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Bilateral central macrogyria Epilepsy pseudobulbar palsy and mental retardationЧa recognizable neuronal migration disorder.

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Bilateral Central Macrogyria: Epilepsy,
Pseudobulbar Palsy, and Mental
Retardation-A Recognizable
Neuronal Migration Disorder
Ruben Kuzniecky, MD,S Frederick Andermann, MD, FRCP(C)," Donatella Tampieri, MD,"
Denis Melanson, MD," Andre Olivier, MD, PhD, FRCS(C)," and I. Leppik, MD1~~
The neuronal migration disorders comprise several morphological entities that are recognizable during life using
current imaging techniques. We studied 4 patients who had a characteristic bilateral central rolandic and sylvian
macrogyria. The patients had pseudobulbar palsy with oromotor incoordination and developmental delay and were
mildly retarded. Minor seizures developed between the ages of 8 and 9 years. Subsequently, atonic drop attacks became
the predominant epileptic pattern. Epileptogenic electrographic abnormalities were secondary generalized or multifocal. The lesions were detected by computed tomography and magnetic resonance imaging in all patients. Bilateral
symmetrical areas of thick cortex surrounding a large sulcus were seen. This syndrome consists of specific clinical,
imaging, electroencephalographic, and epileptic features. It can be suspected clinically and confirmed by imaging
studies. CalIosotomy in two patients helped the intractable seizures.
Kuzniecky R, Andermann F, Tampieri D, Melanson D, Olivier A, Leppik I. Bilateral central macrogyria:
epilepsy, pseudobulbar palsy, and mental retardation-a recognizable neuronal migration disorder.
Ann Neurol 1989;25:547-554
Neuronal migration disorders are the result of specific
derangements in fetal neuronal development. These
malformations may be due to different genetic and
acquired causes 111. Traditional morphological criteria
used in the classification of these malformations delineated agyria (or lissencephaly), macrogyria (or
pachygyria), polymicrogyria, schizencephaly, and other
heterotopias of the gray matter El}. More recently, in
genetic and clinicopathological studies investigators
identified a growing number of specific entities and
causes, best illustrated .by the lissencephalic MillerDieker syndrome associated with deficiency of band
magnetic resonance imaging (MRI). Clinically, they
showed pseudobulbar palsy, mild pyramidal signs with
hyperreflexia, and mild retardation. Their presenting
problem was intractable secondary generalized or multifocal epilepsy. Recognition of this entity explained
many of the previously puzzling features of these
young patients.
Patients and Methods
Macrogyria is a rare neuronal migration disorder [3}.
It is characterized by few and relatively broad gyri and
in its severest form is manifested as agyria. It might be
due to different causes and has only rarely been associated with a distinct clinical syndrome [4}. We report
the cases of 4 patients who had bilateral central macrogyria identified by computed tomography (CT) and
Four patients who had medically intractable epilepsy were
studied. Electroencephalographic (EEG) investigations were
done using 16-channel EEG-video monitoring and coherence-phase analysis [57. Neuropsychological studies were
carried out according to the protocol of Milner [6}.
Radiological investigations included cerebral angiography ,
pneumoencephalography (in 2 patients), and CT scanning
(EM1 1010, GE, 9800). Chromosomal studies including
kariograms and high-resolution chromosome banding were
carried out in Patient 4.
Patients 2, 3, and 4 had MRI studies using a 1.5-Tesla
magnet-Philips Gyroscan S 15 unit; Patient 1 was examined
From the *Department of Neurology and Neurosurgery, McGill
Universitv. and the Montreal Neurological Institute and Hospital,
of Neurology, the UiiverMontreal; Canada; and the
sity of Minnesota, St Paul Ramsey Hospital, St Paul, MN.
Received Sep 5 , 1988, and in revised form Nov 18. Accepted for
Dublication Nov 19, 1988.
Address correspondence D~Andemann, &fontreal ~ ~ ~ ~ l ~ g i ~ a
Institute, 3801 University St, Montreal, PQ, H3A 2B4 Canada
1 7 ~ 1 C21.
$Present address: Department of Neurology, University of Alabama
at Birmingham, Birmingham, AL.
