Inna e and adap i e immuni y in human epilepsies
*Jan Baue , †Albe J. Becke , ‡§Wassim Elyaman, ¶Jukka Pel ola, #S ephan R€
uegg,
**Maa en J. Ti ulae , ††James A. Va ley, and ‡‡E o e Beghi
Epilepsia, 58(Suppl. 3):57–68, 2017
doi: 10.1111/epi.13784
D . Jan Baue ,
Depa men o
Neu oimmunology,
Cen e o B ain
Resea ch, Medical
Uni e si y o Vienna,
Vienna, Aus ia.
SUMMARY
In lamma o y mechanisms ha e been inc easingly implica ed in he o igin o sei-
zu es and epilepsy. These mechanisms a e in ol ed in he genesis o encephali ides
in which seizu es a e a common complain . Expe imen al and clinical e idence
sugges s di e en in lamma o y esponses in he b ains o pa ien s wi h epilepsy
depending on he e iology. In gene al, ac i a ion o bo h inna e and adap i e
immuni y plays a ole in e ac o y o ms o epilepsy. Epilepsies in which seizu es
de elop a e in il a ion o cells o he adap i e immune sys em in he cen al ne -
ous sys em (CNS) include a b oad ange o epilep ic diso de s wi h di e en
(known o unknown) e iologies. In il a ion o lymphocy es is obse ed in au oim-
mune epilepsies, especially he classical pa aneoplas ic encephali ides wi h an ibod-
ies agains in acellula umo an igens. The p esence o lymphocy es in he CNS
also has been ound in ocal ce eb al dysplasia ype 2 and in co ical ube s. Va i-
ous au oan ibodies ha e been shown o be associa ed wi h empo al lobe epilepsy
(TLE) and hippocampal scle osis o unknown e iology, which may be due o he
p esence o i al DNA. Du ing he las decade, an inc easing numbe o an ineu-
onal au oan ibodies di ec ed agains memb anous epi opes ha e been disco e ed
and a e associa ed wi h a ious neu ologic synd omes, including limbic encephali-
is. A majo challenge in epilepsy is o de ine bioma ke s, which would allow he
ecogni ion o pa ien popula ions who migh bene i om immune-modula o y
he apies. Some pe iphe al in lamma o y ma ke s appea o be di e en ially
exp essed in pa ien s wi h medically con olled and medically e ac o y and, as
such, could be used o diagnos ic, p ognos ic, o he apeu ic pu poses. Es ablish-
ing an au oimmune basis in pa ien s wi h d ug- esis an epilepsy allows o e ica-
cious and a ge ed immuno he apy. Al hough cu en immuno he apies can gi e
g ea bene i o he co ec ly iden i ied pa ien , he e a e limi a ions o hei e i-
cacy and hey may ha e conside able side e ec s. Thus he iden i ica ion o new
immunomodula o y compounds emains o u mos impo ance.
KEY WORDS: Inna e immuni y, Adap i e immuni y, Epilepsy, Au oan ibodies,
Encephali ides, Immunomodula o y d ugs.
Accep ed Ma ch 24, 2017.
*Depa men o Neu oimmunology, Cen e o B ain Resea ch Medical Uni e si y o Vienna, Vienna, Aus ia; †Sec ion o T ansla ional Epilepsy
Resea ch, Depa men o Neu opa hology, Uni e si y o Bonn - Medical Cen e , Bonn, Ge many; ‡B igham and Women’s Hospi al and Ha a d Medical
School, Bos on, Massachuse s, U.S.A.; §The B oad Ins i u e, Camb idge, Massachuse s, U.S.A.; ¶Depa men Neu ology, Tampe e Uni e si y Hospi al,
Tampe e, Finland; #Depa men Neu ology, Uni e si y Hospi al Basel, Basel, Swi ze land; **Depa men Neu ology, E asmus Uni e si y Medical Cen e ,
Ro e dam, The Ne he lands; ††Nu ield Depa men Clinical Neu osciences, John Radcli e Hospi al, Ox o d, Uni ed Kingdom; and ‡‡IRCCS-Ma io
Neg i Ins i u e o Pha macological Resea ch, Milano, I aly
Add ess Co espondence o Jan Baue , Depa men o Neu oimmunology, Cen e o B ain Resea ch, Medical Uni e si y Vienna, Spi algasse 4, Vienna
A-1090, Aus ia. E-mail: [email p o ec ed] and E o e Beghi, Depa men o Neu oscience, IRCCS-Ma io Neg i Ins i u e o Pha macological
Resea ch, Via Giuseppe La Masa 19, Milan 20156, I aly. E-mail: e o e.beghi@ma ioneg i.i
©2017 The Au ho s. Epilepsia published by Wiley Pe iodicals, Inc. on behal o In e na ional League Agains Epilepsy.
This is an open access a icle unde he e ms o he C ea i e Commons A ibu ion License, which pe mi s use, dis ibu ion and ep oduc ion in any med-
ium, p o ided he o iginal wo k is p ope ly ci ed.
57
IMMUNITY AND INFLAMMATION IN EPILEPSY (IIE2016)
Immune mechanisms ha e been disco e ed in se e al
neu ologic diseases, some o hem associa ed wi h epi-
lepsy.
1
These mechanisms a e no only p esen in epilepsies
caused by in ec ious and cen al ne ous sys em (CNS)
in lamma o y diseases,
2,3
bu also in epilep ic diso de s no
associa ed wi h a clea in lamma o y pa hophysiology.
4
The
exac ole o he in lamma o y phenomena (cause, e ec , o
bo h) is a ma e o in ense in es iga ion. Rapid ac i a ion
o p oin lamma o y cy okines and dange signals is
obse ed a e acu e epilep ogenic b ain inju ies o a e sin-
gle and ecu en seizu es in bo h expe imen al and clinical
se ings. On he o he hand, he e is e idence o ch onic
o e p oduc ion o cy okines and o he in lamma o y media-
o s du ing epilep ogenesis in animal models, implica ing a
neu omodula o y ole o in lamma ion and i s po en ial
in ol emen in he gene a ion o spon aneous seizu es. The
con ibu ions summa ized in his a icle in es iga e he ole
o immune mechanisms based on he esul s o ecen and
ongoing expe imen s o help imp o e ou unde s anding o
hei ole in epilepsy.
Inna e Immuni y in Epilep ic
Diso de s
(Jan Baue , Jukka Pel ola)
The e is e idence suppo ing ha se e al in lamma o y
media o s ha e a speci ic ole in empo al lobe epilepsy
(TLE) o in neoco ical epilepsies associa ed wi h ocal
mal o ma ions. Rapid ac i a ion o p oin lamma o y
cy okines, such as in e leukin-1b(IL-1b), in e leukin-6
(IL-6), and umo nec osis ac o -a(TNF-a), and dange
signals, such as high mobili y g oup box 1 (HMGB1)-ac i-
a ing in lammasomes ia Toll-like ecep o s (TLRs), is
obse ed a e acu e and ch onic seizu es in animal models
o acqui ed epilepsies.
