

myo

clon

us a

nd a

b-se

nces

Stab

ilize

s vo

ltage

-dep

ende

nt s

o-di

um c

hann

els;

50%

pro

tein

-bo

und;

met

abol

ized

in li

ver;

ha

lf-lif

e of

12–

60 h

r

Mon

othe

rapy

: sta

rt 2

5 m

g da

ily (

intr

oduc

e sl

owly

to a

void

ra

sh);

initi

al m

ain-

tena

nce

ther

apy,

10

0–20

0 m

g da

ily, i

n 1

or 2

dos

es

Dos

e-re

late

d ef

fect

s: d

row

sine

ss,

inso

mni

a, h

eada

che,

dip

lopi

a;

idio

sync

ratic

effe

ct: r

ash

(in

ap-

prox

imat

ely

3.5%

of p

atie

nts19

) so

met

imes

sev

ere

in c

hild

ren

(Ste

vens

–Joh

nson

syn

drom

e),

espe

cial

ly w

hen

take

n w

ith

valp

roat

e; te

rato

geni

city

: dos

e-re

late

d lo

w r

isk

of m

ajor

mal

-fo

rmat

ions

and

ora

l cle

fts

Effe

ct o

n ot

her

agen

ts:

incr

ease

s ca

rbam

aze-

pine

epo

xide

(di

zzi-

ness

, dip

lopi

a); w

ith

high

er d

oses

(>3

00 m

g da

ily),

low

ers

cont

ra-

cept

ive

pill

conc

entr

a-tio

n (u

ncer

tain

mec

ha-

nism

) bu

t no

defin

ite

evid

ence

of c

ontr

acep

-tio

n fa

ilure

; effe

ct o

f ot

her

agen

ts: v

alpr

oate

in

hibi

ts it

s m

etab

o-lis

m, s

o th

at o

nly

half

the

usua

l dos

e of

va

lpro

ate

is n

eces

sary

; ho

rmon

al c

ontr

acep

-tiv

es a

nd p

regn

ancy

lo

wer

its

conc

entr

a-tio

n, p

oten

tially

with

br

eakt

hrou

gh s

eizu

res

Slow

ly in

trod

uced

to a

void

ras

h,

so th

erap

eutic

dos

e no

t re

ache

d fo

r 4–

6 w

k, a

nd a

ddi-

tiona

l ant

isei

zure

med

icat

ion

may

be

war

rant

ed in

that

tim

e;

impo

rtan

t int

erac

tions

with

ot

her

antis

eizu

re m

edic

atio

ns

(not

ably

val

proa

te o

r ca

rbam

-az

epin

e) w

arra

nt d

ose

adju

st-

men

ts; d

ata

supp

ort s

afet

y in

pre

gnan

cy (

earl

y co

ncer

n re

gard

ing

incr

ease

d ri

sk o

f cl

eft d

efec

t not

sup

port

ed b

y su

bseq

uent

stu

dies

); s

erum

co

ncen

trat

ion

decr

ease

s in

pr

egna

ncy,

so

cons

ider

mea

-su

ring

ser

um c

once

ntra

tion

and

tem

pora

ry d

ose

incr

ease

s to

avo

id b

reak

thro

ugh

sei-

zure

s

Leve

tirac

etam

(K

eppr

a,

Row

eepr

a, a

nd

Spri

tam

) fo

r fo

cal-

onse

t sei

zure

s18, 2

0 or

gene

raliz

ed-o

nset

se

izur

es21

; fir

st-li

ne

trea

tmen

t for

foca

l-on

set s

eizu

res

in

sele

cted

pat

ient

s an

d fo

r ge

nera

lized

-ons

et

seiz

ures

in w

omen

of

chi

ldbe

arin

g po

-te

ntia

l

Bin

ds to

syn

aptic

ves

icle

gly

-co

prot

ein

2A; n

ot p

rote

in-

boun

d; n

ot m

etab

oliz

ed in

liv

er; e

xcre

ted

by k

idne

ys

larg

ely

unch

ange

d; h

alf-l

ife

of 6

–8 h

r

Star

t 250

mg

daily

; in

itial

mai

nten

ance

th

erap

y, 1

000–

2000

m

g da

ily d

ivid

ed in

to

2 do

ses

Dos

e-re

late

d ef

fect

: fat

igue

; idi

o-sy

ncra

tic e

ffect

s: ir

rita

bilit

y,

anxi

ety,

and

moo

d ch

ange

s;

