Folia Psychiatrica et Neurologica
Japonica, Vol. 32, No. 1 , 1978

Neuropathology of Secondary Generalized Epilepsy(Lennox-Gastaut Syndrome)-A Case Report
Kenji Ikeda, M.D., Sumie Ikeda, M.D., Tsuyoshi Yoshimura, M.D.,
Hideaki Kato, M.D. and Masuyuki Namba, M.D.
Depurtment of Neuropsychiatry, Giju University School of Medicine, Gifu

INTRODUCTION

Lennox syndrome is commonly known as
an age-dependent childhood epilepsy with
various types of seizures (ex. tonic and
astatic seizures and atypical absences) and
characteristic diffuse slow spike and wave
complex in EEG's. It was taken for
epileptic encephalopathy by Gastaut,2 based
on clinico-electroencephalographic studies.
Many cases in which this syndrome
developed were reported to show encephalopathies originating from various causes,
which emerged mainly at the gerinatal or
infantile period. In fact, recent studies with
computerized transverse axial tomographies" suggest that this syndrome may be
a secondary generalized epilepsy with brain
lesions for a background.
In this report, an atuopsy case is
described-in which the patient had generalized epilepsy several years after suffering
from acute encephalopathy in childhood.
It is thought that the case is a Lennox
syndrome, although the age and the EEG
findings slightly deviate from typical ones.
At the adult period the patient fell into
a state of akinetic mutism caused by a
head injury.
In this report we attempt to clarify the
types and regions of the brain lesions
corresponding to the Lennox syndrome
Received for publication July 20, 1977

through clinico-neuropathological considerations about the formative process of the
lesions, especially the later additional
damage from a head injury occurring in the
adult period. Moreover, we com.pare the
brain lesions of this case with those of
the West syndrome from a viewpoint of
neuropathology.
CASE REPORT
A 23-year-old male

His family history was noncontributory.
The patient's mother had no difficulties
during her pregnancy and the delivery was
normal. He was in perfectly good health
until the age of seven, when he ran a
high fever during the summer and subsequently lapsed into unconsciousness and
convulsive fits. He was admitted to a
hospital for a month under the suspicion
of Japanese encephalitis. He recovered,
remaining mental retardation, and after two
months epileptic seizures of Jacksonian
type occurred, beginning from the left
leg or being sometimes general in nature.
Gradually the frequency of the seizures
increased and an epileptic character change
was also noticed. He was admitted to a
mental hospital at the age of 14 because
of the character change and the frequent
attacks of the astatic seizures which began
at the age of nine in addition to the

I30

K. Ikeda et ul.

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Fig. 1: Diffuse slow spike and wave complex (1.5 - 2 c/s)
with lateralization to the right.

Jacksonian type seizures. After admission,
the astatic seizures could not be controlled
even with various anti-epileptic drugs, and
they were observed two to three times a
day on the average. Almost all Jacksonian
type seizures were accompanied with a
burning sensation before the beginning of
the seizures and sometimes only this
sensation was observed. The frequency of
the seizures dwindled with the course.
N o gross neurological abnormalities were
noticed. Mental deterioration, slowness of
speech and behavior gradually progressed
during the long clinical course.
At the age of 21 years, the patient
lapsed into a coma followed by a violent
fall at a seizure. Subsequently, status epilepticus occurred with the recovery of
consciousness. After two weeks of this
state, the patient lapsed into a prolonged
coma for several weeks. Finally, the
patient fell into an akinetic-mute state and
the epileptic seizures completely disappeared. After two years he died of
pneumonia without recovery from this state.
EEG findings-Electroencephalographic

examinations were performed every six
months since admission at the age of 14.
On admission the EEG findings were
abnormal with diffuse slow spike and wave
discharges (1.5-2 c/s), which lateralized to
the right (Fig. l), but later these discharges
occasionally shifted. In sleep EEG’s, rhythmic spikes were also observed with
lateralization to the right (Fig. 2). Such
characteristic findings continued until the
head injury followed by the akinetic-mute
state at the age of 21. In that state the
EEG’s were characterized by low voltage
fast waves with sporadic 8 waves in all
leads, and no seizure discharges were
observed.
NmEU ROP ATHOLOG ICAL FIN DINGS

Gross

Externally, the brain showed so-called
“gekreuzte Hemiatrophie”.
The right
cerebral and the left cerebellar hemispheres
were markedly reduced in size. There was a
widespread, yellowish-brownish pigmentation on the external surface of the non-

131

Neuropathology of Lennox Syndrome

Fig. 2: Rhythmic spikes with predominancy on the right
frontal region.