5
B ain- esiden inna e immune cells
such as mic oglia as well as as ocy es a e pi o al gene a-
o s o his in lamma o y esponse. The e is also e idence
o ch onic o e p oduc ion o hese molecules and o he
in lamma o y media o s (e.g., cyclooxygenase-2,
p os aglandins, complemen sys em componen s, and
immunop o easomes) in bo h glial cells and neu ons, and
in cellula componen s o he blood–b ain ba ie , in
pa ien s wi h TLE o mal o ma ions o co ical de elop-
men , sugges ing a neu omodula o y ole o in lamma ion
in epilepsy. Indeed, hese in lamma o y media o s we e
shown o play a ole in he mechanisms o seizu es and
epilep ogenesis in animal models.
6–10
In pa icula , he
p esence o IL-1band HMGB1 has been shown in b ains
o pa ien s wi h a ious epilep ic diso de s, such as TLE
and ocal co ical dysplasia (FCD).
6,11,12
In addi ion o he
local o ma ion o seizu e-inducing molecules in he CNS,
molecules such as IL-1b, TNF-a, and IL-6 also migh en e
he b ain om he blood. Fo his o happen, a b each in
he blood–b ain ba ie (BBB) is necessa y, and hus sei-
zu e induc ion by pe iphe al molecules only can play a ole
in diso de s whe e he BBB is opened. In gene al, s udies
on human epilep ic b ain show he p esence o ul as uc-
u al changes and abno mal igh junc ions o ascula u e
endo helial cells, indica ing a b each in he BBB and he
possibili y ha se um p o eins may each he CNS pa -
enchyma.
13
An example o his may be child en wi h eb-
ile seizu es. Measu emen o he abo e-men ioned
p ocon ulsan molecules in he plasma o hese pa ien s
shows a clea inc ease.
14
In addi ion, in an animal model
o TLE, he BBB opening has been shown in he p og es-
sion o he disease. The au ho s ound albumin in he CNS
ollowing s a us epilep icus (SE) and a posi i e co ela ion
be ween he ex en o BBB opening and he numbe o sei-
zu es.
15
On he o he hand, i is unclea o wha ex en
hese molecules en e he CNS. Measu emen s o albumin
and a2-mac oglobulin in he se um and ce eb ospinal luid
(CSF) o child en wi h eb ile seizu es show ha mos chil-
d en ha e he same le els o albumin and a2-mac oglobu-
lin in he CSF as con ols bu o he s clea ly showed an
inc ease o hese molecules in he CSF.
16
I is s ill unknown whe he and in which cell ypes IL-1bis
exp essed in o ms o epilepsy cha ac e ized by ex ensi e
in il a ion o adap i e immuni y cells, such as Rasmussen
encephali is (RE). Baue and colleagues he e o e analyzed
he p esence o IL-1bin RE using immune his ochemical
(IHC) s udies, and hey ound selec i e p esence o IL-1bin
mic oglial nodules in co ical g ay ma e as well as in sub-
co ical whi e ma e , in ag eemen wi h a ecen epo by a
Ramashwamy e al.
17
In he hippocampus, IL-1bwas no
es ic ed o nodules, bu was also p esen in su ounding
mic oglial cells. This immunohis ochemical da a we e sup-
po ed by in si u hyb idiza ion (ISH) s udies wi h a p obe o
IL-1bmessenge RNA (mRNA), which showed speci ic sig-
nals in mic oglial nodules. As ocy es showed a weak
immunos aining o IL-1bbu we e nega i e o IL-1b
mRNA, aising he possibili y ha as ocy es may impo he
cy okine om he ex acellula space, o example, ia ex a-
cellula mic o esicles. In addi ion o using IHC and ISH s ud-
ies, hese au ho s measu ed IL-1bby wes e n blo and
Key Poin s
•In lamma o y mechanisms ha e been implica ed in he
o igin o seizu es in a numbe o encephali ides
•Ac i a ion o bo h inna e and adap i e immuni y seems
o occu in e ac o y o ms o epilepsy
•An ineu onal au oan ibodies ha e been disco e ed and
a e associa ed wi h a ious neu ologic synd omes,
including limbic encephali is
•Immunomodula ion demons a es incomple e e icacy
wi h signi ican side e ec s
•The iden i ica ion o new immunomodula o y com-
pounds emains o u mos impo ance
Epilepsia, 58(Suppl. 3):57–68, 2017
doi: 10.1111/epi.13784
58
J. Baue e al.
enzyme-linked immunoso ben assay (ELISA) in ozen sec-
ions om se en RE pa ien s. Bo h analyses, howe e , did
no show posi i e signals o IL-1b, sugges ing ha he
amoun o eco e ed IL-1bwas unde he de ec ion le el.
Adap i e Immuni y in Epilep ic
Diso de s
(Jan Baue , Maa en J. Ti ulae )
In il a ion o T lymphocy es
Expe imen al and clinical e idence sugges s a di e en
in lamma o y esponse in he b ain o pa ien s wi h TLE,
whe e he inna e immune componen appea s o be p e a-
len , as compa ed o o he e ac o y o ms o epilepsy wi h
p ominen ac i a ion o bo h inna e and adap i e immuni y.
Because inna e and adap i e immuni y ecip ocally a ec
each o he , i is impo an o ecognize he p esence and he
composi ion o he in lamma o y milieu in epilep ic diso -
de s.
Epilepsies in which seizu es de elop a e in il a ion
o cells o he adap i e immune sys em in he CNS a e
an eme ging g oup. I is inc easingly ecognized ha his
g oup consis s o a b oad ange o epilep ic diso de s
wi h di e en known and unknown e iologies (Fig. 1).
In il a ion can be ex emely abundan , in which case he
epilep ic diso de is designa ed as encephali is. Examples
o hese include he pes simplex i us encephali is
18
and
RE.
19
A second g oup o epilep ic diso de s wi h domi-
nan in il a ion o lymphocy es a e he au oimmune
epilepsies (Fig. 1). These consis o classical pa aneo-
plas ic encephali ides wi h an ibodies agains in acellula
umo an igens such as Hu and Ma2, as well as pa aneo-
plas ic and nonpa aneoplas ic cases wi h an ibodies
agains a la ge and s ill-expanding ange o in acellula
and ex acellula /memb anous an igens, as discussed
la e . The numbe o in il a ing lymphocy es in pa aneo-
plas ic cases wi h an ibodies agains he a ious oncoge-
nes is abundan . Mo eo e , mos o hese in il a ing
CD3
+
T lymphocy es a e cy o oxic
20,21
and a ack neu-
ons.
