Clinical Features, EEG Findings and Outcome in Patients ...journals.tubitak.gov.tr/medical/issues/sag-07-37-3/sag-37-3-8-0611... · Introduction Heterotopias are malformations of

Turk J Med Sci2007; 37 (3): 157-165© TÜB‹TAKE-mail: [email protected]

157

ORIGINAL ARTICLE

Clinical Features, EEG Findings and Outcome inPatients with Bilateral Periventricular Nodular

Heterotopia and Epilepsy

Aim: To review the clinical, electrophysiological and neuroimaging data of eight adult patients (4F/4M) withepilepsy and bilateral periventricular nodular heterotopia (PNH) after a long duration of follow-up.

Materials and Methods: The clinical charts were reviewed for demographic and clinical features, seizuretypes and frequency, treatment and prognosis of all eight patients who were under follow-up by one of theauthors (SS). The recordings of video-EEG monitoring with scalp electrodes in five patients and routine EEGsin all patients were reviewed.

Results: The clinical semiology was in accord with seizures originating from temporal lobe region in fourpatients, while an extratemporal onset was assumed in the others (in one with additional temporal seizures).Interictal EEGs were normal in one patient, who was diagnosed as having psychogenic nonepileptic seizure.Abnormalities seen in interictal EEGs were bilateral independent temporal focus in three, unilateralepileptiform abnormalities in two, and generalized 3 cyc/sec discharges mimicking idiopathic generalizedepilepsies in two patients. Only two patients’ MRI revealed bilaterally contiguous heterotopic nodules(symmetric and asymmetric type) and, interestingly, these two patients did not have intractable seizures whilethe other six patients with bilateral, asymmetric and noncontiguous heterotopic nodules suffered fromintractable seizures.

Conclusions: Patients with bilateral PNH have different clinical features, EEG findings and extension of theheterotopic nodules. These patients may be misdiagnosed as having idiopathic generalized epilepsy, temporallobe epilepsy or even psychogenic nonepileptic seizures without high quality MRI because of the misleadingseizure semiology and interictal-ictal EEG findings. Seizures are usually drug-resistant but the patients whohave diffuse symmetric or asymmetric contiguous heterotopic nodules may have good prognosis.

Key Words: Nodular heterotopia, periventricular heterotopia, subependymal heterotopia, epilepsy, EEG,MRI, prognosis

Bilateral Periventriküler Noduler Heterotopi ve Epilepsi - Klinik, ElektrografikÖzellikler ve Prognoz

Amaç: Epilepsi tan›s› alan ve bilateral periventriküler nodüler heterotopi (PNH) saptanan sekiz eriflkin hastan›n(4F/4M) klinik, elektrofizyolojik, nörogörüntüleme ve prognostik özelliklerini uzun süreli takip sonras›ndade¤erlendirmek.

Yöntem ve Gereç: Olgular›n demografik ve klinik özellikleri, nöbet semiyolojileri, tedavi protokolleri ve klinikizlem özellikleri hastane takip dosyalar› incelenerek elde edildi. Rutin EEG incelemesi tüm olgularda yap›lm›fl,ayr›ca befl olgu video-EEG monitorizasyon incelemesi ile de¤erlendirilmifltir.

Bulgular: Klinik semiyoloji dört hastada temporal lob, dört hastada ise ekstratemporal özellikli nöbetler (birolguda efllik eden temporal nöbetler de vard›) ile uyumlu bulundu. ‹nteriktal EEG de üç hastada bilateralba¤›ms›z temporal odak, iki olguda unilateral epileptiform bozukluk, ve iki olguda idyopatik jeneralizeepilepsiye benzer jeneralize 3 Hz desarjlar› gözlendi. Baflvuru öncesinde psikojenik nonepileptik nöbet tan›s›alm›fl bir olguda normal olarak de¤erlendirildi. ‹ki hastada MRG de bilateral devaml›l›k gösteren heterotopiknodüller (simetrik ve asimetrik tipte) gözlendi, bu olgularda nöbetler ilaca dirençli de¤ildi. Di¤er hastalardabilateral asimetrik ve devaml›l›k göstermeyen nodüller gözlendi, bu olgularda nöbetler ilaca dirençliydi.

Sonuç: Bilateral PNH olgular›nda klinik bulgular, EEG bulgular› ve heterotopik nodüllerin yay›l›m› farkl›l›kgösterir. Bu hastalar idiyopatik jeneralize epilepsi, temporal lob epilepsisi ya da psikojenik non-epileptik nöbettan›lar›n›, ayr›nt›l› MRG incelemeleri yap›lmad›¤›nda alabilirler. Nöbetler genellikle ilaca dirençlidir, ancak diffuzsimetrik ya da asimetrik devaml›l›k gösteren olgularda prognoz iyi olabilir.

