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Band heterotopia Correlation of outcome with magnetic resonance imaging parameters.

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Band Heterotopia: Correlation of
Outcome with Magnetic Resonance
Imaging Parameters
A. J. Barkovich, MD,+ R. Guerrini, MD,? G. Battaglia, MD,S G. Kalifa, MD,§ T. N’Guyen, MD,”
A. Parmeggiani, MD,” M. Santucci, MD? P. Giovanardi-Rossi, MD,” T. Granata, MD,# and L. DIncerti, MD””
The “band heterotopia” or “double cortex” is a brain anomaly that is presumed to result from a premature arrest of
neuronal migration, Patients with this anomaly are reported to have a variable clinical course that has been, heretofore,
unpredictable. The clinical records and magnetic resonance (MR) imaging studies of 27 patients with band heterotopia
were retrospectively reviewed in an attempt to determine whether imaging findings are useful in predicting clinical
outcome of affected patients. Statistical analyses revealed the following correlations: (1) severity of T2 prolongation
in the brain with motor delay (p = 0.03); (2) degree of ventricular enlargement with the age of seizure onset (p =
0.04) and with development and intelligence (p = 0.04);(3) severity of pachygyria with the age of seizure onset (p =
0.01), seizure type (p = 0.03), and an abnormal neurologic examination (p = 0.002); (4)parietal involvement with
delayed speech development (p = 0.05); (5) occipital involvement with age of seizure onset (p = 0.006); (6) age of
seizure onset with development and intelligence (p = 0.03) and with an abnormal neurologic examination ( p = 0.04);
and (7) severity of the pachygyria and thickness of band with development of symptomatic generalized epilepsy (p =
0.002 and p = 0.02, respectively) and Lennox-Gastaut syndrome (p = 0.002 and p = 0.01, respectively).
Barkovich AJ, Guerrini R, Battaglia G , Kalifa G , N G u y e n T, Parmeggiani A, Santucci M, Giovanardi-Ross1 P,
Granata T , DIncerti L. Band heterotopia: correlation of outcome with magnetic resonance
imaging parameters. Ann Neurol 1994,36:609-617
Anomalies resulting from disturbed neuronal migration and cortical organization have been recognized for
more than 100 years (11. Until recently, however,
these disorders were thought to be extremely rare and
to cause death at a very young age (1-61. Although
the “double cortex” configuration was initially described more than 50 years ago, it has only been in the
past 5 years that the malformation was “rediscovered”
by the use of modern neuroimaging {7-91. In these
recent publications, the developmental outcome of affected patients has been reported to be extremely variable and, in many cases, considerably less severe than
for other diffuse disorders of neuronal migration.
However, the number of patients in the prior studies
have been insufficient to determine whether any features of the patients or their imaging studies are predictive of outcome. In this multicenter study, the neurologic and developmental outcomes of 27 patients
with “double cortex syndrome” are analyzed and compared with imaging findings.
Patients and Methods
From the “Neuroradiology Section, University of California, San
Francisco, CA; ?Division of Child Neurology and Psychiatry, Stella
Maris Foundation and University of Pisa, Pisa, Divisions of SNeurophysiology and ’Neuropediarrics and **Dep=fmenf ofNe~~oradio1ogy, Neurological Institute “Carlo Besta,” Milano, and hstitute of
Child Neuropsychiatry, University of Bologna, Bologna, Italy; and
SNeuroradiology Section and “Neuropediatric Service, HGpital
Saint-Vincent-de-Paul, Paris, France.
Address correspondence to Dr Barkovich, UCSF, Department of
Radiology, 505 Parnassus Avenue, L-371, San Francisco, CA 941430628.
The MR scans and clinical records of 27 patients (26 female,
1 male) with MR findings of band heterotopia were retrospectively reviewed. Three of the patients have been reported previously {lo]. Patients ranged in age from 3 months
to 40 years at the time of their MR examination (mean age
= 12.5 yr; median age = 12 yr). Age at initial presentation
ranged from the neonatal period to 14 years (mean age =
5.3 yr; median age = 5 yr). The patients’ clinical records
were searched for age of onset of seizures, type of seizure
disorder (if more than one seizure type was present, the age
of onset of each seizure type was recorded), developmental
history (particularly regarding development of motor and language skills), family history of neurologic disorders, electroencephalography (EEG) results, developmental quotient
(DQ, assessed by the Denver Developmental Screening
Test) in patients younger than 2 years old, developmental
level (assessed by the Gessell method) in children between
the ages of 2 and 5 years, and intelligence quotient (IQ,
assessed by Wechsler Intelligence Scale-Revised [WISC-R)
[I 1)) in patients older than 5 years old. Both verbal I Q (VIQ)
Received jan12, 1994, and in revised form M~ 1, ~~~~~~~dfor
publication Mar 24, 1994,
Copyright 0 1994 by the American Neurological Association
609
and performance I Q (PIQ), in addition to full scale IQ, were
available in 5 patients. Developmental history was well documented in 2 1 patients. In the other 6, history was obtained
from the memory of family members and, therefore, was not
as precise. Extracranial EEG investigations were performed
using the International 10-20 system and recorded on 16channel EEG machines. Recordings were obtained during
both wakefulness and sleep.