22–24
Whe eas in pa aneoplas ic cases in il a ion is
se e e, lymphocy e in il a ion in o he au oimmune
epilepsies, in pa icula , hose wi h an ibodies agains
memb ane an igens, is less abundan . Indeed, mode a e
in il a ion o cells in cases o leucine- ich glioma-inac i-
a ed 1 (LGI1) encephali is has been obse ed and lym-
phocy es a e p edominan ly seen in he pe i ascula and
in e s i ial spaces in cases o N-me hyl-D-aspa a e ecep-
o (NMDAR encephali is)
24,25
(Fig. 1). In il a ion o
lymphocy es in he CNS has also been ound in a speci-
ic subg oup o FCD, ha is, hose composed o dysplas-
ic neu ons and balloon cells e med FCD ype IIb by
he In e na ional League agains Epilepsy (ILAE) classi-
ica ion sys em.
12
In mos o he FCD cases, in il a ion
o T lymphocy es is ela i ely low. Baue and colleagues
con i med ha cases o FCD IIb con ain mode a e o
high numbe s o T cells and showed ha some o hese
in il a ing lymphocy es we e cy o oxic in na u e. Finally,
A onica and colleagues ecen ly epo ed ha in lamma-
o y in il a es can also be p esen in a newly iden i ied
subg oup ( ype C) o co ical ube s.
26
Baue and col-
leagues suppo hese indings, showing ha CD3
+
CD8
+
T lymphocy es a e in close apposi ion o balloon cells,
hus sugges ing ha cy o oxic T cells migh speci ically
a ge hese abe an cell ypes.
Ano he la ge g oup o epilep ic diso de s in which in il-
a ion o lymphocy es can be ound a e he cases o TLE
wi h hippocampal scle osis (HS) wi h unknown e iology.
Baue and colleagues p esen ed da a con i ming ha in
some o hese cases, in il a ing T cells a e as nume ous as
in de ini i e limbic encephali is (LE). Thei p elimina y
esul s also e ealed ha especially one subg oup, ha is,
Figu e 1.
Compa a i e T-cell in lamma ion in epilepsy. S aining o CD3
+
T
cells in (A, ba : 100 lm) HSV encephali is, (B) an i-Ma2 Ab pa ane-
oplas ic encephali is, (C) Rasmussen encephali is, (D) an i-GAD65
Ab encephali is, (E) an i-LGI1 Ab Encephali is, (F) an i-NMDAR
(NR1) Ab encephali is. (G) FCD IIb wi h ew T cells (H) TSC. This
case con ains only e y ew in il a ing lymphocy es (I) idiopa hic
TLE, (J) FCD IIb. He e he pa enchyma e eals he p esence o
many T cells (K) TSC ype C, wi h many T cells (L) pos in ec ious
TLE. Numbe s o in lamma o y T cells a e ex emely high. All
images ha e he same magni ica ion. Single T lymphocy es a e indi-
ca ed by a owheads.
Epilepsia ILAE
Epilepsia, 58(Suppl. 3):57–68, 2017
doi: 10.1111/epi.13784
59
Immuni y in human epilepsy
pos encephali ic TLE cases, con ained high numbe s o
in il a ing CD3
+
CD8
+
T lymphocy es (Fig. 1) wi h a smal-
le subg oup o G anzyme-B
+
T cells.
TheRoleo Vi alDNAinHuman
TLE
(Jan Baue , Albe J. Becke )
The eason o he high numbe s o lymphocy es in pos-
encephali ic TLE cases is unknown. Such in lamma ion
migh be due o he p esence o i al DNA in he CNS. High
human he pes i us 6 (HHV-6) DNA load has been de ec ed
in su gical issue o pa ien s wi h TLE, and i al DNA is
mos commonly p esen in pa ien s wi h p e ious in lamma-
o y b ain diseases.
27
Howe e , de ec ion a es ha e been
ound o a y conside ably among s udies. Becke and col-
leagues, in an ini ial limi ed se ies o 38 pha maco esis an
TLE pa ien s e sus 10 au opsy con ols, de ec ed HHV-6
DNA in 55.6% o he TLE pa ien s wi h a his o y o
encephali is, including mesial empo al scle osis (MTS) and
glio ic hippocampi wi hou subs an ial neu odegene a-
ion.
27
They did no ind HHV-6 DNA in lesion-associa ed
TLE o nonlesional MTS wi h o wi hou a his o y o com-
plex eb ile seizu es (CFS). These da a p omp ed hem o
ca y ou a subsequen la ge-scale analysis o i al DNA/
RNA spec um in an ex ended se ies o TLE biopsies.
28
In
addi ion o all He pes i idae, he g oup examined he p es-
ence o po en ially ele an neu o opic RNA i uses. DNA
and RNA we e ex ac ed om 346 esh- ozen epilepsy
su ge y issue samples. F esh- ozen hippocampal issue
samples om 62 pa ien s wi hou ch onic CNS disease
se ed as con ols. Real- ime polyme ase chain eac ion
(PCR) and nes ed PCR we e pe o med o He pes i idae
and RNA i uses, espec i ely. In addi ion, hey analyzed
he clinical eco ds o he pa ien s o he p esence o ea lie
signs o in lamma o y b ain eac ions. Thei esul s e ealed
HHV-6B DNA in 9.8% o he TLE pa ien s and in 12.9% o
he con ol samples. In iguingly, howe e , he TLE sam-
ples we e ound o ha e a highe i us concen a ion. In
pa ien s wi h clinical signs o p e ious b ain in lamma ion,
HHV-6B DNA was obse ed in 15.0%, whe eas only 6.3%
o he samples om pa ien s wi hou eb ile seizu es o
meningoencephali is we e posi i e o HHV-6B DNA. A
me a-analysis o he eigh HHV-6 PCR s udies e ealed
simila esul s. To summa ize, he biopsy-based s udy o
Becke and colleagues e ealed no di e ences in equency
o HHV-6B DNA de ec ion be ween TLE pa ien s and con-
ols. Howe e , he highe i us load in TLE pa ien s and
he inc eased de ec ion a e o HHV-6B DNA in pa ien s
wi h p e ious in lamma o y b ain eac ions may be in line
wi h a po en ial p omo ing ole o HHV-6 in TLE pa ien s
wi h a his o y o encephali is. I is in e es ing o no e ha
especially pos encephali ic TLE cases e ealed inc eased
p esence o cy o oxic lymphocy es, as p esen ed by Baue
and colleagues. As such, new coo dina ed mul icen e
a emp s should be help ul o shed mo e ligh on he ole o
HHV-6 as well as o he neu o opic i uses in he eme -
gence o TLE. The abundance o i al nucleic acids in
epilep ic hippocampal issue ep esen s an aspec ha
equi es pa icula a en ion by u u e s udies.
The Role o Immunologic
Bioma ke s in Re ac o y
Epilepsy
(Wassim Elyaman)
Conside able p og ess has been made in iden i ying ci -
cula ing epilepsy bioma ke s in animal models o epi-
lepsy.