Anahtar Sözcükler: Nodüler heterotopi, perivetriküler heterotopi, subepandimal heterotopi, epilepsi, EEG,MRG, prognoz

Aysun ÜNAL

Serap SAYGI

Department of Neurology,Faculty of Medicine,Hacettepe University,06100 S›hhiye, Ankara - TURKEY

Received: November 06, 2006Accepted: May 11, 2007

Correspondence

Serap SAYGIDepartment of Neurology,

Faculty of Medicine,Hacettepe University,

06100 S›hhiye, Ankara - TURKEY

[email protected]

Introduction

Heterotopias are malformations of corticaldevelopment characterized by the presence of apparentlynormal brain cells in abnormal position. Neurons thatpopulate the adult cortex first occur in the germinal layerof the ventricular zone, and to get to their proper adultlocation, most cerebral cortical neurons migrate alongtracks of radially oriented glial cells. In periventricularnodular heterotopia (PNH), there is a total failure ofmigration of some neurons. These neurons remain in theventricular zone as clumps or nodules of differentiatedneurons, while the remainder of the neurons migratenormally and completely to form the proper six-layeredcortex (1-4).

An X-linked dominant inheritance has been establishedfor familial bilateral PNH in females, a condition alsocharacterized by a high incidence of spontaneousmiscarriages particularly in male fetuses. Linkage analysismapped this disorder to Xq28, and filamin 1 gene wasidentified as the related gene (5-7). Sporadic cases ofbilateral PNH both in females and males have also beendescribed (8,9). Nodular heterotopias are also observedin other conditions with multiple causative genes, andenvironmental etiologies are suggested (10).

Magnetic resonance imaging (MRI) is the best imagingmodality to disclose PNH and describe the morphology,extension, and boundaries of the malformation, and itmay display associated cortical dysplasias or other brainmalformations. High resolution MRI has revolutionizedthe study of cortical dysplasia by showing how importantthese conditions are as a cause of epilepsy (11-14). MRIfeatures of PNH are sufficient to identify it as a distinctneuronal migration disorder. However, while manyrecent papers have described the advances ofneuroradiological aspects of cortical malformations, fewstudies have investigated the clinical, prognostic and long-term follow-up of patients with these malformations(10,14-16).

In this study, we investigated the clinical,neurophysiological, and neuroimaging features of eightepilepsy patients with bilateral PNH, focusing on thecourse and prognosis of epilepsy in this group of corticalmalformations.

Materials and Methods

Six of the eight patients included in the study werereferred to the epilepsy center of our hospital because ofdrug-resistant seizures. The presence of PNH wasassessed by means of MRI in all cases (Figure 1). Thepatients were characterized by bilateral multiple nodulesof heterotopic gray matter in the subependymal region ofventricles.

The clinical histories of the patients were analyzedwith particular attention paid to a family history ofepilepsy, spontaneous miscarriages, early infant or childdeaths and other cardiac, renal or neurological diseases.The presence of risk factors for brain damage duringprenatal or perinatal life; their motor, mental and speechdevelopment; their neurological status; and their mentallevel were all questioned in detail. The epileptic histories,the age and modality of seizure onset, and the semiologyof the seizures were carefully reviewed. Theelectroclinical features and clinical course of the epilepsyas well as the response to different antiepileptic drugtherapies were recorded.

The routine EEG was recorded after the 10-20international systems of electrode positioning with 8-channel Grass EEG machine. Long-term video EEGmonitoring, with 32 channels, and added T1-T2 and ECGelectrodes, could be performed in five patients(Telefactor Beehive or Millennium). Videotapes and ictal-interictal EEGs were also reviewed in detail. The MRIscans were made at a field strength of 1.5 or 3.0 Tesla(including T1-weighted sagittal and transverse, T2-weighted and FLAIR transverse and coronal, 3B T1-weighted gradient echo coronal examinations) with1.5mm slices.

Results

The studied group consisted of eight patients (4males, 4 females; age range: 20 to 59 years).Consanguineous marriage was present in five patients.Miscarriage or early child death was reported in threefamilies. Family history of epilepsy was not reported inany patient. Perinatal risk factors were reported in onepatient with a threatened abortion at the third month ofpregnancy, and she was delivered via caesarian section(Case 1). All patients except one (Case 5) had normalacquisition of early developmental milestones. Only Case5 also had neurological deficit, dysmorphism and severe

158

ÜNAL, A et al. Periventricular Nodular Heterotopia and Epilepsy Turk J Med Sci

mental retardation with chromosomal abnormality. Threepatients had a junior high school diploma, three had asenior high school diploma and one had a universitydegree.