tera

toge

nici

ty: l

ow r

isk

of m

ajor

m

alfo

rmat

ions

Effe

ct o

n ot

her

agen

ts:

no m

ajor

effe

cts,

but

m

onito

r fo

r to

xic

ef-

fect

s (e

.g.,

doub

le

visi

on a

nd d

izzi

ness

) if

adde

d to

car

ba-

maz

epin

e; e

ffect

of

othe

r ag

ents

: no

maj

or

effe

cts

Effe

ctiv

e fo

r bo

th fo

cal-o

nset

and

ge

nera

lized

-ons

et s

eizu

res;

th

erap

eutic

dos

e ac

hiev

ed

quic

kly,

so

wid

ely

used

for

rapi

d se

izur

e co

ntro

l; no

med

i-ca

tion

inte

ract

ions

, so

suita

ble

for

patie

nts

rece

ivin

g ot

her

med

icat

ions

(e.

g., w

arfa

rin)

; da

ta s

uppo

rt g

ood

safe

ty p

ro-

file

in p

regn

ancy




Clinical Pr actice

patients with substantial anxiety may prefer lamo-trigine over levetiracetam, whereas those with obesity or migraines may choose topiramate, which can suppress appetite and reduce the in-cidence of headaches. An overriding consider-ation for women is the effects of medication on potential pregnancy.

Although a detailed discussion of the use of antiseizure medication in women who may become pregnant is beyond the scope of this article, so-dium valproate carries high risks in pregnancy. Approximately 10% of babies exposed to sodium valproate in utero have major congenital anoma-lies,25 and up to 40% have measurable neurode-velopmental delay.26 In the European Registry of Antiepileptic Drugs and Pregnancy (EURAP) Study Group prospective study involving 7555 preg-nancies,27 10.3% of the infants had major con-genital malformations after in utero exposure to valproate, 5.5% had these malformations after exposure to carbamazepine, 3.9% after topira-mate, 3.0% after oxcarbazepine, 2.9% after lamo-trigine, and 2.8% after levetiracetam (as com-pared with a 2.6% risk among infants who had not been exposed in utero to antiseizure medica-tion28). The possible contribution of maternal seizures to the risks of congenital anomalies and neurodevelopmental delay remains unclear.

The EURAP study also showed that major congenital malformations associated with valpro-ate were dose-related and included cardiac defects and hypospadias, each of which was found in 2% of infants with exposure to valproate; cleft lip; gastrointestinal, renal, and neural-tube de-fects; and polydactyly. Cognitive assessments in 6-year-old children who had had in utero expo-sure to valproate showed significant dose-related inverse associations with IQ, verbal ability, and nonverbal ability; these effects were not observed in children with in utero exposure to other anti-seizure medications.26 Thus, valproate should generally be avoided in women of childbearing potential; if valproate is used, effective measures should be taken to prevent pregnancy unless the woman is fully informed about the risks. As part of a licensing requirement since 2018 in the United Kingdom and the European Union, wom-en who receive valproate must use highly reliable contraception (a hormonal implant or an intra-uterine device) or undergo monthly pregnancy tests, and they must sign an annual risk-acknowl-edgment form.29

Med

icat

ion

and

Indi

catio

nM

echa

nism

and

Ph

arm

acok

inet

ic P

rofil

eD

ose

in A

dults

Adv

erse

Eff

ects

Inte

ract

ions

Com

men

ts

Sodi

um v

alpr

o-at

e, v

alpr

oic

acid

(D

epak

ene,

D

epak

ote,

Epi

lim,

and

Stav

zor)

for

gene

raliz

ed-o

nset

se

izur

es (

exce

pt in

w

omen

of c

hild

bear

-in

g po

tent

ial)