29
Howe e , a majo challenge is o de ine bioma ke s
in human epilepsy o allow he ecogni ion o app op ia e
pa ien popula ions ha migh bene i om immunomodula-
o y he apies. Elyaman and colleagues p oposed he
hypo hesis ha pe iphe al in lamma o y media o s a e di -
e en ially exp essed in pa ien s wi h medically con olled
and medically e ac o y epilepsy and, as such, could be
used as a bioma ke o diagnos ic, p ognos ic, o he apeu-
ic pu poses. To cha ac e ize he egula ion o ci cula ing
in lamma o y media o s in epilepsy, Elyaman and col-
leagues assembled a mul idisciplina y eam ha includes
epilep ologis s, immunologis s, epigene icis s, and compu-
a ional biologis s o gene a e comp ehensi e p o eomic
and ansc ip omic da a o pe iphe al (blood) and cen al
(su gical issues) adap i e and inna e immune cells o a
la ge pool o pa ien s wi h epilepsy. Findings om hese
s udies may gi e insigh in o he complex ole o in lamma-
ion in he gene a ion and exace ba ion o epilepsy. In addi-
ion, i should yield new molecula a ge s o he design o
an iepilep ic d ugs, which migh no only inhibi he symp-
oms o his diso de , bu also p e en disease pa hogenesis.
An ibodies and Epilepsy
(Maa en J. Ti ulae )
In he pas 30 yea s >30 an ineu onal au oan ibodies
(ANABs) ha e been disco e ed.
30
These ANABs a e associ-
a ed wi h a ious neu ologic synd omes, which include LE,
epilepsy, ce ebella degene a ion, pe iphe al (poly)neu opa-
hy, Lambe -Ea on myas henic synd ome (LEMS), opso-
clonus-myoclonus synd ome p og essi e encephalomyeli is
wi h igidi y and myoclonus (PERM), and s i -pe son syn-
d ome (SPS). A p esen , i is unclea how he o ma ion o
hese an ibodies is igge ed. The induc ion o an ibodies
agains he NMDAR has been associa ed wi h pos -he pes
simplex i us encephali is,
31–33
bu o o he an ibodies such
an associa ion is absen . The exac ole o hese an ibodies in
seizu e induc ion emains he ocus o esea ch. These in es i-
ga ions ha e al eady e ealed impo an mechanis ic insigh
o a mino i y o an ibodies.
Epilepsia, 58(Suppl. 3):57–68, 2017
doi: 10.1111/epi.13784
60
J. Baue e al.
In he nine ies, ol age-ga ed po assium channel (VGKC)
an ibodies we e desc ibed in associa ion wi h neu omyo o-
nia.
34
In he ollowing yea s, hese an ibodies we e ound o
be p esen in pa ien s wi h LE and in Mo an’s synd ome.
35
Mo e ecen ly, i was shown ha abou hal o hese an ibod-
ies a e di ec ed agains p o eins complexed wi h he VGKC
a he han he channel i sel . Mos pa ien s ha e been ound
o ha e an ibodies agains LGI1.
36,37
A smalle g oup has
an ibodies agains con ac in-associa ed p o ein-like 2
(Casp 2), which is si ua ed in he jux apa anodal loop o
myelin su ounding axons.
37,38
Only a mino i y o pa ien s
ha e an ibodies agains con ac in-2.
37
Recen ly, a p opo -
ion o pa ien s wi h posi i e VGKC-complex an ibodies
bu nega i e LGI1 and casp 2 an igen speci ic es s ha e
been ound o con ain an ibodies agains he in e nal su ace
o he VGKC.
39
The clinical signi icance o hese pa icula
an ibodies is unclea , bu cu en ly he e is no e idence o a
pa hogenic ole o a posi i e VGKC es in he absence o
LGI1 o Casp 2 an ibodies.
40
The e o e, he e m VGKC is
no use ul and diseases should be e e ed o by hei con-
i med a ge an igen.
Mechanis ically, an i-LGI1 an ibodies seem o a ec he
binding o LGI1 o disin eg in and me allop o einase
domain-con aining p o ein 22 (ADAM22), and he eby p e-
en p ope signaling o he p esynap ic VGKC and he
pos synap ic a-amino-3-hyd oxy-5-me hyl-4-isoxazolep o-
pionic acid (AMPA) ecep o .
41
The mechanism o an i-
casp 2 an ibodies has no been s udied ye , bu pa hologic
in es iga ion o a casp 2 encephali is b ain showed
immunoglobulin and complemen deposi ion associa ed
wi h neu odegene a ion in he hippocampus.
42
This an i-
body and complemen deposi ion–associa ed neu odegene -
a ion was also ound in hippocampi o pa ien s wi h an i-
LGI1 encephali is, sugges ing ha , a leas in hese pa icu-
la cases, he casp 2 and LGI1 an ibodies can induce neu-
odegene a ion ia an ibody-dependen complemen -
media ed cy o oxici y.
24
All LGI1 and casp 2 se a con ain
(non–complemen -ac i a ing) IgG4 subclass an ibod-
ies.
43,44
In addi ion o IgG4, IgG1 o IgG2 subclass an ibod-
ies we e ound o some ex en in 42% o LGI1 and 63% o
casp 2 se a. These IgG1 and IgG2 an ibodies a e comple-
men -ac i a ing and he e o e migh be esponsible o he
hippocampal neu odegene a ion desc ibed in some
pa ien s.
24,42
Because he an ibodies agains su ace an igens ha e
been disco e ed only ecen ly, knowledge o he exac
pa hophysiologic mechanisms o such an ibodies is s ill
expanding. An i-NMDAR an ibody was he i s an ibody
o be disco e ed eac ing o an ex acellula an igen.
45
An i-NMDAR encephali is a p esen is also he mos e-
quen au oimmune epilepsy. Mos o he mechanis ic
insigh o an i-NMDAR an ibodies has been desc ibed by
Dalmau and colleagues.
46–48
In i o, he an ibodies seem
o a ec he localiza ion o NMDAR on he synapses o
inhibi o y neu ons, by b eaking he link wi h Eph inB2.
49
This change in localiza ion somehow leads o in e naliza-
ion o he NMDAR and a ne dec ease in NMDAR.
48,50
In i o and in i o s udies in mice e eal ha he
dec ease o NMDAR on he synapse is e e sible a e
emo al o an ibodies.
51
Fu he mo e, in i o expe imen s
sugges ha an o e load o Eph inB2 ligand can p e en
he NMDAR in e naliza ion, and pa ially p e en he
clinical pheno ype. This could o e al e na i e symp-
oma ic ea men s in he u u e. Unlike in LGI1 and
Casp 2 encephali is, no majo pa hologic e ec on indi-
idual ecep o unc ion o cy o oxic o complemen -
media ed e ec s ha e been ound.
24,25,52
A ques ion he e-
o e emains why IgG complemen –ac i a ing subclass
an ibodies om NMDAR encephali is pa ien s do no
seem o induce complemen -media ed pa hology.