Copyright 0 1989 by the American Neurological Association 547
Clinical Findings in Four Patients with Bilateral Central Macrogyria
Full Scale
Age at Onset
of Seizures (yr)
Drop attacks,
Drop attacks,
tonic seizures
right DTR,
Infantile spasms
at 3 months;
Drop attacks,
GTC, head
Drop attacks,
head dropping
Daily seizures,
special school
Daily seizures,
Three-stage, as
complete as
No drop attacks,
N o drop attacks,
GTC = generalized tonic-clonic, DTR = deep tendon reflexes, CPS,
using a 1.5-Tesla Siemens Magneton scanner. Spin echo (SE)
sequences with echo times (TE) of 30 msec and repetition
times (TR) of 550 msec were obtained in the axial, coronal,
and sagittal planes.
Two patients were treated surgically for intractable
epilepsy. This consisted of corpus callosotomy following the
protocol of the Montreal Neurological Institute [7]. After
extensive EEG and neuropsychological investigation, cerebral angiograms and MRI studies were carried out to delineate the anatomy of the corpus callosum and its vasculature. The patients were then given general endotracheal
anesthesia. A curvilinear frontal incision was made parallel to
the midline and a bone rectangle removed. The dura was
opened toward the superior longitudinal sinus and the corpus callosum exposed after careful dissection of the pericallosal vasculature. Dissection was carried out with the Cavitron ultrasonic surgical aspirator (Cooper Medical, Menlo
Park, CA). An anterior callosotomy was done in Patient 4
and an as complete as possible callosotomy was performed in
three stages in Patient 3.
Results in the 4 patients are summarized in the Table.
Case Report of Patient 1
A 15-year-old girl was evaluated for intractable seizures. She was the second child of healthy, unrelated
parents and was born at term following a normal pregnancy. Her delivery was complicated by breech presentation and hip dysplasia. The perinatal period was
548 Annals of Neurology Vol 25 N o 6 June 1989
complex partial seizures.
normal. Early development was delayed. She walked at
20 months, talked at 28 months, and had difficulties
eating solid foods until the age of 3 years. A neurological evaluation at the age of 2 years revealed mild rightsided hyperreflexia and oromotor incoordination.
School performance was below grade level; since
fourth grade she attended a special school. When she
was 8 years old, the first seizure occurred. It was characterized by staring, followed by head dropping, and
lasted 5 to 10 seconds. Eventually she had three main
seizure patterns: (1) staring episodes, followed by head
dropping without postictal symptoms; (2) head dropping, followed by complex automatism and postictal
confusion; and (3) less frequent atonic drop attacks.
Physical examination revealed prominent oromotor incoordination with inability to isolate the tongue from
the mandible on lateral tongue movements or to protrude it. She had dysarthria and a hyperactive jaw jerk,
mild hyperreflexia on the right side, and decreased fine
alternative movements bilaterally. Details of the laboratory data are outlined in the Table.
Clinical Features
Except for Patient 2 , whose mother sustained a mild
fall at 8 weeks’ gestation, the pregnancies were unremarkable. Deliveries were normal in 2 patients; the
other 2 (Patients 1 and 3) were born by breech presentation. All had unremarkable perinatal histories; none
had a history of febrile convulsions, head injury, or
other significant medical problems or a family history
of neurological disease.
Delayed milestones were documented early; all
walked after 18 months and speech and sphincter control were achieved late in childhood. Oral and lingual
incoordination, including difficulties in the ingestion of
solid foods and liquids, became evident in early infancy. Licking was particularly difficult for all patients;
for example, to date, Patients 2 and 4 have been unable to lick an ice cream cone. Cognitive deficits were
present in all. The 4 patients went to regular school up
to grade 4 or 5, but then had to continue in special
programs. Behavior problems, in particular, provocative and aggressive behavior, were present in Patients
2 and 3, and progressive deterioration of their behavior was observed through the years. Patient 4 also had
behavioral and social problems.
Physical examination revealed prominent bulbar
symptoms in all patients. Oromotor incoordination,
which was maximal on lateral tongue movements, and
a brisk jaw jerk were invariably present. Dysarthria
was a prominent feature in three patients. In Patient 2,
speech consisted of monosyllables until the age of 20,
and later he was mute; his speech comprehension was
normal. In addition, mild hyperreflexia and poor
motor skills were observed in all.
Seizures began between the ages of 8 and 9 years. In
Patient 4, early seizures were suggestive of infantile
spasms. He received steroids and anticonvulsants and
after 2 weeks of therapy remained seizure free until
the age of 8.