Median age at onset of recurrent seizures was 15years (range: 6 months – 24 years). Complex partialseizures were reported by seven patients, but secondarygeneralized seizures in five patients. Falling attacks werealso reported in four patients. The clinical semiology wasin accord with seizures originating from temporal regionin four, from extratemporal regions (frontal and parietal)in three, and extratemporal onset together with temporalonset was assumed in one patient (Table 1). The meanfollow-up was 13.4 years, with a minimum of two and amaximum of 35 years from the onset of epilepsy.Although the frequency of seizures decreased with drugs,all patients except two continued to have disablingfrequent seizures. Vagal nerve stimulation was used inone patient (Case 1). At least one drug was used in

therapy. On the 35th year of follow-up, Case 4 stillreported complex partial seizures with three antiepilepticdrug combinations.

Routine interictal EEG recordings showed a normalbackground activity in five patients. Slow backgroundactivity was recorded in three patients. Focalabnormalities, nonspecific (theta activity) or epileptiform,were present in seven recordings. In one patient, allroutine EEG examinations (6 recordings) were regardedas normal (Case 8). No patient showed photic driving orother EEG changes during photic stimulation. Isolatedspike activity was recorded in two patients. 3-3.5cyc/secgeneralized spike–wave activity mimicking primarygeneralized epilepsy was detected in two cases (Figure 2).Video-EEG monitorization with scalp electrodes wasperformed in five patients. Ictal rhythmic activity wasrecorded in four patients. Twenty-six seizures wererecorded during 1-3 days (mean: 6.5 seizures perpatient). Ictal EEGs of four patients showed rhythmic

159

Vol: 37 No: 3 Periventricular Nodular Heterotopia and Epilepsy June 2007

Figure 1. MRI. All cases have simple bilateral PNH. (a) Case 1, coronal T2 weighted image displays periventricular nodulesin the left peritrigonal region and bilateral frontal horns (arrow). The signal from the nodules is homogeneousand consistent with grey matter. (b) Case 2, bilateral nodules are present along the posterior cavity boundary.(c) Coronal TSE IR T1 weighted image from Case 3, with bilateral PNH. (d) Coronal T2 weighted image fromCase 4, shows nodules localized at the level of posterior trigones, larger in number in the right side (arrows).(e,f) Cases 5 and 6, axial T2 weighted images show multiple subependymal heterotopic nodules in occipital hornsof ventricles.

a b c

d e f

160


Tabl

e 1.

Clin

ical

, dem

ogra

phic

, his

tory

, neu

roim

agin

g an

d fo

llow

-up

resu

lts o

f th

e pa

tient

s w

ith b

ilate

ral P

NH

(BP

NH

).

Age/

Pare

ntal

Seiz

ure

Fam

ily h

isto

rySe

izur

e ty

pes

in h

isto

ry a

ndN

odul

eAn

tiepi

lept

icD

rug

resp

onse

sex

cons

angu

inity

onse

t (a

ge)

follo

w-u

plo

catio

nth

erap

y

Case

122

/FFi

rst-

degr

ee15

Unr

emar

kabl

e1.

CPS

: at

age

15, 7

-8/d

ayVN

S2.

FS

w/w

o G

TCS:

at

age

16,

BPN

H+

once

in 2

-3 m

onth

s(O

+T+F

)LT

G 2

00 m

g/d

CPS:

4-6

t/d

3. F

allin

g se

izur

es, l

ook-

like

(Fig

1a)

PB 2

00 m

g/d

FS: s

topp

edat

onic

sei

zure

s: in

last

CBZ

800

mg

Falli

ngs:

2 t

/m18

mon

ths,

5-6

t/m

LTC

1000

mg/

d

Case

222

/FSe

cond

-deg

ree

13U

nrem

arka

ble

1. G

TCS:

at

age

13, o

nce

inBP

NH

CBZ

400

mg/

d2-

3 m

(O+T

) CL

Z 2x

0.5

mg/

dG

TCS:

sto

pped

2. C

PS: 2

-3 t

/m(F

ig 1

b)PB

125

mg/

dCP

S: 4

-12

t/d

Case

320

/M(-

)18

Mot

her

had

two

1. C

PS: 1

0-12

t/w

eek

OxC

BZ 1

500

mg/

dCP

S: 2

-3 t

/dm

isca

rria

ges

in t

he2.

GTC

S: o

nly

once

BPN

HLT

C 10

00 m

g/d

FS: s

topp

edfir

st t

rim

este

r3.