MR scans were performed with a number of different techniques because they were performed at many institutions.
Axial T2-weighted spin echo images, with slice thickness
varying from 4 to 7 mm, repetition time (TR) varying from
2,000 to 3,000 msec, echo time (TE) varying from 20 to 40
msec for the first echo and 70 msec to 120 msec for the
second echo were obtained in 22 patients. Axial T1-weighted
spin echo images, with slice thickness varying from 4 to 6
mm, TR varying from 500 to 667 msec, and TE varying
from 15 to 20 msec were obtained in 11 patients. Sagittal
T1-weghted spin echo images, with slice thickness varying
from 5 to 10 mm, T R from 300 to 616 msec, and TE from
9 to 20 msec were obtained in 16 patients. Coronal T1weighted spin echo images, with slice thickness varying from
5 to 8 mm, T R from 440 to 600 msec, and TE from 9 to
20 msec were obtained in 11 patients. Coronal T2-weighted
images, with slice thickness of 5 or 6 mm, TR of 2,100 to
3,000 msec, TE of 20 to 50 msec (first echo) and 70 to 100
msec (second echo) were obtained in 7 patients. Coronal
T1-weighted inversion recovery images were obtained in 2
patients, and axial T 1-weighted inversion recovery images
were obtained in 1 patient.
The MR images were analyzed for degree of pachygyria
(number of gyri and depth of sulci), width of the band of
heterotopic gray matter in the frontal, parietal, and occipital
lobes (measured by calipers off the hard copy of the films),
location of the band, and the presence of other anomalies of
the brain (such as foci of T2 prolongation, increased ventricular size, subependymal heterotopia, anomalies of the corpus
callosum, or anomalies of the cerebellum). The images were
reviewed twice by a single neuroradiologist (A. J. B.), who
was blinded both times to the patients’ identities. The imaging findings from the two reviews were then correlated;
the agreement was 0.97.
Correlation of the data was then assessed by statistical analysis using the Kendall coefficient of concordance C12). Location of the band, thickness of the band, degree of pachygyria,
degree of ventriculomegaly, and severity of T 2 prolongation
were considered input variables. The input variables were
correlated with the following outcome variables: age of seizure onset, seizure type, DQ for patients less than 2 years
old, I Q for patients more than 2 years old, motor development, speech development, seizure syndrome, and normality
of neurologic examination. Age of seizure onset, seizure syndrome, and seizure type were also analyzed as input variables
and correlated with the other outcome variables. To test the
inciependence of the input variables, each was paired with
every other input variable and tested for correlation.
For purposes of statistical analysis, sulcal pattern was
graded from 1 (normal) to 3 (frank pachygyria). Thickness
of the band was graded 1 (<4 mm at thickest point), 2 (4-7
mm), 3 (8 - 1 1 mm), or 4 (>12 mm). The presence or absence
of pachygyria in the frontal, parietal, and occipital lobes was
610
Annals of Neurology
Vol 36 No 4
October 1994
recorded. Ventricles were graded by the frontal horn ratio
(FHR, the ratio of the distance between the lateral tips of
the frontal horns to the distance between the inner tables of
the frontal horns at the level of the frontal horns { 131) as
normal (numerical grade = l), mildly dilated (35% < FHR
5 40%, grade = 2), moderately dilated (40% < FHR 5
SO%, grade = 3), or severely dilated (FHR > 50%, grade
= 4).T2 prolongation in the cerebrum was graded as normal
(grade = l), periventricular (grade = 2), subcortical (grade
= 3), or both subcortical and periventricular (grade = 4).
Seizure onset was graded as I if first seizure was at age 11
years or later, 2 if first seizure was from age 6 years to age
10 years, 3 if first seizure was from age 3 years to age 5
years, and 4 if first seizure was prior to age 3 years. D Q / I Q
was graded 1 if more than 90, 2 if 71 to 90, 3 if 51 to 70,
and 4 if 50 or less. Developmental history and neurologic
examination results were entered as normal (grade = 1) or
abnormal (grade = 2) with regard to motor development,
speech development, and most recent neurologic examination.