Fig. 8: Regions with necrosis and severe looseness of tissue on coronal
scctions of the right cerebrum are indicated by oblique lines

(m).

132

K. Ikeda et ul.

Fig. 4: Old, pseudolaminar necrosis
with organization along the wall of the
gyrus. Right precentral gyrus. HE stain.

atrophied left cerebrum. On frontal sections
of the right cerebrum, widespread old
necroses with cysts were seen. The necroses
were mainly in the white matter near the
cortex and spread to the valleys of the
cortical gyri.
The necrotic areas in the right cerebrum
were divided into three main regions as
follows (Fig. 8): The greatest one was seen
consecutively from the central part of the
mid-temporal gyrus to the occipital lobe and
spread more widely in the dorsal and the
ventral directions as they moved caudally.
The second one mainly impinged upon the
precentral and the mid-frontal gyri and
partially involved the supra- and post-central
gyri and the insula. The smallest one was
found in the pre-frontal area of the orbital
and the rectal gyri.
On the other hand, the necroses in the
left cerebrum were predominantly in the
cingulatc and the parahippocampal gyri and
partially in the insula cortex. Moreover,
small linear necroses were also found in the
left pulvinar and the tectum of the midbrain
along the wall of the I11 ventricle and the
cerebral aqueduct.
Light microscopy
Cerebrum-Every

necrotic region in the

Fig. 3: A lobular sclerosis composed of predominant atrophy and
fibrous gliosis in the right cerebral
hemisphere. Old necrosis is seen near
the border of the cortex and the
medulla. Holzer stain.
right cerebral hemisphere had common findings as follows; tissue desolation with many
cysts of various sizes among severely
atrophied white matter, especially near the
border of the cortex and the medulla. The
white matter contiguous to the necrotic
regions was vastly demyelinated and the
surviving coarse axons were also separated.
An extension of the necroses to the cortex
was observed especially in the valleys of
the gyri, where almost all the layers were
destroyed.
These necroses spread as
pseudolaminal along the walls of the gyri
(Fig. 4), so the gyri were far apart. The
tops of the gyri mostly survived, but some
of the middle Po large neurons underwent
ischemic cell changes.
These necrotic

Neuropathology of Lennox Syndrome

133

Fig. 5 : Cortical necrosis with hypertrophic astrocytes, fat granule cells and
vascularization in the left cingulate gyrus.
HE stain.

regions of the right cerebral hemisphere
represented a complete organization by the
proliferation of the parenchyma, especially
by the prominent fibrous gliosis. The
fibrous gliosis predominantly
spread
throughout the whole white matter. The
gray matter Of the right hemispheric
surface, such as the cingulate and the hippocampal gyri, was well preserved (Fig. 3).
In the left hemisphere, necroses were
mainly found in the gray matter of the
cingulate and the parahippocampal gyri.
The destruction of these limbic areas was
accompanied with cleaning, restorative and
organizing processes; there were many fat
granule cells, prominently proliferated
hypertrophic astrocytes, vascularization and
fibrous gliosis (Figs. 5 and 6). There was
widespread hemosiderin deposition along
the sulci in the pia mater and on the
external surface of the left hemispheric
cortex. But in the necrotic
dePositions were not detected.
Pathological findings in the basal ganglia and the brain stem nuclei were found
mainly on the side having a fiber connection with the damaged right cerebrum,
where there was more chronically formed
degeneration.

Fig, 6 : Prominent fibrous gliosis in the
limbic system of the left cerebral hemisphere.

H o l x r stain,

Fig.

lo:

loss

and

atrophy with prominent glial cell proliferation in the lateral part of the right thalamus.
Nissl’s stain.