FS:

onc

e in

2-3

mon

ths

(O+T

) G

TCS:

sto

pped

Has

2 h

ealth

y si

ster

s (F

ig 1

c)

Case

459

/MSe

cond

-deg

ree

24A

sist

er d

ied

in t

he f

irst

1. C

PS: 1

0-12

t/m

BPN

HLT

C 20

00 m

g/d

CPS

with

pur

eye

ar; h

as a

hea

lthy

son

2. G

TCS:

1-2

t/y

ear

(O+T

+F)

CBZ

1200

mg/

dam

nesi

a: 2

-3 t

/man

d a

heal

thy

daug

hter

;3.

Fal

ling

seiz

ures

: 1-2

t/m

(Fig

1d)

PB 2

50 m

g/d

Falli

ngs:

stop

ped

His

dau

ghte

r ha

s on

eG

TCS:

sto

pped

mis

carr

iage

Case

526

/MSe

cond

-deg

ree

6 m

onth

sM

othe

r re

port

ed 3

ear

ly1.

FS

with

SG

TCS:

1 t

/mBP

NH

LTG

100

mg/

din

fant

dea

ths

2. F

allin

g se

izur

es: 1

-2 t

/m(O

+T+F

) CL

Z 1x

2 m

g/d

FS w

sG

TCS:

1-2

tM

ater

nal a

unt

expe

rien

ced

(Fig

1e)

DPH

: 400

mg/

din

6 m

onth

s3

earl

y ch

ild d

eath

sFa

lling

s: 1

-2 t

/m

Case

620

/MFi

rst-

degr

ee

14U

nrem

arka

ble

1. C

PS: 2

5-30

t/m

BPN

H(O

+T)

LTC

2000

mg/

dCP

S:15

-20

t/m

(Fig

1f)

TPM

100

mg/

dCB

Z 60

0 m

g/d

Case

727

/F(-

)16

Unr

emar

kabl

e1.

CPS

: onc

eBP

NH

2. G

TCS:

2 t

imes

in t

he f

irst

(con

tiguo

us n

odul

es)

CBZ

900

mg/

dSe

izur

e-fr

eeye

ar o

f fo

llow

-up

(Fig

3a)

Case

826

/F(-

)14

Unr

emar

kabl

e1.

SPS

and

CPS

: 1-2

t/w

BPN

HCB

Z 20

0-60

0 m

g/d

SPS

with

aut

onom

ic(C

ontig

uous

nod

ules

,sy

mpt

oms:

1-2

t/w

pred

omin

antly

on

the

righ

t si

de)

(Fig

3b)

CPS:

Com

plex

par

tial s

eizu

re. F

S: F

ocal

mot

or s

eizu

re. G

TCS:

Gen

eral

ized

ton

ic-c

loni

c se

izur

e. F

SwsG

TCS:

Foc

al m

otor

sei

zure

with

sec

onda

ry g

ener

aliz

atio

n. t

: Tim

es. m

: Mon

th. O

: Occ

ipita

l. T:

Tem

pora

l. F:

Fro

ntal

.VN

S: V

agal

ner

ve s

timul

atio

n. L

TG: L

amot

rigi

ne. P

B: P

heno

barb

ital.

CBZ:

Car

bam

azep

ine.

LTC

: Lev

etir

acet

am. C

LZ: C

lona

zepa

m. O

xCBZ

: Oxc

arba

maz

epin

e. D

PH: D

iphe

nylh

ydan

toin

. TPM

: Top

iram

ate.

161


Tabl

e 2.

Ict

al a

nd in

teri

ctal

ele

ctro

grap

hic

and

clin

ical

fin

ding

s of

the

pat

ient

s.

Icta

l EEG

Inte

rict

al E

EGSe

mio

logy

of

seiz

ures

EEG

foc

us

Case

1

Left

tem

pora

l 5-6

cyc

/sec

, rh

ythm

icBa

ckgr

ound

act

ivity

: 7-

8 cy

c/se

c Is

olat

ed

Loss

of

cons

ciou

snes

s, b

linki

ng,

Bila

tera

l tem

pora

l with

left

shar

p w

aves

, th

en g

ener

aliz

ed s

harp

spik

e ac

tivity

ove

r le

ft p

oste

rior

tem

pora

lw

ith a

utom

atis

ms

in h

ands

and

pred

omin

ance

and

slow

wav

e co

mpl

exes

(10

-30

sec)

regi

on a

nd 3

-3.5

cyc

/sec

gen

eral

ized

spi

keur

inar

y in

cont

inen

ce (

15-2

0 se

c)w

ave

activ

ity (

Fig

2)

Case

2

Seve

n se

izur

es r

ecor

ded;

rhy

thm

ic s

harp

Back

grou

nd a

ctiv

ity.:

9-10

cyc

/sec

CPS

with

out

auto

mat

ism

sBi

late

ral i

ndep

ende

nt t

empo

ral

thet

a an

d al

pha

activ

ity in

the

left

tem

pora

lCe

ntra

l, ri

ght

cent

ro-p

arie

tal a

nd(2

0-30

sec

)re

gion

in f

our

and

the

sam

e ac

tivity

in t

hebi

late

ral f

ront

al s

pike

s Pa

roxy

smal

act

ivity

righ

t te

mpo

ral r

egio

n in

thr

ee o

f th

eof

inde

pend

ent

thet

a, d

elta

slo

w a

nd s

harp

seiz

ures

wav

es o

ver

bila

tera

l tem

pora

l reg

ions

Case

3

Dur

ing

5 da

ys m

onito

riza

tion

noBa

ckgr

ound

act

ivity

: 9-

10 c

yc/s

ec(R

ecor

ded

duri

ng f

ollo

w-u

p)Le

ft t

empo

ral r

egio

nse

izur

e w

as d

etec

ted

Back

grou

nd a

ctiv

ity:

9-10

cyc

/sec

Amne

sia

and

conf

usio

n w

ithou

tau

tom

atis

ms

(pur

e am

nest

ic)

Case

4

Back

grou

nd a

ctiv

ity;

9-10

cyc

/sec

Isol

ated

sha

rp w

aves

ove

rU

nfor

ced

devi

atio

n of

hea

d t

o ri

ght

Rig

ht t

empo

ral r

egio

npa

riet

o-oc

cipi

tal a

lpha

and

5-7

cyc

/sec

righ

t t

empo

ral r

egio

nsi

de,

auto

mat

ism

in t

he r

ight

han

d,ce

ntra

l the

ta B

ilate

ral f

ast

activ

ity f

ordy

ston

ia in

the

left

han

d,5

sec,

then

5-7

cyc

/sec

the

ta o

ver

righ

tun

cons

ciou

snes

s (4

0-60

sec

) te

mpo

ral r

egio

n an

d bi

late

ral d

elta

and

thet

a ac

tivity

with

vol

tage

dep

ress

ion

Case

5

Not

per

form

edBa

ckgr

ound

act

ivity

: 7-

8 cy

c/se

c(h

isto

ry)

L pa

riet

o-oc

cipi

tal r

egio

nsl

ow a

nd s

harp

wav

es in

left

par

ieto

-occ

ipita

lCl

onic

mov

emen

ts in

the

rig

htre

gion

arm

spr

eadi

ng t

o ri

ght

leg

then

seco

ndar

y ge

nera

lizat

ion.

Case

63-

4 cy

c/se

c hi

gh a

mpl

itude

del

taBa

ckgr

ound

act

ivity

: 7-

8 cy

c/se

c th

eta

Voca

lizat

ion,

loss

of

cons

ciou

snes

s,R

ight

tem

pora

l reg

ion

activ

ity o

ver

righ

t te

mpo

ral r

egio

n,1-

2cyc

/sec

slo

w-s

harp

wav

e de

lta a

ctiv

ityau

tom

atis

ms

in b

oth

hand

ssp

read

ing

to ip

sila

tera

l hem

isph

ere

over

rig

ht t

empo

ral r

egio

nw

ith a

mpl

itude

asy

mm

etry

hig

her

than

50%

, th

en g

ener

aliz

atio

n

Case

7

Not

per

form

edSl

ow-s

harp

wav

es in

bila

tera

l tem

pora

l(h

isto

ry)

Bila

tera

l tem

pora

l reg

ions

regi

ons

with

left

pre

dom

inan

ceVi

sual

hal

luci

natio

ns,

mov

emen

tsw

ith le

ft p

redo

min

ance

in h

er le

ft a

rm a

nd le

g th

at w

ould

spre

ad t

o in

volv

e th

e fa

ce a

ndsu

bseq

uent

ly h

er e

ntir

e bo

dy

Case

8N

ot p

erfo

rmed

Nor

mal

,(h

isto

ry)

Coul

d no

t be

det

ecte

dBa

ckgr

ound

act

ivity

: 9-

10 c

yc/s

ec

Left

sid

ed f

ocal

mot

or-s

enso

ryse

izur

es

w/w

o se

cond

ary

gene

raliz

atio

n Is

olat

ed s

eizu

res

with

auto

nom

ic s

ympt

oms

(tac

hyca

rdia

,ch

est

pain

and

sw

eatin

g)

CPS:

Com

plex

par

tial s

eizu

re.

w/w

o: W

ith o

r w

ithou

t.

activities over the temporal lobes initially. Ictal andinterictal EEG changes with seizure semiology arepresented in Table 2.