Results
Clinical Presentation and Outcome
Eighteen patients initially presented with seizure disorders, 7 with developmental delay, and 2 with delayed
speech development.
Family and prenatal
histories were available in 25 patients (2 were
adopted). Three patients in the study were related, i.e.,
a mother and 2 daughters. Another woman in the study
has 2 sons with congenital brain anomalies, 1 with lissencephaly and another with an undetermined anomaly
(a request for an imaging study was refused). The details of these families are being reported elsewhere. A
family history of mental retardation was reported for
2 other patients.
Only 1 patient related a history of abnormal prenatal
events; the patient’s mother reports an episode of
vaginal bleeding during the first trimester of pregnancy.
FAMILY AND PRENATAL HISTORY.
DEVELOPMENTAL HISTORY.
A history of delayed motor
development was noted in 14 patients. Walking was
delayed in 13 patients; this was mild (walking at 18-24
mo) in 4 patients, but 6 patients were severely delayed
and did not begin walking until age 30 months or later.
One child, at age 8 months, showed poor head control
and was not rolling over, remaining nonmotile in the
supine position.
Language acquisition was delayed in 17 patients.
Most of the affected patients were noted to have poor
articulation (10 patients) and some had poor comprehension (4 patients) as well. The typical patient in our
series uttered her first words between ages 24 and 30
months, put together short sentences of two to three
words at age 36 to 40 months, and slowly gained
skills thereafter. Of the 22 patients age 6 years or
older, 8 were unable to form sentences until age 5
years. Poor school performance was noted in 10 patients; 5 attend special schools, whereas the other 5
attend normal schools but need special tutoring. Seven
patients were nonreading at age 8 years or older.
NEUROLOGIC EXAMINATION.
Neurologic examination
was normal in 12 patients. Of the patients with neurologic abnormalities, mild proximal hypotonia was present in 5 patients, poor fine motor control was noted
in 4 patients, weak oromasticatory muscles in 3 patients, and upper motor neuron dysfunction (spasticity,
weakness, and clonus) was found in 3 patients.
INTELLIGENCE TESTING. Four patients were only evaluated prior to their second birthday. DQ was 50 in 1
patient evaluated at age 8 months. Three patients evaluated at 18 months had DQ values of 60, 80, and 90.
Of the 23 patients evaluated past the age of 2 years,
numerical IQs were available in 16. Of the 7 patients
who did not have formal testing, 2 were judged to be
severely retarded by their physicians, 3 were judged
to be moderately retarded, 1 was judged to be mildly
retarded, and 1 was considered normal or mildly retarded. Of those formally evaluated, the full scale I Q
values ranged from 37 to 80 (mean = 57; median
= 66). Of the patients who had results of verbal and
performance I Q tests available, no appreciable difference was found in the results of the verbal, performance, or full scale I Q results.
Two patients had formal I Q (WISC-R) testing performed sequentially. One patient (Patient 26) had improvement in full scale IQ from 51 at age 7 years to
58 at age 10 years. The other (Patient 27) deteriorated
from a full scale I Q of 75 at age 5 years to 52 at 10
years and 40 at age 12 years.
Seizure Histoy
Seizure disorders were present in 25 patients (Table).
Age at seizure onset ranged from 2 months to 14 years
(mean age = 5.2 yr; median age = 5 yr). Sixteen
patients had partial motor seizures; in 11 of the patients
so affected, the seizure underwent secondary generalization. Five patients had primarily generalized tonicclonic seizures (GTCS). Complex partial seizures were
diagnosed in 5 patients (1 also had atonic seizures, 1
had GTCS and atonic seizures, and 1 had partial motor
seizures with generalization and atonic seizures), atypical absences in 5 patients (2 also had GTCS and 2 had
both focal motor seizures with secondary generalization and atonic seizures), and atonic seizures in 5 patients (2 of these also had focal motor seizures with
generalization and atypical absences, 1 also had focal
motor seizures with generalization and complex partial
seizures, 1 also had complex partial seizures, and I also
had partial complex and GTCS).