Clinical Aspec s o Immuni y in
Epilepsy
(S ephan R€
uegg, Maa en J. Ti ulae )
F om an epilep ologic poin o iew, LE is he mos
impo an immune synd ome associa ed wi h he newly dis-
co e ed ANABs. The main ea u es o he synd ome a e
subacu e onse o wo king memo y de ici s, al e ed men al
s a us, con usion, deli ium, o psychia ic symp oms. Fu -
he mo e, one can ind p og essi e impai men o con-
sciousness up o coma. Fo he possibili y o an LE, a leas
one o he ollowing obse a ions should be p esen : de
no o seizu es o e en s a us epilep icus, a new ocal neu o-
logic de ici , CSF pleocy osis, o MRI ea u es sugges i e
o encephali is. Excluding al e na i e causes o he
pa ien ’s condi ion is also impo an . Swi ecogni ion o
he diso de is key because he e a e e ec i e he apies and
da a inc easingly sugges ha ea ly s a o ea men is
associa ed wi h be e ou come.
30,53
Excellen e iews on
his opic ha e been published ecen ly.
54–58
Ano he impo an an ibody associa ed wi h epilepsy
was he en i y di ec ed agains he cy osolic enzyme glu a-
ma e deca boxylase (GAD). GAD ca alyzes he con e -
sion om glu ama e o c-aminobu y ic acid (GABA), and
he p esence o an ibodies agains GAD a e associa ed
wi h epilepsy,
59
s i pe son synd ome (SPS), and LE
60,61
(Table 1). Mos o he ea ly de ec ed ANABs (de ec ed
be o e 2007) ecognize in acellula epi opes and we e
associa ed wi h umo s causing pa aneoplas ic synd omes,
whe eas hose ANABs iden i ied mo e ecen ly a e less
equen ly pa aneoplas ic and a e di ec ed mainly owa d
an igens a he cell memb ane. An i-GAD an ibody
encephali is is an excep ion because he an ibodies agains
in acellula an igens a e induced in he absence o a
umo . A con o e sial ansien ex acellula a ailabili y
a he synapse has been sugges ed o explain hei
pa hogenici y.
62
Since 2007, many new ANABs ha e
been disco e ed (Table 2) and he clinical di e si y o he
Epilepsia, 58(Suppl. 3):57–68, 2017
doi: 10.1111/epi.13784
61
Immuni y in human epilepsy

ANAB-media ed synd omes has la gely expanded, main-
aining he link wi h epilepsy in mos o hese ANABs.
These aspec s a e discussed in b ie below.
An i-NMDAR encephali is
In 2013, Ti ulae e al.
53
p esen ed a la ge coho o 577
pa ien s, including 212 child en, wi h NMDAR encephali-
is, and epo ed p ecise da a on clinical ea u es, ea men ,
and ou come. The majo i y (81%) had a good ou come
(modi ied Rankin ou come scale 0–2), whe eas 6% died.
P ognos ic ac o s p edisposing o a good ou come in bo h
adul s and child en we e ea ly onse o ea men and nonad-
mission o an in ensi e ca e uni . Relapse isk was 12%
wi hin he i s 24 mon hs, bu elapses ended o be milde
han he ini ial mani es a ion. The EEG phenomenon o “ex-
eme del a b ush”(ex ensi e on al be a ac i i y supe im-
posed on almos gene alized hy hmic high-ampli ude del a
ac i i y) occu s in abou 30% o se e ely a ec ed in ensi e
ca e uni (ICU)–bound pa ien s and is hough o be speci ic
o he diso de .
63
Psychia ic symp oms a e impo an in
he ea ly cou se o he disease, as 75% o adul pa ien s a e
seen ini ially by a psychia is .
64
These symp oms we e he
ini ial mani es a ion in 59% o he na ional F ench coho
(n =111), wi h 40% expe iencing hallucina ions and 23%
dep ession. A mino i y o hese pa ien s we e d ug esis an
o an ipsycho ics o an idep essan s. Re e al o a neu o-
logic (in ensi e ca e) uni was o many o he causes like
e ol ing seizu es and s a us epilep icus and, in pa icula ,
o de elopmen o a neu olep ic malignan synd ome in 21
pa ien s. Fo y pe cen o he pa ien s we e i s hospi alized
in psychia ic ins i u ions, howe e , mo e han hal o hese
pa ien s also had a leas one neu ologic sign and u he
38% de eloped neu ologic symp oms wi hin days. These
indings con i m p e ious s udies o an i-NMDAR
encephali is cases a psychia ic wa ds
65
and ask o ca e ul
neu ologic ( e-)examina ion o pa ien s wi h new-onse , el-
a i ely acu e psychia ic illness.
66
In young child en, sei-
zu es and dyskinesias a e he ini ial symp oms in hal o he
pa ien s. In his g oup, psychia ic ea u es as p esen ing
symp oms, howe e , a e less equen (abou one- hi d).
53
The symp oms o he diso de e ol e g adually and seem o
esol e in e e se o de o onse .
67
An i-LGI1 encephali is
Sho ly a e he disco e y o he LGI1-associa ed LE,
I ani e al.
68
epo ed a unique epilep ic synd ome o “ acio-
b achial dys onic seizu es”(FBDS), wi h o he g oups
epo ing simila semiologies in he same con ex .
69
These
seizu es a e e y sho , las ing abou 1–3 s, and consis o
sho dys onic s i ening o one a m and g imacing o he
ipsila e al mimic muscula u e, o , less equen ly, he leg.
They may occu up o 50–100 imes pe day and, in 70% o
cases, hey p ecede he onse o LE by an a e age o
35 days. Abou 10% o pa ien s do no de elop LE. Due o
hei unusual and cha ac e is ic semiology, FBDS may be
missed o misin e p e ed as “psychogenic”o “ ics.”Elec-
oencephalog aphy (EEG) a ely shows epilep ic abno -
mali ies.
68
LGI1 encephali is is he second mos equen
au oimmune encephali is, wi h an incidence o sligh ly less
han one pe million.
40
I is in equen ly (10–15%) associ-
a ed wi h umo s ( hymoma, lung cance ), and is sligh ly
mo e p e alen in men and in pa ien s >50 yea s. Seizu es
a e ei he ocal in he ea ly s ages (FBDS o s e eo ypic
ocal seizu es wi h dyscogni i e o au onomic ea u es)
68
o
gene alized onic–clonic, a la e symp om as pa o an LE.
Wi h he onse o LE, memo y loss, con usion, and pe son-
ali y changes a e equen .
70
Mild o mode a e hypona-
emia (115–130, mos o e 125 mmol/L) is p esen a onse
in wo hi ds o pa ien s. The ou comes can be se ious, as
65% o pa ien s ha e pe sis en mild o se e e cogni i e de -
ici s.
40,71
In addi ion, 13% o pa ien s de elop a cogni i e
encephalopa hy wi hou seizu es.
43
A e adequa e ea -
men , an i-LGI1 encephali is e ol es in o ch onic epilepsy
in one in se en pa ien s.