21, 2

2 ; al

so e

ffect

ive

for

foca

l-ons

et s

eizu

res

but n

ot w

idel

y us

ed

for

this

indi

catio

n

Incr

ease

s γ-

amin

obut

yric

aci

d co

ncen

trat

ion

(unc

erta

in

mec

hani

sm);

90%

pro

tein

-bo

und;

met

abol

ized

in li

ver;

ha

lf-lif

e of

12–

17 h

r, b

ut

ther

apeu

tic e

ffect

long

er

Star

t 200

–500

mg

daily

; in

itial

mai

nten

ance

th

erap

y, 5

00–1

500

mg

daily

, in

1 or

2

dose

s

Dos

e-re

late

d ef

fect

s: g

astr

oint

es-

tinal

ups

et, t

rem

or, i

rrita

bil-

ity, p

oor

slee

p, c

onfu

sion

; id

iosy

ncra

tic e

ffect

s: h

air

loss

, w

eigh

t gai

n, p

olyc

ystic

ova

ries

, hy

pera

mm

onem

ia (

occu

lt ur

ea-

cycl

e di

sord

ers)

, hep

atot

oxic

ef

fect

s (e

spec

ially

in c

hild

ren

with

PO

LG1

mut

atio

ns o

r th

e A

lper

s sy

ndro

me

[in 1

/50,

000

child

ren]

); h

igh

risk

of t

erat

o-ge

nici

ty: m

ajor

mal

form

atio

ns,

incl

udin

g sp

ina

bifid

a, in

up

to

10%

of i

nfan

ts, n

euro

deve

lop-

men

tal d

elay

iden

tifia

ble

in u

p to

40%

of c

hild

ren

Effe

ct o

n ot

her

agen

ts:

enzy

me

inhi

bitio

n in

crea

ses

lam

otri

gine

co

ncen

trat

ion

(car

e in

com

bina

tion)

, in

crea

ses

carb

amaz

e-pi

ne-1

0,11

-epo

xide

co

ncen

trat

ion,

and

in

crea

ses

seda

tion

with

alc

ohol

; pro

tein

-bo

und

disp

lace

men

t in

crea

ses

free

con

cen-

trat

ion

of o

ther

med

i-ca

tions

(e.

g., w

arfa

rin)

; ef

fect

of o

ther

age

nts:

en

zym

e-in

duci

ng m

ed-

icat

ions

low

er to

tal v

al-

proa

te c

once

ntra

tion

(e.g

., ca

rbam

azep

ine,

ph

enyt

oin)

; pro

tein

-bo

und

med

icat

ions

(e

.g.,

aspi

rin)

dis

plac

e an

d in

crea

se fr

ee v

al-

proa

te c

once

ntra

tion

Hig

hly

effe

ctiv

e fo

r ge

nera

lized

-on

set s

eizu

res,

but

pow

erfu

l te

rato

geni

city

and

neu

rode

-ve

lopm

enta

l del

ay s

ever

ely

limit

its u

se in

you

ng w

omen

; en

zym

e in

hibi

tor,

so

use

cau-

tion

with

alc

ohol

and

oth

er

med

icat

ions

met

abol

ized

by

the

liver

; con

trai

ndic

ated

in

patie

nts

with

som

e m

itoch

on-

dria

l dis

ease

s (l

iver

failu

re

may

occ

ur in

pat

ient

s w

ith

POLG

1 m

utat

ions

)





Data from pregnancy registries have shown no consistent safety signals for lamotrigine or leve-tiracetam30 and no clear evidence of neurodevel-opmental delay associated with these agents.31 In observational studies, maternal folate supple-mentation has been associated with a reduced risk of neurocognitive abnormalities among ba-bies with in utero exposure to antiseizure medi-cations,32 and such supplements are routinely recommended in women who may become preg-nant while receiving such medication.