Most patients had a history of progressively more
complex seizure disorder as they grew older. Four patients had a history of infantile spasms. Fourteen patients presented with partial motor seizures as their
initial seizure type; 3 of these patients had manifested
spasms as an infant and 1 had a single febrile seizure
at age 13 months, 5 months before his first nonfebrile
seizure. Six of the patients initially presenting with focal motor seizures eventually developed GTCS and 3
others developed atypical absences, GTCS, and atonic
seizures. Three patients initially presented with partial
complex seizures; 1 went on to develop atonic spells
and another developed both atonic seizures and GTCS.
Three patients presented with GTCS as their initial
seizure type; 1 of these went on to develop complex
partial seizures. Two patients presented with atypical
absences; 1 went on to develop GTCS. One patient
presented with oculocephalic deviation and unresponsiveness.
Attempting to classify these patients by epileptic
syndromes [141, we classified 11 patients (Patients
3-5, 8, 9, 14, 16, 17, 22, 23, and 26) as having partial
epilepsies, 4 patients as presenting with West syndrome (3 [Patients 7, 10, and 151 evolved into partial
epilepsies and 1 {Patient 241 into a symptomatic generalized epilepsy), 4 patients (Patients 6, 12, 18, and 27)
as having Lennox-Gastaut syndrome, and 2 patients
(Patients 11 and 13) as having symptomatic generalized
epilepsy. Patients 1 and 25 were difficult to classify
because of missing clinical information and classification of Patients 19 and 20 was problematic because of
their normal EEG findings.
ElectroencephaLographic Results
Electroencephalographic results were available in 13
patients. Four had normal EEGs by report. In the other
9 patients, abundant generalized interictal theta activity
was noted bilaterally. Focal (predominantly frontal and
temporal) and diffuse spikes and spike wave activity
was noted in 7 patients. High voltage anterior fast
rhythms were noted anteriorly in 3 patients. Central
temporal slowing was noted in 2.
Imaging Findings
No patient had a completely normal cerebral cortical
gyral pattern (see Table). Cortical abnormalities varied
from mildly shallow sulci (Fig 1) to frank pachygyria,
with shallow sulci and broad gyri (Fig 2). The pachygyria was most severe in the frontal lobes in 11 patients,
in the parietal lobes in 2 patients, in the frontal and
parietal lobes in 4 patients, in the frontal, parietal, and
occipital lobes in 9 patients, and in the temporal, parietal, and occipital lobes in 1 patient. Cortical thickness
(gray matter external to the band) was normal to
slightly decreased in all patients, compared with normal
MR values of 3 to 4 mm {l5}.
Barkovich et al: Band Heteroropia
611
Patient Data
Patient
AgelSex
Cortical W d t h ,
Pattern
Band
Other Anomalies
Seizures
(Age Onset)
2-8 mm; absent in
temporal lobe,
thinnest in occipital lobe, thickest
m frontal lobe
3-11 nun,thinnest
~n occipital and
temporal lobes,
thickest in frontal
lobes
2-8 mm, absent in
temporal lobe,
thinnest m occipital lobe, thickest
in frontal lobe
None
3 yr
Long T2 In perwentriculat and suhcortical white matter,
ventriculomegaly
None
None
7 yr
Partial complex
WISC-R
Type
DQllQ
Motor Function
language
Partial complex;
atonic
60-70
Normal
Slightly pressured
but fluent speech,
below average
comprehension
80
Delayed walking, orherwise normal
Shun sentences
Delay in attaining
milestones (fine
and gross motor),
generalized
hyperreflexia,
bilateral nonsusrained ankle clonus
Slightly slow acquisition; expressive
problems
1
19 yrlF
Sulci slightly
shallow
2
I X molF
Shallow sulri
3
9 yrlF
Sulci slightly
shallow
4
17 yrlF
Shallow sulci
2-10 nun, equal Ln
frontal. parietal,
and occipital
lobes; thinner 111
temporal lobe
Ventriculomegaly,
prominent CSF
spaces
3 Y'
Partial with generalization
50-70
Delayed fine and
gross motor
Regressed to simple
sentences
5
6 yrlF
Slightly shallow
2-7 mm, absent in
temporal lobe,
thinnest i n occipital lobe, thickest
in frontal lobe
2-9 nun;thinner in
anterior, temporal. and inferior
temporal lobes
Inferior vermian hypoplasia
2 yr
Partial motor
70
Delayed gross and
tine motor
Slow acquisition (sentences at age 3);
now age appropriate
Small hererotopiar
adjacent to frontal
horns
? yr
Panial with generalization; atypical absences; atonic
50-60
Deficient gross and
fine motor
Slow acqursition.