Well-defined small nodules of heterotopic grey matterappeared isointense as normal grey matter on all imagingsequences. The nodules were localized along the walls ofthe ventricles bilaterally in all cases. Nodules weremultiple, but not contiguous in six patients. Bilaterallylocated contiguous nodules were present in two patients;one symmetric and one asymmetric (Cases 7 and 8,Figure 3). None had nodules along the third or fourthventricles. Nodules were located in occipital and temporalhorns in four patients, and in occipital, temporal andfrontal horns in two patients (Table 1). No patient wasaffected by PNH associated with other more pronouncedbrain malformations (i.e., schizencephaly andpolymicrogyria) or structural abnormality, but in MRI ofCase 8 hippocampal morphological asymmetry was seen.

Discussion

A wide variety and heterogeneity of clinical pictureshave been reported in patients with PNH. Many reportedseries have included all kinds of heterotopias, orperiventricular heterotopias with other corticaldysgenesis or structural brain abnormalities. Dubeau etal. (17) divided PNH patients according to the type of the

heterotopic grey matter into two groups as simple PNH(patients with PNH without other cortical and/or cerebralmalformations) and PNH-plus (PNH patients with othercortical and/or cerebral malformations). The nodules canalso be anatomically subdivided into two types: unilateralor bilateral in disposition and focal or diffuse inlocalization (10,18,19). Therefore, it will be better toanalyze PNH patients first in two groups as simple andplus, and then as bilateral symmetric, asymmetric, andunilateral. In this study, PNH demonstrated by highresolution MRI was found as an isolated anomaly (simplePNH), and all nodules were bilaterally located in theperiventricular region. One was bilateral diffusesymmetric and the other seven were bilateralasymmetric.

Epilepsy has been reported in the second or thirddecade of life or earlier in PNH patients with nodysmorphic features (10,14). Seizure frequency rangesfrom rare to very frequent, and seizures are oftenresistant to polytherapy (5,14,18). Six of the eightpatients in the presented study came to medical attentionbecause of their intractable seizures. In two patients, withbilateral diffuse PNH, response to medical therapy wasgood (Cases 7 and 8). Resistant seizures and severemental retardation with dysmorphic features werepresent in Case 5. He was followed-up for 25 years withthe diagnosis of cerebral palsy and mental retardation.Case 6 and Case 4 were misdiagnosed and followed-up astemporal lobe epilepsy for years. Case 8 was diagnosed asanxiety and panic attack disorder and none of the routine

162


Figure 2. 3.0-3.5 Hz generalized spike-wave activity recorded duringlong-term video EEG monitoring of Case 1.

Figure 3. a) Axial SE T1 weighted image from Case 7, shows bilateralsymmetric heterotopic grey matter localized alongsubependymal region of lateral ventricles. b) T2 weightedimage of Case 8 with bilateral asymmetric located PNH.

a b

EEG examinations revealed any abnormality. Evaluationwith detailed MRI was helpful in the proper diagnosis inall presented cases. Therefore, it is important firstly toknow and call to mind PNH, and then to examine theperiventricular walls, especially with high resolution MRI,in searching the cause of epilepsy.

Incidence of complex partial seizures with severalclinical symptoms suggesting mesial or neocorticaltemporal and parieto-occipital onset was striking. Limbicand visual auras were recorded in two patients. Threepatients presented with focal motor seizures suggestingcentral or frontal origin. Three patients tended to havebilateral independent temporal epileptic abnormalities.Isolated spike activity was recorded in two patients. 3-3.5cyc/sec generalized spike–wave activity mimickingprimary generalized epilepsy was detected in two cases.Raymond et al. (18) first mentioned generalizeddischarges mimicking primary generalized epilepsy in1994 in three of the 13 PNH patients in their series. In1995, Dubeau et al. (17) mentioned the same activity inone patient. We evaluated the characteristics of thesepreviously reported four cases; nodules were locatedbilaterally asymmetric in three of them, as in our cases,and unilateral in the remaining one. However, Battaglia etal. (10) in 1997 reported that EEG abnormalities werealways focal in their cases, unlike previously describedones. In 14 cases of Battaglia’s series, PNH wasassociated with another structural abnormality of thebrain. The remaining three cases were in simple PNHform, but the location and type of PNH was bilateral inonly one of them. In five of the six patients with 3-3.5 Hzgeneralized spike-wave activity (including ours), noduleswere located bilaterally and asymmetric.