By history, the initial seizures consisted of minor
absence episodes in Patients 1, 2, and 4, whereas in
Patient 3, generalized tonic-clonic seizures were reported first. Subsequently, in Patients 2 and 4 atonic
drop attacks and minor atonic seizures developed. Patients l and 3 had complex automatisms occasionally
preceded in Patient 3 by tingling in the left hand and
arm and at times on the right. However, at the time of
referral, atonic drop attacks and minor atonic seizures
were the predominant seizure pattern. These attacks
consisted of a slow or rapid forward drop of the head
andor upper trunk lasting 5 to 10 seconds, with no
postictal confusion. More severe attacks began with a
sudden fall, occasionally associated with obvious loss of
consciousness. In addition to atonic seizures, generalized tonic-clonic and tonic attacks were recorded. In
Patient 3, generalized tonic-clonic seizures followed by
Todd's paresis on the left or right side were observed.
The frequency of seizures varied in each patient
from 1 to 20 attacks per day. Interestingly, periods of
freedom from seizures (6 months to 4 years) were
reported by the families. Although the attacks were
intractable at the time of referral, they were intermit-
tently controlled by polytherapy for variable periods of
NONEPILEPTIFORM ABNORMALITIES. The background activity was usually in the range of 8 to 10 Hz
with admixed theta waves. In 2 patients, the theta activity was recorded from both posterior regions of the
head, whereas in the other 2, this rhythm predominated in one hemisphere. Three patients had intermittent bilateral, asynchronous delta and theta activity, maximally in frontocentrotemporal regions, with
predominance over the left hemisphere.
EPILEPTIFORM ABNORMALITIES. I n t e r i d epileptiform abnormalities consisted of bursts of bilaterally
synchronous spike or sharp and slow wave, or polyspike and slow wave discharges recorded from anterior
and central regions of the head at a frequency of 2.5 to
3 Hz (Fig 1). In addition, bilaterally independent sharp
and slow wave complexes were recorded from frontocentral regions (2 patients) and from temporal regions
with predominance over one hemisphere.
Seizures were recorded in all
patients. In 2 patients, generalized attenuation of background activity followed by lateralized rhythmic sharp
discharges at 5 Hz was recorded. In Patients 1, 3, and
4, seizures characterized by generalized rhythmic bilateral synchronous spike and polyspike/wave discharges
at a frequency of 4 to 12 cycles/sec were documented;
in 2 of these patients the ictal discharges were associated with head dropping and hypotonia of the upper
limb. Coherence and phase analysis showed no time
difference in the generalized epileptiform discharges
recorded from frontal and parasagittal regions, but
there was a lateralized lead in the epileptiform discharges recorded from the temporal regions.
Zmging Studies
Radiographs of the skull and pneumoencephalograms
revealed mild diffuse cerebral atrophy in 2 patients.
Cerebral angiography (in Patients 2 and 4 ) showed
shallow indentation of the middle cerebral artery and
absence of the sylvian point. In addition, the sylvian
triangle appeared small and disorganized in the lateral
CT scans revealed symmetrical bilateral sylvian and
rolandic macrogyria extending high into the parietal
regions (Fig 2). The cortex appeared thick and smooth,
with the underlying white matter diminished. The abnormality was limited to the sylvian-rolandic region
without extension to frontal or occipital areas. MRI
studies confirmed the CT findings but showed that the
abnormal cortex had a slightly lower signal, as corn-
Kuzniecky et al: Bilateral Central Macrogyria 549
P3-01 d
W d ?
C4-P4 /
2 sec I50 pV
P4-02 U
Fig I . Representative section of interictal electroencephalograph
showing burst of bihteraLsynchronous spike and slow waue discharges with phase reversals overfrontal regions (F3-F4).
Fig 2. Computed tomography demonstrating thick and smooth
cortex in the central region. See diagram. {A) Patient 1. (B)
Patient 2. (C)Patient 3.
550 Annals of Neurology Vol 25 No 6 June 1989
Kuzniecky et al: Bilateral Central Macrogyria
Fig 3. Patient 3. Magnetic resonance imaging showing abnormally thick cortex, of slightly lower signal in the central region.
pared to the normal gray matter of the frontal and
occipital regions (Fig 3).
Treatment and Folhu-up
Follow-up in the 2 patients who had callosotomies for
intractable drop attacks ranged from 12 to 48 months.