poor verbal skills
S"k1
=
76
6
10 yrlM
Shallow sulci
7
2 5 yrlF
Shallow sulci
5-10 mm, thickest
in frontal
Small foci of long T 2
in rlght frontal
white matter
h mo
Spasms, partial motor
90
Mild proumal hypotonia
Slightly delayed [four
to five word sentences)
8
24 yrlF
Slightly shallow
sulci
14 yr
Partial with generaliaarron
50-70
Normal
Regressed. now only
short sentences
9
10 yrlF
Slightly shallow
sulci
8
Partial with generalization
80
Normal
Normal
10
3 yrlF
Very shallow
2-5 mm; absent in
Prominent CSF
spaces
temporal lobe,
thinnest in occipital lobe, thickest
in frontal lobe
2-5 mm. minimal in Ventrrculomegal y
temporal lobe;
equal in frmtal.
parietal, and occipital lobes
4-10 mm, Icast in
Ventnculomegaly;
anterior temporal
T 2 prolongation in
white matter adlalobe and occipital
pole; most in froncent to frontal
tal and parietal
horns (multifocalj
and in subconical
white matter; incomplete opercularization
Neonatal
Spasms, partial motor
60
Axial hyporonia
Ventnculomegaly.
T 2 prolongation m
white matter adlacent to frontal
horns (hdateral)
and in some subconical white matter, incomplete
opercularization
6 yr
Partial complex, vegetatwe and visual
complexes
Partial with generalization
Atonrc (R) with
drops
Severe MR
Mild right body pyrmmidal signs
Second band ~n occipital lobe (heremtopla), 5-12
mm everywhere
Ventriculomegaly.
T 2 prolongation in
white matter d j a cent to frontal
horns (bilateral)
9 yr
GTCS
Severe MR
11 yr
PC with atonic
SUICI
11
15 yrlF
Very shallow
SUlCl
2-11 mm; least in
anterior temporal
lobe and Kclpitdl
pole; most in parletal
12
12 yr/F
Very shallow
sulc,
I 0 yr
13 yr
Delayed
Delayed
13
15 yrlF
Very shallow
sulci
5-12 mm ev
erywherr
Ventriculomegaly; incomplete opercularlzarion
1 yr9mo
10 yr
GTCS llyr
Daily "spasms"
Moderate MR
Mild hypotonia; severe dyrarthria;
weak oromasticatov muscles,
brisk, symmetrical
DTRs
No expressive language, poor comprehension
I4
4 ydF
Very shallow
SUICl frontally. less
shallow posterior frontal. parietal,
and occipital
1-8 nun; most se-
Ventnculomegaly,
T 2 prolongation in
periventricular and
subconical white
matter
I ? mo
18 mo
Single febrile
Partial with generalization
Moderate MR
ModerAte proxlnial
hypotonia
Two to three word
sentences at age 3
yr, poor art1culation
Slightly shallow
everywhere
2-8 mm, least se"ere in frontal and
remporooccipaal
lobes
Marked ventriculomegaly; diminished white matter;
significant T 2 prolongation around
frontal, occipital
horns
Newborn
3 years
Infantile spasms
Partial motor (Icft
arm) with generalization
30-50
Delayed in attaming
milestones; no focal neurological
deficits; weak oromasticatory muscles
Delayed acquisition;
poor articulation;
fax comprehension
15
14 vriF
vere frontally
Patient Data (continued)
Conical Width,
Patient
Ageisex
Pattern
Band
16
8 yr/F
Slyhtly s h d o w
everywhere
17
10 yrlF
Slightly shallow
everywhere;
cortex
slightly thick
2-9 mm everyMild ventriculowhere; thinnest at
megaly
occipital pole and
in temporal lobe
2-8 mm; none in an- Normal ventricle size
terior temporal;
minimal in occip-
18
11 yr1F
Very shallow
everywhere
Other Anomalies
Seizures
(Age Onscr) Type
10 yr/F
20
12 yr/F
21
._
7)
23
3- yr/F
3 mo/F
1.1 yr/F
2’1
8 yr/F
25
’K) y d F
26
I iyr/F
GTCS, parrial motor
(llwk)
WISC-R = 72;
V I Q = 74;
PIQ = 73
10 yr
Head deviation and
loss of consciousness
WISC-R = 37;
V l Q = 46;
PIQ = 11
5-12 mm, least severe in temporal
and occipital lobes
18 mo
2 yr
Clonic limb jerks
Atypical absence,
myoclonic
G T C S aronic
WISC-R = 37
4-10 mm frontal; 2
mm parietal, none
Sllghrly shallow
cverywhere
.4-9 mm; least sa-
Slightly shallow
posterior,
frontal, and
parietal
Very shallow
everywhere,