An i-Casp 2 encephali is
Mo e a e han LGI1 encephali is, an i-Casp 2 encephali-
is has been epo ed in abou 100 pa ien s o da e. E e y
i h pa ien has pa aneoplas ic disease (lung, colon cance ,
Table 1. An ibodies associa ed wi h epilepsy: s a e o a
in 2010
An ibody Epi ope loca ion (Non-)pa aneoplas ic Re s
An i-Hu In acellula Pa aneoplas ic 118,119
An i-Ma1;
Ma2/an i-Ta
In acellula Pa aneoplas ic 120,121
An i-amphiphysin Memb anous Pa aneoplas ic 92
An i-Ri In acellula Pa aneoplas ic 122
An i-AMPAR
(GluR1/2)
Memb anous 2/3 Pa aneoplas ic 73
An i-GABA
B
R Memb anous 1/2 Pa aneoplas ic 123
An i-GAD Cy osolic ca. 10% Pa aneoplas ic 59
An i-AMPAR
(GluR3)
Memb anous Nonpa aneoplas ic 124
An i-NMDAR
(NR1/2)
Memb anous 1/3 Pa aneoplas ic 45
An i-LGI1 Memb anous 10% Pa aneoplas ic 36
An i-Casp 2 Memb anous 20% Pa aneoplas ic 37
Table 2. An ibodies associa ed wi h epilepsy disco e ed
since 2010
An ibody Epi ope loca ion (Non)pa aneoplas ic Re s
An i-mGluR5 Memb anous Pa aneoplas ic 79
An i-DPPX-6 Memb anous Ra ely pa aneoplas ic 82
An i-GABA
A
R Memb anous Me ely non-pa aneoplas ic 88
An i-glycineR Memb anous Non-pa aneoplas ic 95,125
An i-GABA
A
R Memb anous Me ely non-pa aneoplas ic 90
Epilepsia, 58(Suppl. 3):57–68, 2017
doi: 10.1111/epi.13784
62
J. Baue e al.
hymoma). The e is s ong p eponde ance o male
pa ien s (60–95% in di e en se ies), mainly olde han
age 60. Pa ien s can p esen wi h LE, a axia, pe iphe al
ne ous sys em in ol emen (neu omuscula hype ex-
ci abili y, including neu omyo onia, o pain) o a combi-
na ion o pe iphe al and cen al symp oms and signs,
such as Mo an’s synd ome.
44,71,72
Seizu es occu in
50–90% o pa ien s.
44
An i-AMPAR encephali is
A e a i s se ies o 10 pa ien s,
73
he e a e now >50
pa ien s epo ed wi h AMPA encephali is, which has a
pa aneoplas ic ( hymoma, lung cance ) backg ound in wo
hi ds o hese pa ien s.
73–75
The e is emale p eponde ance
and pa ien s end o be olde han 40 yea s o age. The ol-
lowing ou ypes ha e been epo ed: (1) a con usional ype
wi h p edominan agi a ion up o psychosis; (2) a mainly
amnes ic o m; (3) an epilep ic o m wi h gene alized and
mo e a e ocal seizu es, wi h impai men o consciousness;
and (4) a ulminan ype wi h a se e e cou se. Seizu es
occu in 20–40% o pa ien s only, and pa ien s end o
elapse al hough ea men esponse is good e en in hese
ecu en episodes.
72,74
An i-GABA
B
R encephali is
This o m o encephali is is inc easingly ecognized and
among he mos p e alen a e NMDAR and LGI1
encephali is. Mo e han hal o cases a e pa aneoplas ic,
mainly associa ed wi h small cell lung cance . O in e es ,
an i-GABA
B
ecep o an ibodies a e absen in la ge coho s
o pa ien s wi h small cell lung cance , indica ing ha he
p esence o he an ibodies can exe hei pa hogenic e ec
in he absence o a umo . The e is p eponde ance o male
pa ien s olde han 40 yea s who p esen wi h seizu es (pa -
ial complex, seconda ily gene alized seizu es, o equen ly
e ac o y s a us epilep icus [SE]). In addi ion, pa ien s ha e
memo y loss, con usion, and se e e insomnia. Ra e symp-
oms include a axia and opsoclonus/myoclonus syn-
d ome.
76–78
An i-mGluR5 encephali is
Encephali is media ed by an ibodies agains he me abo-
opic glu ama e ecep o sub ype 5 (mGluR5) is always
pa aneoplas ic and associa ed wi h Hodgkin’s lymphoma.
79
The signs o his ex emely a e condi ion (only se en
cases epo ed) include ma ked and subacu e memo y
loss, dep ession, delusions, hallucina ions, and psychosis
oge he wi h umo symp oms o cachexia, e e , and
nigh swea s. The combina ion o encephali is, dep ession,
delusion, and cachexia led o he e m “Ophelia syn-
d ome,”coined by he au ho o he i s case (his own
daugh e ).
80
An ibodies agains he mGluR1 ecep o cause
a comple ely di e en neu ologic, ce ebella (a axic) syn-
d ome despi e la ge homology o he mGluR1 ecep o
wi h he mGLuR5 ecep o .
79,81
An i-dipep idyl-pep idase-like p o ein-6 (DPPX)
encephali is
This is a a e synd ome whe e an ibodies agains he epi-
ope DPPX o he ol age-ga ed po assium channel K 4.2
cause classical symp oms o LE wi h con usion, memo y
loss, psychosis, o dep ession, bu addi ionally b ains em
signs (eye mo emen dis u bances, a axia, dysa h ia, dys-
phagia, and espi a o y ailu e), sleep di icul ies, and myo-
clonus. As a unique clinical hallma k, p o use and di icul
o ea , nonin ec ious dia hea p ecedes LE weeks o
mon hs in wo hi ds o cases.
82–84
This may esul om he
exp ession o he epi ope in bo h in es inal cells and neu-
ons. Seizu es a e a ely obse ed (abou 15%). The an i-
bodies ha e also been ound in cases o p og essi e
encephalomyeli is wi h igidi y and myoclonus (PERM).
85
An i-GABA
A(b3/c2)
R-encephali is
LE associa ed wi h an ibodies agains GABA
A
ecep o
subuni s b3andc2 is a e and, in wo hi ds o cases, a ec s
men be ween 3 and 74 yea s. The eason o his gende dis-
pa i y is unknown bu in e es ing, since male p edominance
in au oimmune diso de s is a e. One migh specula e ha
emale sex ho mones, such as allop egnanolone, o o al con-
acep i es may consolida e c2-subuni s
86
and be p o ec i e
agains seizu es and SE. GABA
A
ecep o s, especially he
ex asynap ic, can be modula ed by neu os e oids wi h sex-
ho mone–like s uc u e.
87
Abou 20% o pa ien s ha e can-
ce . Main symp oms a e he ones ypical o LE, bu 50–70%
o pa ien s ha e se e e seizu es, up o almos in ac able SE.