Effectiveness of Medications

A single-center observational study involving 525 patients with epilepsy of various types showed that approximately half became seizure-free for at least 1 year after they began to receive a first antiseizure medication.33 Many randomized, con-trolled trials of the efficacy of new antiseizure medications have assessed their use as add-on medications in patients with treatment-resistant epilepsy. In these short-term trials, these new medications reduced the frequency of seizures 2 to 4 times more than placebo34 but often at doses that were higher than those generally used in practice.

The management of epilepsy, which is a long-term condition, is largely informed by the Stan-dard and New Antiepileptic Drugs (SANAD) trials, which involved long-term, head-to-head, unblinded comparisons of existing standard agents with newer medications. The first SANAD trial involving patients with generalized and un-classified epilepsies compared valproate (then the standard of care) with lamotrigine or topira-mate and showed the superiority of valproate over topiramate with respect to treatment failure and the superiority over lamotrigine with respect to 12-month remission.22 For focal epilepsies, lamotrigine was superior to carbamazepine (then the standard of care), gabapentin, and topira-mate with respect to treatment failure and was noninferior to carbamazepine with respect to 12-month remission.17 More recently, the SANAD II trial involving patients with generalized and unclassified epilepsies did not show noninferior-ity of levetiracetam to valproate with respect to 12-month remission; valproate resulted in a high-er incidence of 12-month remission (36% vs. 26%) and a similar incidence of adverse events, and it was more cost-effective.21 For focal epilep-sies, zonisamide but not levetiracetam was non-

inferior to lamotrigine with respect to 12-month remission; however, as compared with both leve-tiracetam and zonisamide, lamotrigine resulted in lower incidences of treatment failure and ad-verse events, and it was more cost-effective.18

Thus, the first-line medication for patients with generalized-onset seizures is sodium val-proate, or levetiracetam for girls and women of childbearing potential. For patients with focal-onset seizures, lamotrigine is usually the first-line medication, although levetiracetam or other agents may have advantages in some patients (Table 4 and Fig. S2).

The main disadvantage of lamotrigine is its low starting dose, with increases to the full treatment dose over a period of several weeks. This gradual dose adjustment is necessary to re-duce the risk of the Stevens–Johnson syndrome and toxic epidermal necrolysis (from 1.0% to approximately 0.01 to 0.10%)35; initial coverage with another antiseizure medication may be war-ranted. The main adverse effects of levetiracetam are irritability and anxiety, especially in patients with preexisting anxiety.

Lifestyle Factors

Clinicians should engage in joint decision mak-ing with patients and share verbal and written information. Information on driving eligibility is particularly important. In the United Kingdom and the European Union, a 6-month driving re-striction is mandated for patients who have had a single seizure with a low risk of recurrence, and a 12-month restriction is mandated for pa-tients with epilepsy, including those who have had a single seizure and who have a high risk of recurrence (e.g., those with an abnormal EEG, neurologic deficit, or both). In the United States, eligibility for a driver’s license in persons who have had a single seizure or in those with epilepsy varies among states,36 although the rules are generally less restrictive than those in Europe.

Advice from clinicians regarding other activi-ties depends on the characteristics and frequency of the patient’s seizures; these factors are bal-anced against individual priorities. Clinicians should inform patients of the risks associated with seizures, including drowning and SUDEP; the likelihood of seizure recurrence (Table 1); and suggested lifestyle modifications (e.g., avoid-ing being alone during certain activities such as caring for children or bathing, so that another




Clinical Pr actice

person can help if a seizure occurs, and appreci-ating the risks of ladders and heights).

Patients should be encouraged to adhere to the regimen of antiseizure medication and a regular sleep schedule and to limit the use of alcohol. Considerable observational data provide support for a relationship between insufficient sleep and seizure risk or abnormal EEG activ-ity.37 A short-term randomized trial38 involving 84 patients with medication-resistant focal epi-lepsy in whom the dose of antiseizure medica-tion was being tapered showed no significant differences in seizure frequency between the group of patients with sleep deprivation and the control group. However, these trial findings may not be applicable to patients with early epilepsy, and the promotion of sleep hygiene in patients with epilepsy remains prudent. Alcohol use is an important seizure precipitant, mainly because of the risk of seizure during alcohol withdrawal and the tendency of alcohol to disrupt sleep, interfere with adherence to antiseizure medica-tions, or both. A meta-analysis of observational studies showed a dose–response relationship be-tween the amount of alcohol consumed daily and the probability of development of epilepsy; for an average of 4, 6, and 8 drinks daily, the relative risks were 1.81 (95% confidence interval [CI], 1.59 to 2.07), 2.44 (95% CI, 2.00 to 2.97), and 3.27 (95% CI, 2.52 to 4.26).39 Alcohol absti-nence is probably unnecessary, but consumption should be limited to modest amounts. Illicit drugs that disrupt sleep, especially cocaine and amphetamine, should be avoided, but high-quality data on the recreational use of cannabis in persons with epilepsy are lacking.