incomplete
operculanrat u n ; dighrly
thick cortex,
small calcarme sulci
Slighrly shallow
frontally
2-9 mm; temporal,
parietal, and occipltal
Moderate ventriculu
megab
9 yr 6 mo
Atypical dbsence,
GTCS
Moderate retardation
Mild-moderate venrnculomegaly
Slight increased T2
in frontal periventrrcular white
matter
Mild ventriculomegdy; hypogenetic
cerebellar vermis
10 yr
GTCS
IQ = 66
Walked at 30 mo
Mild retards-
Walked at 30 mo
Muked venrriculomegaly
elsewhere
2-6 mm; only
frontal
2-3 mm; only
frontal
None
L body partial motoi
D Q < 60
Mild ventriculome&
7 yr 10 mo
Partial with secondary generalization
IQ = 54;
4-11 mm; second
band around tri
gones
Moderate ventriculomegaly
5 mo
8 yr
Spasms
Atypical absence
2-4 mm, only
frontal
Increased T 2 around
frontal horns and
rngones
Mild-moderate ventriculomegaly, increased T 2 subinsular white matter
11 yr
GTCS
3 yr 6 ma
3 yr 8 mo
Myoclonus
Fncal tonic seuure
5 yr
Tonic seizure
10 yr
Atypical absence
12 yr
GTCS
2-9 mm
Shallow everywhere
3-9 mm; thinnest
at
frontal and occipital poles
Mild ventriculo-
4
Poor head control at
8 mo; not rolling
over; remans nonmmle in supine
position
Normal
T o o young
I Q = 37
Walked at age 3 yr 6
mo
Puts together word5
6 yr. short senrencer 8 y r
Normal YS
mild retardation
Age 7 yr; 1Q
= 5 I WIQ
= 57, PIQ
= 54)
Age 10 yr, 1Q
Normal
Nnrmal
Walking at 2 yr tdelayed by club feet)
Iklayed
A t age j yr, slow
with pixx syntax
and S(lm*ntlcS
Walked at 15 mn
O n l y m h t e d wordc
at S yr
V I Q = 57,
P I Q = 61
=
1 3 yr/F
Poor speech until
Yr
Normal
110”
7 mo
“ere in occipital
lobes
everywhere;
most severe
frontally
27
Language
Normal milestones;
Normal
normal neurological exam, normal
school
Ilelayed; words at 24
Delayed cognitinn;
mo, sentences at 5
slightly delayed
motor; severe
yr
learning disability;
clumsy; no focal
neurological
deficits
Slightly delayed mo- Normal until seizure
tor and cognitive
onset
development, arrested cognitive development after
seizure ( m e t
Walked at 2 yr
Poor speech until 5
yr
ital
Shallow fronrally, frontal
conrx thick
Slightly shallow
frorirally
Slightly shallow
frontally
Slyhtly shallow
M a n x Function
7 yr 6 mo
7 Yr
I!,
DQIIQ
megaly
ti]
assess
Speech delayed (40
ma), prcsent lanwage deficit
58
Age 5 yr; D Q
= 15
Age 10 yr; I Q
= 32
Age 12 yr, I Q
= 40
GTCS = generalized tonic-clonlc seizures; NIA
perfurmance IQ; L = left; R = right.
=
not avadable; MR
=
mental retardation, I Q
The band of heterotopic neurons, itself, varied in
thickness among patients and varied among locations
in individual patients. In most patients, the band was
thinnest in the temporal lobes and at the frontal and
occipital poles, and thickest in the posterior frontal and
parietal lobes (see Fig 1). In 9 patients, the band was
not observed in che anterior half of the temporal lobe;
in 3 of these patients, the band was present only in the
frontal lobe, and in another the band was present only
in the fronta! and parietal lobes (Fig 3). The thickest
part of the band varied from 3 mm, in a patient with
the band restricted to the frontal lobes, to 12 mm. In
=
intelligence quotient; DQ
=
developmental
quotient;
VlQ
=
verbal IQ, PIQ
=
those patients with a continuous, complete band
around the entire cerebrum, the thinnest areas, usually
in the temporal and occipital lobes, varied from 2 to
5 mm.
In 2 patients (Patients 12 and 24), a “double layer”
of heterotopic neurons was present in the peritrigonal
region. In these patients, a triangular area of heterotopic gray matter was separated from the medially lying
trigone of the lateral ventricle and laterally lying band
by thin layers of myelinated white matter (see Fig 2).