Bilateral diffuse symmetrical form of PNH has beenreported more than bilateral asymmetrical and unilateralforms in the literature. The patients with bilateralasymmetrical PNH were thought to share similar featureswith patients with bilateral symmetrical or unilateral PNH(16). Most of the reported patients with bilateralasymmetrical PNH in the literature have associatedstructural abnormalities of the posterior fossa, and apositive family history for epilepsy, as in the case ofbilateral symmetrical PNH, but the localization of nodulesare more pronounced in the paratrigonal regions, as inunilateral PNH. Although clear female predominance andfrequent familial occurrence in bilateral, symmetrical, anddiffuse cases have been reported, unilateral and bilateral

asymmetric cases are not associated with sex prevalence.In accord with the previously reported bilateralasymmetric PNH cases, two of the six presented cases inthis study were female.

Recent human and experimental studies have shownneuronal connections between heterotopic nodules andbetween nodules and cortex (6). These studies havesuggested that intranodular neurons have alteredexcitatory or inhibitory transmission. Hannan et al. (20)showed, in surgical specimens obtained from epilepticchildren with nodular heterotopia, that the heterotopia,either subcortical or subependymal, had sparseconnections with each other and with other parts of thehemisphere, including the cortex (21). Aghakhani et al.(22) analyzed the respective roles of heterotopia,temporal and extra-temporal neocortex and mesialtemporal lobe structures in the generation of epilepticactivity in a relatively large series of patients with PNHand focal epilepsy. They confirmed that nodules ofheterotopic grey matter can generate both normal andabnormal electrical activity (23). Bilateral multiple orcontiguous PNH were often associated with widespreadepileptogenesis, where classical surgical approaches(temporal resection) are unlikely to be effective (24).Aghakhani et al. (22) used amygdalo-hippocampectomyin two patients (outcome: Engel class Id and III),amygdalo-hippocampectomy plus removal of an adjacentheterotopion in two patients (class Ia), resection of twocontiguous nodules plus a small rim of overlying occipitalcortex in one patient (class Id) and hippocampectomy plusremoval of three adjacent heterotopia in one patient(class IV) as the surgical approaches. In unilateral nodules,they suggested that investigation by stereo-EEG mayindicate a focal resection, and a good outcome may beexpected (Engel class I). In this study, there were twopatients with bilateral noncontiguous asymmetric nodulesand they were the most intractable ones of the operatedcases (Engel class III and IV).

In 2003, d’Orsi et al. (14) compared clinical andelectrophysiological findings of eight simple PNH patientswith eight PNH-plus patients. PNH cases with unilateralor bilateral asymmetric localization were evaluated. Theyfound that neurological deficits were more common andseizure frequency was higher in the PNH-plus group anddrop attacks were experienced only in these patients. Werecorded three patients with falling attacks similar toatonic seizures. Although the number of reported cases

163


with falling attacks is so small, this finding suggests thatfalling attack is another seizure type that can be seen inbilateral asymmetric PNH cases. It was exciting for us tosee that the clinical symptoms of one of the cases inD’Orsi’s series were similar with those of Case 5: facialdysmorphisms, small penis and undescended testes,hypoplastic distal and middle phalanges, obesity, mentalretardation and epilepsy.

Generalized tonic-clonic seizures occurred duringthe early phases of epilepsy in five patients in our study,and were completely controlled by treatment in all exceptone. However, complex partial seizures were mainlyresistant to therapy. The oldest patient of published casesis presented here, at 59 years of age; he is quite welldespite the intractable focal seizures. Surprisingly, twopatients became seizure-free.

In conclusion, patients with bilateral PNHs havevariable clinical features, EEG findings and extension ofthe heterotopic nodules. These patients may bemisdiagnosed as having idiopathic generalized epilepsy,temporal lobe epilepsy or even psychogenic nonepilepticseizures without high quality MRI because of themisleading seizure semiology and interictal-ictal EEGfindings. Seizures are usually drug-resistant but thepatients who have diffuse symmetric or asymmetriccontiguous heterotopic nodules may have goodprognosis. Studies taking into account the type,multiplicity and localization of the nodules will be morehelpful in explaining the clinical characteristics and follow-up strategies in patients with PNH.

164


References1. Pearlman AL, Faust PL, Hatten ME, Brunstrom JE. New directions

for neuronal migration. Curr Opin Neurobiol 1998; 8(1): 845-854.

2. Fox JW, Walsh CA. Periventricular heterotopia and the genetics ofneuronal migration in the cerebral cortex. Am J Hum Genet1999; 65: 19-24.

3. Pilz D, Stoodley N, Golden JA. Neuronal migration, cerebralcortical development, and cerebral cortical anomalies. JNeuropathol Exp Neurol 2002; 61(1): 1-11.