Thalamus-The
right thalamus lost its
normal shape and size, and became thin
under the severe atrophy of its lateral
portion. The lesions consisted of neuronal
loss and atrophy, prominent glial cell

134

K. Ikeda et al.

Fig. 11: Well preserved nucleus laminaris internus (Lai) and moderately
degenerating nucleus medialis dorsalis (Md)
of the right thalamus. Nissl's stain.
proliferation and mild fibrous gliosis (Fig.
10). These chronic types of degenerative
processes were found rather diffusely
throughout almost all the nuclei of the
thalamus except the nonspecific nuclei
(ex. Cm, La) (Fig. 11). However, some
regional differences in the severity of the
lesions were seen (Fig. 9). The lateral and
the ventral nuclei had a similar regional
tendency, that is, the dorsal and the lateral
parts, especially their anterior portion,
showed severe changes. The lateral part
of the Mda and all the regions of the Mdp
showed a moderate loss of neurons. The
anterior nucleus was rather well preserved.
In the pulvinar, a heavy neuronal loss and
prominent glial cell proliferation were
observed in the all regions except the
medial and a part of the lateral regions.
The nuclei of the so-called nonspecific
nuclei had the mildest findings. The left
thalamic nuclei were well preserved except
for moderate degeneration in a part of the
anterior nucleus. The linear necrosis in the
left pulvinar seemed to be formed somewhat mechanically, where the stria medullaris was torn along the 111 ventricular
wall. This finding continued to the
midbrain tectum as already described.

Fig. 9: Secondarily dcgencrativc rcgions
of the right thalamus.
scvcrc,m;
n i o d e r a t e , m ; mild) A; N. anterior, Cm;
N. centrum medianum, GI ( r n ) ; Corpus

(m;

geniculatum lat. (med.), La; N. larninalis,
Lva, Lvp; N. lateralis ventralis, Mda, Mdp;
N. medialis dorsalis, Pf; N. parafascicularis,
Pi, PI, Pm; N. pulvinalis, Rm; N. reuniens
medianus, Rt; N. reticularis, Val(m),
Vpl(m); N. ventralis (nomenclature by
Niimi).
Striatum and pallidum-Both
the striatum and the pallidum were reduced in size
in the right brain. The neurons did not
diminish in number, but atrophied and
cell gliosis was diffuse and pronounced.
The left was well preserved.
Hypothalamus-The
left hypothalamus
showed a looseness of the tissue along the
I11 ventricular wall, where glial clustering
and also fibrous gliosis were detected. This
lesion related to the linear necrosis of the
pulvinar and the midbrain tectum.
Midbrain-The
right cerebral peduncle
was moderately demyelinated. The substantia nigra of both sides had small
cystic necrosis. Slight neuronal loss, melanin

Neuropathology of Lennox Syndrome

135

nent finding in the medulla was severe
demyelination of the right pyramis, especially in its inner part. Neurons of the right
inferior olivary nucleus were slightly reduced
in number and also some were simply
atrophied. The tectal regions showed no
change.
Cerebellum4ome limited atrophies in
the cortex that consisted of thinning of the
molecular layer, Purkinje’s and granule cell
loss and Bergmann’s glial proliferation
existed in the medial region of the left
hemisphere. In particular, Purkinje’s cell
loss and/or atrophy were detected even in
the rather well preserved folia. Many
neurons of the left dentate nucleus showed
simple atrophy, and gliosis was noted at
the hilus. The right hemisphere and the
vermis were well preserved.
DISCUSSION
Fig. 7: Linear necrosis with many fat
granule cells in the left midbrain tectum.
HE stain. Inset: Fibrous gliosis around
and cerebral aqueduct.
necrosis (+)
Holzer stain.