The combined thickness of the band and the more
medial heterotopion was approximately equal to the
Barkovich et al: Band Heterotopia
613
Fig 1 . Patirnt 9. Axial T2-wcighted imagr shou.s mild pachygyria and niildfy enlarged t:entricles. The band heterotopia is
thinnest at the frontal and occipital polej. thickest iti the posterior frontal and parietal lobes.
Fig 2. Patient 24. Axial TI -toeightrd iniage shou:r .frdnk
shallour sulci and broad ~1ri. ~rndn~odrrute
p a c h y ~ r i a with
.
i'entricular edargenzent. A second layer of hrtrrotopii-gru1 nutleer (arrowheads) is present lateral to t b e i~entrii-u/urtri,yone~,
thickness of the band in the frontal lobes. Both patients
with double layer heterotopia were severely retarded.
The other common anomalies noted in the affected
patients were ventriculomegaly, T2 prolongation in the
white matter, and cerebellar vermian hypoplasia. Ventricular enlargement (see Figs 2, 4 ) was present in 21
patients; mild in 14, moderate in 5 , and severe in 2.
T2 prolongation (see Fig 4 ) was present in 11 patients;
periventricular in 5 , subcortical in 1, and both periventricular and subcortical in 5 . Cerebellar vermian hypoplasia was present in 2 patients; both were moderately
retarded.
Statisticul AmzLysis
The following correlations were established: ( 1) the
severity of T2 prolongation in the brain with motor
delay ( p = 0.03);(2) the degree of ventricular enlargement with the age of seizure onset ( p = 0.04) and
with DQ/IQ Cp = 0.04);( 3 ) the severity of pachygyria
with the age of seizure onset ( p = 0.01), severity of
seizure type (P = 0.03),and the Presence Of an abnorn e u r o b i c examination (P = 0.002); ( 4 ) the PreSence of parietal involvement with delayed speech development ( p = 0.05); ( 5 ) the presence of occipital
614 Annals of Neurology
Vol 36
No 4
October 1994
Fz,q 3. Patient 25. Coronal TI -uietghted image shous the presence of a thin band of heterotopic-nenr0n.i in the frontal lobes
(arrowheads). No nidence oj'a bujid K J ~ present
J
in the parietal or occipital lobes.
Fig 4. Patient 15. Axial T2-weighted image shows severe ventriculomegaly and periventricular T 2 prolongation (arrows)adjacent to the frontal and occipital horns of the lateral ventricles.
involvement with age of seizure onset ( p = 0.006);
(6) the age of seizure onset with DQ/IQ ( p = 0.03)
and with the presence of an abnormal neurologic examination ( p = 0.04);and (7) the severity of the pachygyria and the thickness of the band with the development
of a symptomatic generalized epilepsy ( p = 0.002 and
p = 0.02, respectively) and the Lennox-Gastaut syndrome ( p = 0.002 a n d p = 0.01, respectively).
Analysis of correlations of the input variables revealed that the thickness of the band correlated with
the degree of ventricular enlargement (j = 0.006),
and, not surprisingly, the thickness of the band correlated with the degree of pachygyria (p = 0.0001).
Discussion
Although the studies by Barkovich and co-workers C91,
Livingston and Aicardi [S], and Palmini and colleagues
[ 7 } established that patients with band heterotopia (the
plural noun is heterotopia; the singular noun is heterotopion) are present in numbers larger than suspected,
the number of patients in their studies was too small
to draw any conclusions concerning the frequency of
associated findings. Moreover, it was not possible to
correlate the presence of clinical or MR findings with
outcome variables. By pooling together patients from
several institutions, we have attempted to assemble a
cohort of patients large enough to establish the range
of clinical and radiological manifestations of this brain
anomaly. Moreover, because of the reported variability
of patient outcome [7, SJ, we have statistically analyzed
the relationship of various measures of patient outcome to imaging parameters. In our analysis, we believe we have answered some questions while raising
others.
Our data confirm the previous reports that patients
with band heterotopia have a variable clinical course,
ranging from mildly impaired to severely retarded. Not
surprisingly, our statistical analysis indicates that patients with more severe cortical anomalies (pachygyria)
and more severe ventricular enlargement have significantly earlier onset of seizure disorders than patients
with less severe pachygyria and smaller ventricles.
Moreover, those with early seizure onset, more severe
pachygyria, and greater ventricular enlargement have
significantly worse prognoses for intelligence (at least
so far as can be determined by testing) and normal
neurologic development. This association between degree of impairment and band thickness was suggested
by Palmini and colleagues [7}; however, they had no
measurements or statistics to confirm their suspicions.