Patient 3 had a three-stage, as complete as possible
callosotomy between 1984 and 1986. She improved
after the first two operations, but only after the complete section did the drop attacks cease. In addition,
her behavior improved considerably. Patient 4 had an
anterior callosotomy; after the procedure the drop attacks diminished and after 10 months disappeared
completely. He continues to have absence attacks in
which he does not fall.
Patients 1 and 2 continued to have frequent seizures
despite trials of multiple anticonvulsants. The symptoms of Patient 2 deteriorated and at the time of writing he lived in an institution for the mentally retarded.
H e continued to have daily seizures and recently sustained a fracture of the odontoid during a drop attack.
These 4 patients had strikingly similar clinical features
and comparable radiological and electrographic abnor552
Annals of Neurology
Vol 25 No 6 June 1989
malities. Developmental delay, mild mental retardation, prominent pseudobulbat involvement, and mild
corticospinal long-tract signs were the predominant
clinical features. Seizures, with onset around the age of
8 years, and characterized by head dropping, atonic
drop attacks, and generalized tonic-clonic attacks were
the distinctive epileptic pattern. Focal symptoms suggesting independent seizure onset in both hemispheres
were confirmed electrographically in Patient 3. The
neurological findings, the mild to moderate mental retardation, and the generalized epileptiform discharges
indicated a more diffuse cortical process.
The CT scans and MRIs of all 4 patients revealed a
thick, smooth cortex involving both rolandic and sylvian regions. This most likely represents pachygyria or
macrogyria. These thick cortical structures surround a
large central sulcus, reminiscent of a fetal sylvian
fissure. Pathological material was not available for
study. We believe that this condition can be detected
by using high-resolution CT scan and MRI. This has
been confirmed recently by Van Der Knapp and Valk
181 in patients with diffuse pachygyria and in those
with related migration disorders C9- 121. Similarly, diffuse or generalized thickening of gray matter associated with smooth cerebral surface, wide sylvian
fissures, variable degree of ventricular dilatation, and
other abnormalities has been described in patients with
the lissencephaly syndromes 112- 131. In schizencephaly 1141 one may see bilateral symmetrical clefts
that can resemble the findings of our patients. In this
condition, however, the clefts are vertically oriented
and wide on the cerebral convexity, they are lined by
polymicrogyria and heterotopias, and associated malformations are usually present, thus suggesting that our
patients represent a different entity.
Macrogyria is not common 13, IS]. In what appears
to be the first reported case, Matell 1161 described the
case of a retarded epileptic woman who died at the age
of 27. In another series, Crome 131 encountered 2
patients with pachygyria among a large number of microcephalic individuals. Both patients died in infancy
and were severely retarded. More recently, Jellinger
and Rett 1171 described 4 patients with pachygyria,
mental retardation, and seizures. These children were
severely impaired, developed early seizures, and died
before the age of 5 years. Analysis of pathological
specimens revealed diffuse pachygyria, while in one,
temporal lobe pachygyria was associated with bifrontal
microgyria. Other reports have described similar patients, emphasizing different embryological and morphological aspects 14, 15, 183.
At present, the cause of this particular malformation
in our patients is unknown. There was no consanguinity among the parents, perinatal complicating factors,
or any evidence to suggest maternal or environmental
causes. Results of chromosomal studies in Patient 4
were normal. Although congenital cytomegalic virus
infection has been reported in association with migration disorders 1191, there was no clinical or radiological
evidence, such as chorioretinitis, sensorineural deafness, or periventricular calcifications to suggest this
Severe psychomotor retardation has been described
in the majority of patients with macrogyria. Microcephaly, hypotonia, feeding difficulties, the absence of
a typical phenotype, and severe mental retardation
were noted in virtually all reported patients 115-171.
Two of our patients had a broad nose with slight
notching; this did not appear to be due to phenytoin
and resembled what is seen in patients with midline
syndromes. In addition, our patients had mild retardation and minor though specific neurological findings.
Slurred, dysarthric speech as a result of pseudobulbar
palsy was found in all. The mutism of one of the patients was a subject of much debate. Reluctantly, we
attributed it to the retardation, but since this was mild
such an explanation was hardly satisfactory. Only when
the bilateral lesions were identified was it possible to
explain the unusual absence of speech. It is likely that
our patients were less impaired because of the restricted nature of their lesions.