4. Guerrini R. Genetic malformations of the cerebral cortex andepilepsy. Epilepsia 2005; 46 (suppl 1): 32-37.

5. Huttenlocher PR, Taravath S, Mojtahedi S. Periventricularheterotopia and epilepsy. Neurology 1994; 44(1): 51-55.

6. Eksioglu YZ, Scheffer IE, Cardenas P, Knoll, J, DiMario F, RamsbyG et al. Periventricular heterotopia: an X linked dominant epilepsylocus causing aberrant cerebral cortical development. Neuron1996; 16: 77-87.

7. Fink JM, Dobyns WB, Guerrini R, Hirsch BA. Identification ofXq28 associated with bilateral periventricular nodularheterotopia. Am J Hum Genet 1997; 61: 379-387.

8. Sisodiya SM, Free SL, Thom M, Everitt AE, Fish DR, Shorvon SD.Evidence for nodular epileptogenicity and gender differences inperiventricular nodular heterotopia. Neurology 1999; 52: 336-341.

9. Sheen VL, Topcu M, Berkovic S, Yalnizoglu D, Blatt I, Bodell A etal. Autosomal recessive form of periventricular heterotopia.Neurology 2003; 60(7): 1108-1112.

10. Battaglia G, Granata T, Farina L, D'Incerti L, Franceschetti S,Avanzini G. Periventricular nodular heterotopia: epileptogenicfindings. Epilepsia 1997; 38(11): 1173-1182.

11. Barkovich AJ. Magnetic resonance imaging: role in theunderstanding of cerebral malformations. Brain Dev 2002; 24:2–12.

12. Barkovich AJ, Kuzniecky RI, Jackson GD, Gueprini R, Dobyns WB.Classification system for malformations of cortical development.Neurology 2001; 57: 2168–2178.

13. Barkovich AJ, Kjos BO. Gray matter heterotopias: MRcharacteristics and correlation with developmental and neurologicmanifestations. Radiology 1992; 182: 493-499.

14. D’Orsi G, Tinuper P, Bisulli F, Zaniboni A, Bernardi B, Rubboli Get al. Clinical features and long term outcome of epilepsy inperiventricular nodular heterotopia. Simple compared with plusforms. J Neurol Neurosurg Psychiatry 2004; 75: 873-878.

15. Chang BS, Ly J, Appignani B, Bodell A, Apse KA, Ravenscroft RSet al. Reading impairment in the neuronal migration disorder ofperiventricular nodular heterotopia. Neurology 2005; 64(5):799-803.

16. Battaglia G, Chiapparini L, Franceschetti S, Freri E, Tassi L,Bassanini S et al. Periventricular nodular heterotopia:classification, epileptic history, and genesis of epileptic discharges.Epilepsia 2006; 47(1): 86-97.

17. Dubeau F, Tampieri D, Lee N, Andermann E, Carpenter S, LeblancR et al. Periventricular and subcortical nodular heterotopia. Astudy of 33 patients. Brain 1995; 118: 1273-1287.

165


18. Raymond AA, Fish DR, Stevens JM, Sisodiya SM, Alsanjari N,Shorvon SD. Subependymal heterotopia: a distinct neuronalmigration disorder associated with epilepsy. J Neurol NeurosurgPsychiatry 1994; 57: 1195-1202.

19. Kothare SV, VanLandingham K, Armon C, Luther JS, Friedman A,Radtke RA. Seizure onset from periventricular nodularheterotopias: depth-electrode study. Neurology 1998; 51(6):1723-1727.

20. Hannan AJ, Servotte S, Katsnelson A, Sisodiya S, Blakemore C,Squier M et al. Characterization of nodular heterotopia inchildren. Brain 1999; 22: 219-238.

21. Tassi L, Colombo N, Cossu M, Mai R, Francione S, Russo GL et al.Electroclinical, MRI and neuropathological study of 10 patientswith nodular heterotopia, with surgical outcomes. Brain 2005;128: 321-337.

22. Aghakhani Y, Kinay D, Gotman J, Soualmi L, Andermann F, OliverA et al. The role of periventricular nodular heterotopia inepileptogenesis. Brain 2005; 128: 641-651.

23. Jakobs KM, Kharazia VN, Prince DA. Mechanisms underlyingepileptogenesis in cortical malformations. Epilepsy Res 1999;36(2-3): 165-188.

24. Li LM, Dubeau F, Andermann F, Fish DR, Watson C, Cascino GDet al. Periventricular nodular heterotopia and intractable temporallobe epilepsy: poor outcome after temporal lobe resection. AnnNeurol 1997; 41: 662-668.

Documents

Clinical Features, EEG Findings and Outcome in Patients ...journals.tubitak.gov.tr/medical/issues/sag-07-37-3/sag-37-3-8-0611... · Introduction Heterotopias are malformations of