Also not surprisingly, patients with more severe pachygyria had significantly more severe ventricular enlargement and thicker heterotopic bands, indicating that the
neuronal arrest impairs the development of cortical
gyri and the white matter tracts in the cerebrum.
The finding that more severe pachygyria (and a
thicker band of arrested neurons) is associated with a
poorer developmental prognosis supports the reported
findings of Aicardi Cl6) in his analysis of patients with
the agyria-pachygyria complex. It also supports the
concept that only neurons that reach the cortical plate
establish normal synaptic contacts with local and distant
neurons during the organizational phase of brain development 117-19). We postulate that, as more neurons
reach the cerebral cortex, more form normal synaptic
circuits and differentiate into mature cortical neurons.
More mature, differentiated cortical neurons and more
circuits would be expected to result in better cortical
function.
The function of the band of arrested neurons is not
known. Miura and associates [20} have reported that
the band has glucose uptake similar to the overlying
cortex, as measured by [l8FJfluorodeoxyglucose positron emission tomographic (PET) scanning. Moreover,
by using depth electrodes, Morel1 and collaborators
[2 1) have found epileptiform discharges arising from
the heterotopic “band,” independent of activity in the
overlying cortex. Histologic examination of the band
shows large, well-differentiated ganglion cells without
lamination [7}. It is likely, therefore, that the neurons
Barkovich et al: Band Heterotopia 615
in the band form synaptic circuits with other neurons.
However, it is not known whether the circuits are
formed locally, with neurons within the band, or with
normal cortical or subcortical neurons. Our data indicate that the circuits formed by the neurons of the
band do not contribute significantly to neurologic or
intellectual function.
The correlation between the thickness of the band
heterotopion and the degree of pachygyria can be explained by the theory of Richman and co-workers [22].
Using a model derived from geology, these authors
postulated that gyral formation is caused by an imbalance between the number of cells near the surface of
the cerebrum and the number of cells located more
centrally within the cerebrum. Fewer cells migrating
to the cortex, as in type 1 lissencephaly, lessens the
imbalance and results in the formation of fewer gyri.
(Conversely, a pattern of more superficial neurons with
fewer deep neurons results in an increased number of
small gyri, as in polymicrogyria.) Using this theory,
we postulate that thicker bands of heterotopic neurons
result in thinner outer cortices and more severe pachygyria. Conversely, the thinner the band of heterotopic
neurons, the more neurons will reach the cortex and
the greater the formation of gyri.
The statistical correlation of delayed motor development with severity of T2 prolongation in the white
matter is most easily explained by postulating that the
T2 prolongation represents damage to tracts involved
in motor function. T2 prolongation of the white matter
is well known to represent lack of myelin, damage to
myelin, or damage to both myelin and axons. Most
of the white matter damage was in the periventricular
(primarily peritrigonal) and subcortical areas, regions
that are frequently involved in perinatal hypoxicischemic injury [23-25}. Affected patients commonly
exhibit motor delay and signs and symptoms referable
to the pyramidal tracts [25}. None of the patients in
our cohort had any history of perinatal or intrapartum
asphyxia. Presumably, the injuries in patients with
band heterotopia occur prior to birth. We postulate
that manifestations of pyramidal tract injury (spasticity,
hyperreflexia, weakness) are absent because the greater
plasticity of the more immature brain allows more recovery of function.
Three findings in this study are difficult to explain.
The first of these is the association between parietal
involvement and speech delay. The second is a confirmation of the marked female predominance that has
been previously commented upon 171 and suggests that
a defective gene on the X chromosome is a causative
factor in the migration arrest. Both of these observations require further study. They may be clarified as
our knowledge of the genetic aspects of this disease is
clarified. The third confusing finding is the second
band of heterotopic neurons found in 2 patients. We
616 Annals of Neurology Vol 36 No 4 October 1994
prefer not to speculate on the mechanism by which
the second band of neurons is arrested; the reason will,
doubtless, become clear as the molecular biology of
neuronal migration becomes further elucidated.
In summary, we have analyzed the imaging studies
of 27 patients with MR diagnosis of double cortex or
band heterotopia. We have found a correlation of the
degree of migration arrest, manifest as thickness of the
band of heterotopic neurons and the degree of pachygyria, with both developmental and neurologic outcome. We suggest that band heterotopia are part of a
continuum that includes type 1 lissencephaly and
pachygyria and, therefore, should be considered a mild
form of lissencephaly. Further study is necessary to
investigate the overwhelming female predominance
and the cause of developmental speech abnormalities.
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