In addi ion, some pa ien s also ha e SPS o opsoclonus/my-
oclonus synd ome. Response o seizu es and SE o immuno-
supp ession is ema kable, whe eas classical an iseizu e
d ugs a e ine ec i e agains epilep ic ac i i y.
88,89
An i-GABA
A(a1/c2)
R encephali is
A second ype o an i-GABA
A
ecep o an ibody has been
epo ed ecen ly. These an ibodies we e disco e ed in a
la ge coho o pa ien s es ed o au oimmune CNS disease.
The an ibodies we e di ec ed agains he ecep o sub ypes
a1 and c2, and high i e s a e associa ed wi h bo h seizu es
and memo y impai men in 47% o pa ien s, in 33% wi h
hallucina ions, and 20% wi h anxie y.
90
A clea encephali ic
synd ome could no be iden i ied and impo an clinical
in o ma ion on hese pa ien s ( i e s in CSF, cou se o dis-
ease, e ec o ea men , e c.) we e lacking; hus hese an i-
bodies may no cause LE sensu s ic o.
91
An i-amphiphysin encephali is
An i-amphiphysin encephali is has been e y a ely
epo ed. Abou 40% o cases we e pa aneoplas ic and
mainly caused by small lung cell and b eas cance . Men
we e mo e equen ly a ec ed, and mean age o onse is
54 yea s. The classical o m includes memo y loss, cogni-
i e decline, mood changes, dep ession, and some imes hal-
lucina ions up o a ank psychosis. Seizu es occu in abou
Epilepsia, 58(Suppl. 3):57–68, 2017
doi: 10.1111/epi.13784
63
Immuni y in human epilepsy
40% o pa ien s (gene alized > ocal wi h impai men o
consciousness). Some pa ien s also expe ience b ains em
signs, like e igo, c anial ne e palsies, and a axia.
92,93
An i-glycineR encephali is
Al hough abou 3% o wo la ge coho s o adul pa ien s
wi h newly diagnosed and es ablished epilepsy ha bo ed
an ibodies agains glycine ecep o s,
94
only h ee young
boys younge han age 6 yea s ha e been epo ed o ha e
(sub-)acu e encephali is, ocal seizu es, and e en SE associ-
a ed wi h hese an ibodies.
95–97
The an i-glycine ecep o
an ibodies a e no mally linked o SPS and PERM.
98
In summa y, he incidence o all ypes o encephali is
is es ima ed a 1:15,000
99
and he LE caused by
ANABs is p obably a ound 1:100,000, al hough exac
epidemiologic da a a e lacking. The incidence o sei-
zu es in hese cases s ongly a ies acco ding o he
speci ic ype o ANABs (Table 3). Con e sely, ANABs
a e ound in abou 1–3% o pa ien s wi h newly es ab-
lished epilepsy, bu in a highe p opo ion (10–15%) in
pha maco esis an pa ien s.
94,100,101
This emains an
impo an a ea o unce ain y because he signi icance o
he p esence o ANABs in pa ien s wi h epilepsy alone
is s ill poo ly unde s ood, as is he alue o an ibody
es ing in high- h oughpu coho s, wi hou u he
explo a ion o he signi icance o hese posi i e esul s.
A e hey me ely bys ande o a eliable su oga e ma -
ke o pha maco esis ance when hese pa ien s we e
ea ed only wi h an iseizu e d ugs bu no immunomod-
ula ing agen s? Such ea men s yielded ema kable he -
apeu ic e ec s in one s udy o highly selec ed pa ien s,
bu p ospec i e andomized con olled s udies a e s ill
lacking.
102,103
T ea men s in Au oimmune
Encephali is
(James A. Va dley)
The i s -line ea men o au oimmune encephali is com-
bines s e oids wi h ei he plasma exchange o in a enous
immunoglobulin (IVIG) o , occasionally, bo h. Second-line
ea men s a e wi h cyclophosphamide and i uximab.
53
The
bes e idence o ea men o au oimmune encephali is is
p esen ed in NMDAR-Ab encephali is, as his is he mos
common.
53
A ound 50% o NMDAR-Ab pa ien s espond
o i s -line ea men wi h a “good ou come”o an modi ied
Rankin scale (mRS) o 0–2 a 24-mon h ollow-up. In he
emaining 50%, a good ou come can be achie ed by sec-
ond-line ea men . The e a e nuances in his da a, as only
50% o pa ien s s udied e ospec i ely had ollow-up da a
a 24 mon hs. Second-line ea men also hal ed he elapse
incidence in 25% o pa ien s, and ea ly ea men was asso-
cia ed wi h a highe chance o a be e ou come, some hing
ha has been mi o ed in a small p ospec i e coho in LGI-
Ab encephali is.
104
E idence o i uximab is equi ocal in
LGI-Ab encephali is bu hese da a a e on a small sample
size.
105
In o he an ibody encephali ides, because o hei a i y,
he e is a less clea idea o ea men esponses. In gene al,
a ound 70% o pa ien s espond o ea men . He e, ac o s
associa ed wi h a poo ou come include coexis en umo ,
delay o ea men , and poo ini ial unc ional s a us. In addi-
ion, he highe mo ali y seen in cases associa ed wi h an i-
bodies such as GABA
A
, GABA
B
, and AMPA- ecep o
an ibodies can be explained by he mo e equen occu -
ence wi h umo s.
106
Nex -Gene a ion Ta ge ed
Immunomodula o y The apies
(James A. Va dley)
Mo e speci ic a ge ed he apies a e an a ac i e p o-
spec , as he b oad immunosupp essi e he apies ha e a
wide ange o side e ec s ha con ibu e signi ican ly o
mo bidi y. E o s ha e been made using he ollowing med-
ica ions o in e en ions.
Immunoabso p ion
Plasma exchange is well es ablished as a ea men
op ion, bu a ial o immunoabso p ion (IA) was ecen ly
epo ed.
107
Eigh y-six pe cen o pa ien s wi h ANABs
imp o ed, whe eas pa ien s wi h in acellula ly a ge ed
an ibodies an igens did no . An ibody clea ance was also
in e es ing, wi h i e s dec easing by 97% (se um) and 64%
(CSF) 4 days a e IA and alling u he o 98% (se um) and
88% (CSF) a 4 weeks, showing a p olonged ea men
e ec . I is wo h no ing ha his is highe han epo ed in
Table 3. F equency o seizu es du ing/a e limbic
encephali is (LE)
An ineu onal an ibody F equency o seizu es Incidence o LE
An i-GABA
B
R-IgG
1
90% Low o medium
An i-GAD-IgG 25–100%
a
High
An i-Hu-IgG 60–100% Low o medium
An i-GABA
A
R-IgG
1>3
50–100% Medium
An i-LGI1-IgG
4>2>1
90% Medium o high
An i-NMDA1/2R-IgG
1
70% High
An i-GABA
A(b3/g2)
R-IgG
1>3
47% Medium
An i-Casp 2-IgG
4>1
20–65% Low o medium
An i-Ma1/2-IgG 30–40% Low o medium
An i-AMPAR-IgG
1
33% Low o medium
An i-DPPX-IgG 15% Low
An i-mGluR5-IgG 20% Ve y low
An i-amphiphysin-IgG 10–20% Low
An i-CV2/CRMP5-IgG Ra e Low o medium
An i-glycineR-IgG Ra e Low
a
Depending on he de ini ion o acu e immune LE.