Severe epilepsy is a constant and persistent feature
in patients with macrogyria. Generalized seizures have
been noted in the vast majority of patients whose cases
have been reported 13, 15-18]. In children, the most
common pattern consists of infantile spasms, which
carry a poor prognosis. Patient 4 had infantile spasms
that responded to treatment. Our patients had a number of stereotyped seizure patterns, which varied during the evolution of their epileptic syndrome. During
the early years, absence and tonic-clonic seizures were
observed in all. Later, partial simple and complex manifestations were observed in association with other seizures in 2 patients. Subsequently, the manifestations of
secondary generalized epilepsy, including atonic, tonic,
and tonic-clonic seizures, became the predominant
epileptic pattern in all. The absence of focal motor
seizures, focal myoclonus, jacksonian march, or epilepsia partialis continua, the usual epileptic patterns associated with discharges originating in the premotor gyrus, is striking; this may be related to the abnormal
cortical organization in that area.
The evolution of the clinical pattern correlated partially with the EEG changes. We were able to follow
the EEG from childhood to adulthood in 2 of our
patients. During the first years, generalized as well as
independent multifocal epileptic activity was recorded;
later, a regional epileptic disturbance became the predominant EEG abnormality in association with generalized discharges. Subsequently, a significant degree of
bilateral independent epileptiform abnormality followed by generalized slow spike-and-wave activity appeared. Similar evolution of changes has been observed in some of the reported cases 115, 17, 201.
Radiological studies in patients with migration
anomalies have demonstrated the underlying gross abnormahties. Pneumoencephalography and angiography
allowed detection of certain abnormalities 121, 22).
More recently, real-time ultrasound has been used,
with some success, in the prenatal diagnosis of such
abnormalities 123, 241. CT scanning is suitable for recognition of the majority of abnormalities in lissencephaly and related conditions 12, 11-13]. However,
it lacks sufficient resolution to demonstrate some subcortical anomalies, and because of bone artifact, critical
details of cortical architecture might not be recognized.
MRI is superior and more sensitive than CT, because
of better contrast between gray and white matter and
because the use of contiguous sagittal slices allows precise definition of the cortical gyral pattern, thus allowing identification of cortical abnormalities.
The role of surgical treatment in patients with gyral
architectonic malformations is beginning to be explored. We recently reported the results of focal resections in 3 patients with unilateral rolandic macrogyria
due to focal cortical dysplasia 1257. In another report,
Andermann and colleagues 1261 described 6 patients
with unilateral rolandic macrogyria associated with intractable partial complex seizures. In these patients,
Kuzniecky et al: Bilateral Central Macrogyria 553
the maximal epileptogenic abnormalities involved the
temporal regions; all patients improved after temporal
resections but were not completely seizure free. In
patients with intractable seizures, unilateral macrogyria, and hemimegalencephaly, surgical removal of the
most epileptogenic area might lead to worthwhile improvement though not to complete cessation of attacks. In our patients, a focal resection was not indicated because the diffuse involvement and the
predominant seizure pattern suggested the presence of
a secondary generalized epileptic process. Two patients underwent corpus callosotomy, with the drop
attacks ceasing after maximal section in one; partial
section led to improvement in the other patient. Because of the location and extension of the lesions, it
seems plausible to suggest that complete callosotomy
may be the procedure of choice in patients who have
this malformation and intractable epilepsy.
The clinical and imaging features of these patients
suggest a distinct and specific condition. These malformations appear to result from specific derangement of
neuronal migration. CT scan enables recognition of the
bilateral macrogyria, and the additional information
provided by MR allows more precise anatomical correlation. This in turn permits the institution of an appropriate therapy.
Note: Our attention has been drawn to the report on
developmental Foix-Chavany-Marie syndrome in identical twins by Graff-Radford and colleagues (Ann Neurol 1986;20:632-635). This condition, masked by the
eponyms, seems identical to the one described here.
A version of this paper was presented in part at the Annual Meeting
of the American Epilepsy Society, San Francisco, CA, October
We thank Yvonne Zelenka for her helpful criticism, Drs Arnold
Gold and Neenan Pillai for referring the patients, and Guy
Durocher for assistance with the art work.
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central, macrogyria, recognizable, migration, disorder, neuronal, retardation, palsy, bilateral, mental, pseudobulbar, epilepsy
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