For the complexity of the clinical course
and the brain lesions of our case, we must
make clear the relation between the two to
know the neuropathological aspect of
Lennox syndrome.

pigment releasing and glial proliferation
were also found there. These findings
were more marked on the right side.
As for the tectal region, lineally running
necrosis was seen in the left central gray
matter along the cerebral aqueduct. Around
the necrosis, the aqueduct and the superior
colliculus, fibrous gliosis was observed
(Fig. 7). All the small necrosis in the midbrain was accompanied by many fat
granule cells and cellular infiltrations.
Pons-The tectal regions and the pontine
nuclei of both sides were well preserved,
but demyelination and slight fibrous gliosis
of the pontine longitudinal fibers were seen
on the right side.
Medulla oblongata-The
most promi-

I)

Clinicopathological analyses of the
prolonged coma and the akinetic
mutism

The necrotic lesions of both the right and
left cerebral hemispheres are thought to be
formed in close correspondence to the
acute, severe clinical symptoms. But the
distributional and microscopical differences
of the necrotic regions between both
hemispheres (i.e., in the right, mainly in the
white matter with complete organization;
in the left, on the internal surface of the
cortex yet with a cleaning process) are
thought to indicate the differences of the
pathogenesis and of the time when the
lesions were formed.
The left brain had necrotic regions in the

136

K. Ikeda et al.

cingulate and the parahippocampal gyri,
and linear ones were found along the I11
ventricle and the cerebral aqueduct. Such
distributions of necrosis are characteristic.
Here we must take into consideration the
fact that hemosiderin deposition was
widespread on the external surface of the
left hemisphere, diffused along the sulci
and never found in the necrotic regions,
which suggests that the patient had an
episode of subarachnoidal hemorrhage."
A series of these neuropathological findings on the left brain can be understood to
correspond to the clinical course after the
age of 21. Thus, the comatose state after
the violent fall, the prolonged coma after
the epileptic status and the subsequent
akinetic-mute state may be explained as
follows. Subarachnoidal hemorrhage most
likely resulted from the violent fall, and
falx and tentorial herniations of the
cingulate and the parahippocampal gyri
occurred due to brain edema caused by the
frequent convulsions lasting two weeks.
These herniations may have led to the
mechanical compression and the circulatory
disturbance in the brain stem, and subsequently to the linear necrotic lesions.
Thus, the long-lasting unconscious state
after being freed from convulsions may be
due to the midbrain tectal lesions as
described by G. Peters14 and others.'" The
lesions of the limbic system may play an
important role in the formation of the
akimtic-mute state developing after the
acute period.'? A series of these left brain
lesions has no relation to Lennox syndrome.
2)

Brain lesions during the period of
Lennox syndrome.

Lennox syndrome in the present case
was secondarily derived from encephalopathy when the patient was seven years old.
It is well known that lobular sclerosis or
cerebral hemispheric atrophy of similar

kind is often formed by perinatal injuries
or acute encephalopathies in the infantile
period.e As the pathogenesis of such
lesions, Scholzl6 stresses a circulatory
disturbance, while a damage mainly in the
white matter caused by edematous changes
is stressed by Hallervorden et aL5 In any
case, the right hemispheric sclerosis of the
patient may be caused by encephalopathy
at the age of seven. The white matter
predominancy of the necrosis leads us to
the presumption of the edematous damage
as the pathogenesis. The patient presented
Lennox syndrome at the age of nine
probably, or at the latest from 14 to 21
years old. Brain lesions of this period are
assumed to be the right hemispheric sclerosis and the degenerative changes of the
basal ganglia, especially of the thalamus due
to the hemispheric damage.
The severe lesions of the latero-dorsal
part of the thalamus suggest convulsive
damages.
Findings of no disseminated
change and no neuronophagia against
Scholz's description1g and degeneration of
the pulvinar, which is damaged very rarely
by convuIsions,lg suggest that the convulsions must have played only an accessory
role of the formation of the thalamic
lesions.
The lateralities of the basal ganglional,
the brain stem nuclear and the celebellar
damages according to fiber connections
with the right cerebrum lead us to the
conclusion that the thalamic lesions may be
mainly retrograde degeneration derived from
the initial cerebral damages.
Jacob's
description? of retrograde and transneuronal
degeneration of these rcgions coincides
with our findings.
The above described relationships
between the clinical course and the formation of the brain lesions are summarized in
Table 1. The neuropathological background
of Lennox syndrome derived from our case

Neuropathology of Lennox Syndrome

137

Table 1: Formation Process of Brain Lesions and
Cliniconeuropathological Relationship
7

AKO

7-

f-14-21

V

I1

21 - 2 5

cl1"IC.l
events

acute anc.ph.lop.thy
hish fever *to.