Epilepsia, 58(Suppl. 3):57–68, 2017
doi: 10.1111/epi.13784
64
J. Baue e al.
plasma exchange se ies
108
; howe e , hose p io s udies
we e published 20 yea s ago and ec ui ed pa ien s wi h
in acellula an igens. The p ecise clinical e ec o IA is
con ounded by he coadminis a ion o immuno he apy in
his s udy, bu i does appea o be an e ec i e ea men
alongside s anda d immuno he apy and spa es he use o
p ecious ans usion p oduc s equi ed wi h plasma
exchange and a oids he associa ed side e ec s.
Tocilizumab
B cells a e hough o be c ucial o he ongoing immune
esponse in pa ien s wi h ANABs. IL-6 is a cy okine hough
o be a key playe in B-cell ma u a ion and e minal di e -
en ia ion in o plasma cells, which sec e e copious an i-
body.
109
A s udy o neu omyeli is op ica (NMO) wi h
aquapo in-4 an ibody–posi i e pa ien s iden i ied IL-6 as a
key cy okine o B-cell ma u a ion and disease-speci ic
an ibody p oduc ion.
110
P elimina y da a using Tocilizu-
mab, an an i-IL-6 monoclonal an ibody, in NMO and
au oimmune encephali is is encou aging, and mo e wo k
mus be done o assess he e icacy o his as a s andalone
second-line he apy.
111
Low-dose IL-2
A Ko ean g oup has ea ed pa ien s wi h ocilizumab in
combina ion wi h low-dose IL-2 o s imula e T egula o y
cells, which is known o educe T-cell ac i a ion and a enu-
a e B-cell ma u a ion in ge minal cen e s, wi h encou aging
esul s.
112
A ca ea is ha i is impossible o un angle he
e ec o indi idual ea men s when mul iple ones a e gi en
con empo aneously. This s udy is u he hampe ed by
small sample size and he absence o con i ma ion o neu-
onal su ace an ibodies in some o he pa ien s.
Bo ezomib
Plasma cells a e key componen s o he humo al immune
esponse. Bo ezomib was o iginally designed as a ea -
men o myeloma and unc ions by inhibi ing p o easome
unc ion in cells.
113
This is hough o a ec he immune
sys em in a a ie y o ways, bu plasma cells, due o hei
p o ein syn hesis, a e s ongly dependen on p o easomal
unc ion. Bo ezomib, he e o e, is hypo hesized o cause an
accumula ion o p oapop o ic ac o s and a ge ed cell
dea h, especially in plasma cells. This ea men has been
ialed in NMDAR-Ab encephali is in wo e ac o y
pa ien s and demons a ed p omising ini ial esul s.
107
Fu -
he s udies wi h ca e ully selec ed pa ien s a e needed.
Immunomodula o y ea men s a e no wi hou ad e se
side e ec s. Ad e se e ec s o immunoabso p ion include
coloniza ion o ca he e ip wi h coagulase-nega i e s aphy-
lococci and enous ai embolism.
107
Uppe espi a o y ac
in ec ion and pha yngi is o nasopha yngi is can be e-
quen ly obse ed in pa ien s ecei ing acilizumab.
114
In
hese pa ien s, clinical labo a o y abno mali ies include
neu openia and ele a ed amino ans e ase le els. One o
he mos common side e ec s o bo ezomib is pe iphe al
neu opa hy ha is p edominan ly senso y wi h bu ning
pa es hesia, hype es hesia–hypoes hesia, neu opa hic pain,
and weakness.
115
Conclusions and Fu u e
Di ec ions
An i-in lamma o y d ugs ha e been epo ed o con ol
seizu es in d ug- esis an epilepsy and in selec ed epilepsy
synd omes e en in he absence o a clea in lamma o y
basis. An au oimmune e iology is inc easingly iden i ied
among pa ien s wi h epilepsy in whom no unequi ocal
causes a e de ec ed wi h he p esen diagnos ic aids. In addi-
ion, seizu es can ini ia e b ain in lamma ion in glial cells
and p omo e BBB dis up ion independen o leukocy es o
blood-bo ne in lamma o y molecules.
116
Howe e , wi h
one excep ion,
117
he p esen e idence o seizu e educ ion
by an i-in lamma o y d ugs in humans elies mos ly on case
epo s o small se ies. In hese cases, a chance associa ion
be ween he disease and biological ma ke s o al e ed
immuni y is s ill possible. We canno e en con i m ha d ug
esis ance has an au oimmune basis in hese pa ien s
because a mo e igo ous in es iga ion o immune mecha-
nisms is ypically pe o med in pa ien s wi h he mos se e e
disease a ie ies. Resea ch in he ield o au oimmune
epilepsies is a a as pace, wi h mul iple new au oan ibodies
disco e ed e e y yea . Nume ous ques ions mus be
answe ed. These can be di ided in hose ega ding basic
mechanisms and hose ega ding clinical e alua ion and
he apy. Fo ins ance, a p esen i is comple ely unclea
why an ibodies such as an i-LGI mos ly a ge he limbic
egions bu almos no pa hologic o clinical changes a e
ound in egions ha also ha e high concen a ions o he
a ge an igen such as he ce ebellum. Some o he mo e
basic ques ions ha he e o e need o be add essed in he
u u e a e he concep o an ibody o ma ion, he mecha-
nisms by which he an ibody gains access o he CNS, and
he eason ha he BBB ( o ins ance in an i-LGI encephali-
is) seems o be b eached mos ly in limbic s uc u es. Fu -
he mo e, he associa ion o he pes simplex i us wi h an i-
NMDAR an ibodies sugges s ha i al in ec ion, a leas in
some pa ien s wi h an i-NMDAR encephali is, migh acili-
a e a b eak in ole ance gi ing ise o disease. I is s ill
unclea whe he o he an ibody-associa ed limbic epilepsies
a e also seconda y o a p ima y ( i al) in ec ion.
F om a clinical poin o iew he sea ch o u he an i-
bodies is equi ed because his may dec ease he numbe o
pa ien s wi h clinical, MRI, and CSF indings o LE bu no
iden i iable ANABs. A he same ime, i is impo an ha
awa eness o cha ac e is ic clinical synd omes is imp o ed
o allow o ea ly iden i ica ion and ea men , gi en he
bene icial e ec o p omp ea men on ou come. In addi-
ion, he ques ion should be asked whe he i is use ul ha
Epilepsia, 58(Suppl. 3):57–68, 2017
doi: 10.1111/epi.13784
65
Immuni y in human epilepsy