A r e a s of Uncerta in t y

The clinical diagnosis of epilepsy may be incor-rect in up to 20% of patients40 unless episodes are captured on EEG with video. Many patients with a diagnosis of epilepsy are later recognized to have psychogenic seizures, and additional psychogenic seizures may later develop in per-sons with established epilepsy. Clinicians must repeatedly question the diagnosis in patients with medication-resistant epilepsy.

The potential long-term effects of new anti-seizure medications, which are typically pre-scribed as lifelong treatments, warrant further study. Notoriously, for 8 years after licensing,

vigabatrin was used worldwide to manage sei-zures until it was recognized that long-term use of this agent caused permanent visual-field defects in more than half of patients.41 Data are lacking to inform pregnancy and offspring out-comes associated with new antiseizure medica-tions; several worldwide pregnancy registries regularly update clinicians on the teratogenicity of these agents (Table S3).30

Genetic characterization has enabled both targeting of more effective treatments for some complex epilepsies (e.g., stiripentol for the Dra-vet syndrome42 and a ketogenic diet for glucose transporter type 1 deficiency syndrome43) and screening for the HLA-B*1502 allele in Han Chi-nese populations to predict the carbamazepine-induced Stevens–Johnson syndrome.44 Further understanding of the effect of genetic factors on the risk of recurrent seizures and on the efficacy and risks of various medications is needed to guide treatment decisions.

Guidelines

In 2015, the American Academy of Neurology and the American Epilepsy Society provided joint guidelines on the management of unprovoked first seizure in adults.2 The 2012 guidelines45 of the National Institute for Health and Care Excel-lence in the United Kingdom are undergoing revision. The current recommendations differ from these older guidelines with respect to spe-cific medications recommended, since the re-sults of the SANAD II trial were published after these guidelines were issued.

Conclusions a nd R ecommendations

In the patient described in the vignette, the first generalized tonic–clonic seizure developed after sleep loss and alcohol use. Careful questioning revealed that this was an isolated event, with no previous myoclonic jerks or absences. Evaluation should include MRI of the head, interictal EEG, and 12-lead ECG. I would discuss with the pa-tient lifestyle factors such as the importance of regular sleep and limiting alcohol consumption, the risks associated with seizures (including drowning and SUDEP), and driving eligibility. Antiseizure medications are not routinely recom-mended for patients who have had a single seizure;





however, if interictal EEG showed spike-and-wave activity, indicating a high risk of recurrent seizure, I would recommend initiation of an antiseizure medication. Provided that this pa-tient did not have depression or anxiety, I would favor levetiracetam administered with a folate supplement since the patient is of childbearing

potential. I would arrange follow-up in 2 months to review the patient’s response and adherence to the medication regimen and any adverse effects.

No potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

References1. Hauser WA, Beghi E. First seizure definitions and worldwide incidence and mortality. Epilepsia 2008; 49: Suppl 1: 8-12.2. Krumholz A, Wiebe S, Gronseth GS, et al. Evidence-based guideline: manage-ment of an unprovoked first seizure in adults: report of the guideline develop-ment subcommittee of the American Acad-emy of Neurology and the American Epi-lepsy Society. Neurology 2015; 84: 1705-13.3. Fiest KM, Sauro KM, Wiebe S, et al. Prevalence and incidence of epilepsy: a systematic review and meta-analysis of international studies. Neurology 2017; 88: 296-303.4. Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014; 55: 475-82.5. Kim LG, Johnson TL, Marson AG, Chadwick DW. Prediction of risk of sei-zure recurrence after a single seizure and early epilepsy: further results from the MESS trial. Lancet Neurol 2006; 5: 317-22.6. Jones S, Pahl C, Trinka E, Nashef L. A protocol for the inhospital emergency drug management of convulsive status epilepticus in adults. Pract Neurol 2014; 14: 194-7.7. Derry CP. Sleeping in fits and starts: a practical guide to distinguishing noc-turnal epilepsy from sleep disorders. Pract Neurol 2014; 14: 391-8.8. Fisher RS, Cross JH, French JA, et al. Operational classification of seizure types by the International League Against Epi-lepsy: position paper of the ILAE Com-mission for Classification and Terminol-ogy. Epilepsia 2017; 58: 522-30.9. Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epi-lepsia 2017; 58: 512-21.10. Brugada P, Geelen P. Some electrocar-diographic patterns predicting sudden cardiac death that every doctor should recognize. Acta Cardiol 1997; 52: 473-84.11. Duncan JS. Brain imaging in epilepsy. Pract Neurol 2019; 19: 438-43.12. Collins S, Iansek R. A prospective study of the predictive value of electroen-cephalographic abnormalities for epilep-tic loss of consciousness. Clin Exp Neurol 1988; 25: 103-8.13. Hauser WA, Rich SS, Annegers JF, An-

derson VE. Seizure recurrence after a 1st unprovoked seizure: an extended follow-up. Neurology 1990; 40: 1163-70.14. King MA, Newton MR, Jackson GD, et al. Epileptology of the first-seizure pre-sentation: a clinical, electroencephalo-graphic, and magnetic resonance imag-ing study of 300 consecutive patients. Lancet 1998; 352: 1007-11.15. Geut I, Weenink S, Knottnerus ILH, van Putten MJAM. Detecting interictal dis-charges in first seizure patients: ambula-tory EEG or EEG after sleep deprivation? Seizure 2017; 51: 52-4.16. Koutroumanidis M, Bruno E. Epilep-tology of the first tonic-clonic seizure in adults and prediction of seizure recur-rence. Epileptic Disord 2018; 20: 490-501.17. Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effective-ness of carbamazepine, gabapentin, lamo-trigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369: 1000-15.18. Marson A, Burnside G, Appleton R, et al. The SANAD II study of the effective-ness and cost-effectiveness of levetirace-tam, zonisamide, or lamotrigine for new-ly diagnosed focal epilepsy: an open-label, non-inferiority, multicentre, phase 4, ran-domised controlled trial. Lancet 2021; 397: 1363-74.19. Mani R, Monteleone C, Schalock PC, Truong T, Zhang XB, Wagner ML. Rashes and other hypersensitivity reactions asso-ciated with antiepileptic drugs: a review of current literature. Seizure 2019; 71: 270-8.20. Brodie MJ, Perucca E, Ryvlin P, Ben-Menachem E, Meencke HJ; Levetiracetam Monotherapy Study Group. Comparison of levetiracetam and controlled-release car-bamazepine in newly diagnosed epilepsy. Neurology 2007; 68: 402-8.21. Marson A, Burnside G, Appleton R, et al. The SANAD II study of the effective-ness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial. Lancet 2021; 397: 1375-86.22. Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilep-