Jaskmonian epilepmy
dementia

I m n o x myndromo
amtatis meiiure mte.

prolonged o o u

.kin.tic

brain
lacion

(A);

".CrOBIa

(mainly white matter

(i);
R-homiiphmric
old lemion
(presentralis mtc.)

(d)ttB); basal Ian6lionls degensrmtion
(R-thaluus mtc.)

t C ) ; L-Xmbls nymtew
and mainly mldbrain
tectal a*sromim

u i n l y tAj+tb;Llimbic and midbrain
t.e1
old leaion

edematous ehanso

.car lonation

retrograde, sonvulm i l . degeneration

fala, tentriel
kmrniation

oldnoam of leaion

R-henlepheris

.it".

.tC.

m;necrosis and severe looseness of t i s s u e . m ; nonspecific type of degeneration.

is that of a unilateral basal ganglional
degeneration of a later, secondarily formed
type based on the diffuse cerebral lesions
and good preservation of the nonspecific
thalamic nuclei.
As for the Lennox syndrome, Otahara
et al.13 make much account of thalamus,
especially the nonspecific nuclei, from electroencephalographical and physiological
considerations.
The nonspecific nuclear
groups of this case were better preserved
than the specific nuclear groups, and such
a tendency of thalamic lesions is common
to physically and mentally severely disturbed
children"' and some thalamic degenerative
diseases.l2 This common tendency of
thalamic degeneration may be one of the
developing factors in common syndromes
such as "Lennox" with brain damage of
various origins in children.
It is difficult to localize the cerebral
regions responsible for Lennox syndrome
in our case with diffuse cerebral lesions of
the hemisphere. We should consider this
syndrome from the viewpoint of the functional relations between cerebrum and basal

ganglia, and of intrathalamic connections
based on such nonspecific brain lesions.
Considering the fact that epileptic seizures
completely disappeared after the age of
21, when the brain lesions may have
spread to both hemispheres, the cerebral
functions would have to be preserved in
some degree for Lennox syndrome to occur.
In this sense, cerebral lesions may work
only as a pacemaker for seizures as Gloor4
and others16 described. Accordingly, the
manner or the degree of damage in the
cerebrum should be more significant than
the regional specificity.
Some reports of West syndrome,"' which
is clinically closely related with Lennox
syndrome, are quite suggestive. Morimatsu"
pointed out common findings of West
syndrome in the cerebrum, the basal
ganglia and the brain stem tectum on his
own autopsy cases. Comprehensively, the
difference between both types of secondary
generalized epilepsies depends on whether
or not the brain stem tectum is damaged.
Moreover, the brain stem tectal lesions of
his cases belonged to such a type of

K. Ikeda et al.

138

hypoplasia.
This fact may explain a
possibility of the shift from West to Lennox
syndrome according to the maturation of
brain, such as myelinization. Here we
point out one of the functions of brain stem
tectum for a good preservation of synchronization in EEG’s, because of a characteristic hypsarrhythmia in West syndrome. It
is again significant that the disappearance
of the seizures and desynchronization of
the EEG’s were observed after the brain
lesions spread to both hemispheres and
reached the brain stem.
SUMMARY

Neuropathological considerations were
performed on a case, who went into Lennox
syndrome after an acute encephalopathy at
the infantile period, and moreover who fell
into an akinetic-mute state derived from
brain damage by herniation caused by a
head injury and subsequent status epilepticus.
Neuropathological background in the
present case of Lennox syndrome is
thought to be based on the widespread
unilateral cerebral lesions and the basal
ganglional, especially thalamic, degenerations derived secondarily from the diffuse
cerebral damage.
The patient revealed akinetic mutism
with the disappearance of the epileptic
seizures and the desynchronization of the
EEG’s, when the brain lesions formed at
the adult period spread over the opposite
hemispheric limbic system and the brain
stem tectum.
ACKNOWLEDGMENT

The authors would like to thank Jikei
Psychiatric Research Institute for excellent
technical assistance.

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