sy: an unblinded randomised controlled trial. Lancet 2007; 369: 1016-26.23. Sveinsson O, Andersson T, Mattsson P, Carlsson S, Tomson T. Clinical risk fac-tors in SUDEP: a nationwide population-based case-control study. Neurology 2020; 94(4): e419-e429.24. Marson A, Jacoby A, Johnson A, et al. Immediate versus deferred antiepileptic drug treatment for early epilepsy and sin-gle seizures: a randomised controlled trial. Lancet 2005; 365: 2007-13.25. Weston J, Bromley R, Jackson CF, et al. Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane Data-base Syst Rev 2016; 11: CD010224.26. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol 2013; 12: 244-52.27. Tomson T, Battino D, Bonizzoni E, et al. Comparative risk of major congeni-tal malformations with eight different anti-epileptic drugs: a prospective cohort study of the EURAP registry. Lancet Neurol 2018; 17: 530-8.28. Veroniki AA, Cogo E, Rios P, et al. Comparative safety of anti-epileptic drugs during pregnancy: a systematic review and network meta-analysis of congenital malformations and prenatal outcomes. BMC Med 2017; 15: 95.29. New measures to avoid valproate ex-posure in pregnancy endorsed. European Medicines Agency. July 6, 2018 (https://www . ema . europa . eu/ en/ medicines/ human/ referrals/ valproate - related - substances - 0).30. Tomson T, Battino D, Craig J, et al. Pregnancy registries: differences, similari-ties, and possible harmonization. Epilep-sia 2010; 51: 909-15.31. Baker GA, Bromley RL, Briggs M, et al. IQ at 6 years after in utero exposure to antiepileptic drugs: a controlled cohort study. Neurology 2015; 84: 382-90.32. Meador KJ, Pennell PB, May RC, et al. Effects of periconceptional folate on cog-nition in children of women with epilep-sy: NEAD study. Neurology 2020; 94(7): e729-e740.33. Kwan P, Brodie MJ. Early identifica-tion of refractory epilepsy. N Engl J Med 2000; 342: 314-9.34. Marson AG, Kadir ZA, Chadwick DW.




Clinical Pr actice

New antiepileptic drugs: a systematic re-view of their efficacy and tolerability. BMJ 1996; 313: 1169-74.35. Mockenhaupt M, Messenheimer J, Ten-nis P, Schlingmann J. Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptics. Neurology 2005; 64: 1134-8.36. State driving laws database. Epilepsy Foundation (https://www . epilepsy . com/ driving - laws/ 2008801/ 2008731).37. Rossi KC, Joe J, Makhija M, Golden-holz DM. Insufficient sleep, electroen-cephalogram activation, and seizure risk: re-evaluating the evidence. Ann Neurol 2020; 87: 798-806.38. Malow BA, Passaro E, Milling C,

Minecan DN, Levy K. Sleep deprivation does not affect seizure frequency during inpatient video-EEG monitoring. Neurol-ogy 2002; 59: 1371-4.39. Samokhvalov AV, Irving H, Mohapatra S, Rehm J. Alcohol consumption, unpro-voked seizures, and epilepsy: a systematic review and meta-analysis. Epilepsia 2010; 51: 1177-84.40. Chadwick D, Smith D. The misdiag-nosis of epilepsy. BMJ 2002; 324: 495-6.41. Maguire MJ, Hemming K, Wild JM, Hutton JL, Marson AG. Prevalence of vi-sual field loss following exposure to viga-batrin therapy: a systematic review. Epi-lepsia 2010; 51: 2423-31.42. Frampton JE. Stiripentol: a review in

Dravet syndrome. Drugs 2019; 79: 1785-96.43. Kass HR, Winesett SP, Bessone SK, Turner Z, Kossoff EH. Use of dietary ther-apies amongst patients with GLUT1 defi-ciency syndrome. Seizure 2016; 35: 83-7.44. Ferrell PB Jr, McLeod HL. Carbamaze-pine, HLA-B*1502 and risk of Stevens-Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations. Pharmacogenomics 2008; 9: 1543-6.45. Epilepsies: diagnosis and manage-ment clinical guideline. National Insti-tute for Health and Care Excellence. Janu-ary 11, 2012 (www . nice . org . uk/ guidance/ cg137).Copyright © 2021 Massachusetts Medical Society.

images in clinical medicine

The Journal welcomes consideration of new submissions for Images in Clinical Medicine. Instructions for authors and procedures for submissions can be found on the Journal’s website at NEJM.org. At the discretion of the editor, images that

are accepted for publication may appear in the print version of the Journal, the electronic version, or both.



Initial Management of Seizure in Adults - BINASSS

Documents

Transcript of Initial Management of Seizure in Adults - BINASSS