NEUROPSICOLOGIA

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177
Cerebellar
and Cerebral
Abnormalities
in Rett Syndrome:
A Quantitative
James W. Murakami1
Eric Courchesne12
Richard H. Haas2’3
Gary A. Press4
Rachel Yeung-Courchesne1
Rett syndrome
is a neurodegenerative
disease
of young girls that begins in early
childhood
with autismhike
behavior
and loss of language
skills, and progresses
with
marked deterioration
of the motor system in the second decade of life. The purpose of
this study was to determine
if neuroanatomic
changes
detected
with MR imaging could
help to explain the clinical presentation
and progression
of signs and symptoms
in these
patients.
Accordingly,
computer-assisted
planimetry
was used to measure
various
dimensions
of cerebral,
cerebellar,
and brainstem
structures
on sagittal and transverse
MR images of 13 patients with Rett syndrome
and 10 healthy volunteers.
Dimensions
of
the cerebrum,
basal ganghia, cerebellum,
and brainstem
were measured
on transverse
images.
Areas of cerebellar
vermian
lobules, the fourth ventricle,
the pituitary
gland,
and the corpus cahlosum were measured
on sagittal images.
Fourteen
dimensions
and
areas were measured
in each patient and each control subject; according
to two-tailed
Student’s
t tests, all but two values were significantly
smaller in the patients with Rett
syndrome
than in control subjects.
Graphing
the measurements
against age by using
simple linear regression
revealed
progressive
cerebellar
atrophy without evidence
of
atrophy of the brainstem
or cerebrum.
Our results indicate that patients with Rett syndrome
have global hypoplasia
of the
brain and progressive cerebellar atrophy increasing with age. Cerebellar
atrophy with
age may contribute
to the deterioration
of the motor system seen in older patients with
Rett syndrome.
AJR
Received
September
16, 1991;
revision February 5, 1992.
This work
R01-NS19855
was supported
awarded
to
CIDA grant K08-N501024
accepted
after
by NINDS grant 5E. Courchesne,
NIH
and a March of Dimes
MR Analysis
159:177-183, July 1992
Rett syndrome,
originally
described
by Andreas
Rett in 1966 [1 , 2], is estimated
to affect 8000 girls in the United States. The estimated
prevalence
of this syndrome
is approximately
the same as that of phenylketonunia:
one in iO,000
live female
births [3]. Rett syndrome
is a degenerative
neurologic
disease
characterized
by
grant awarded
to A. H. Haas, and the General
Clinical Research
Center
(NIH MOl -AR00827)
of
the University
of California
at San Diego.
I Neuropsychology
Research
Laboratory,
Chil-
the appearance of autismhike behaviors,
language skills after apparently
normal
drome progresses, with the development
dren’s Hospital
Research
Center,
San Diego, CA 92123.
2 Department
of Neurosciences,
years. The clinical staging
icine,
University
of California,
CA 92093. Address
chesne.
8001
School
San Diego,
reprint requests
3 Department
of Pediatrics,
University
of California,
San
92093.
4 Department
of Radiology,
Resonance,
Kaiser Hospital,
Diego, CA 92120.
Frost
St.,
of MedLa Jolla,
to E. Cour-
School of Medicine,
Diego, La Jolla, CA
Section on Magnetic
4647 Zion Ave., San
0361 -803X/92/1
591-0177
© American
Roentgen
Ray Society
abnormalities,
progression
seizures,
through
and marked
system
four stages
loss of purposeful hand use, and loss of
development.
In most patients, the synof stereotypic hand movements, breathing
deterioration
of Hagberg
of the motor
system
and Witt-Engerstrom
in Rett syndrome;
the onset
in the later
[4] classifies
of stage
a
4, commonly
during teenage or early adult life, is defined by difficulty walking. Even the ambuhatory older patients have deterioration
of the motor system with hypotonia, ataxia,
and pathologically
brisk tendon reflexes.
CT and MR findings in patients with Rett syndrome are commonly reported as
normal,
with a small percentage
of the patients
described
“minimal”
cortical
atrophy
[2, 5-i 2]. To determine
whether
changes
dimensions
MR images
correlated
with
clinical
findings
in Rett
syndrome,
as having
“mild”
any neuroanatomic
or
we measured
the
and areas of structures
of the cerebellum,
cerebrum,
and bnainstem
in 13 patients
with Rett syndrome
and 1 0 control subjects.
on
MURAKAMI
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i78
Materials
and
Patients
Thirteen
female
patients
with
of California
Rett
syndrome
(San Diego)
were
recruited
from
Rett Syndrome
Clinic.
Eleven
patients had classic Aett syndrome according to the Rett Syndrome
Diagnostic Criteria Work Group [1 3J. Two patients were atypical in
that they had a higher level of function;
nevertheless,
they met most
ofthe diagnostic
critenafor
Rett syndrome.
Neither of the two atypical
patients had any signs or symptoms
of Rett syndrome.
include apparently
that would exclude the diagnosis
Necessary
diagnostic
criteria
normal prenatal and perinatal
for Rett syndrome
period, apparently
normal psychomotor development through the first 6 months, decaleration of head growth between ages 5 months and 4 years, development of severely impaired expressive
and receptive language,
and
stereotypic
hand movements
such as hand wringing
or squeezing
[i3J. Supportive diagnostic criteria for Rett syndrome include breath-
ing dysfunction, abnormalities
on electroencephalograms,
spasticity, and peripheral
vasomotor
disturbances
[13].
excluding
Rett
syndrome
as a diagnosis
include
seizures,
Criteria
intrauterine
less than
the second
July 1992
for
percentile
for eight
of the
Sagittal
images
were
acquired
of view of 16-24 cm after
tion
Ti -weighted
two
spin-echo
with
a 256
x 256
to four excitations.
sequence
was
matrix
and
were
were
a field
A sagittal multisec-
used
with
a repetition
time
(TA) of 600-800 msec and an echo time (TE) of 20-25 msec. Sagittal
images were obtained only after the patient was adequately positioned (verified with preliminary transverse and sagittal images) to
ensure that a true midsagittal
image of the brain would be obtained.
The sections were 5 mm thick; consecutive
slices were separated
by
a 2.5-mm gap.
Transverse
images were acquired with a 256 x 1 92 or 256 x 256
matrix and a field of view of 20-24 cm after one to two excitations.
A multisection
spin-echo
axial sequence
was used with a TA of
2000-3000
msec and TEs of 30 msec and 70-80 msec. The trans-
verse images were obtained immediately after the sagittal images.
The sections were 5.0 mm thick; consecutive slices were separated
by a 2.5-mm gap.
growth
retardation, signs of storage disease, microcephaly at birth, and other
identifiable metabolic or progressive neurohogic disorders [i 3]. Thirteen patients between 5 and 25 years old (i 2.0 ± 6.3 years, mean ±
SD) were imaged in the transverse plane; 12 were imaged also in the
sagittal plane. Rett syndrome ranged from stage 2 to stage 4. Head
circumference
was less than the 50th percentile for all 13 patients
and
AJR:i59,
Electric Medical Systems, Milwaukee, WI). The control subjects
imaged without sedation; the patients with Rett syndrome
sedated with chloral hydrate (50-60 mg/kg body weight).
Methods
with Rett Syndrome
the University
ET AL.
1 3 patients.
Eleven of i 3 patients had seizures. All patients with seizures were
being treated with antiseizure
medications;
only four patients
had
been treated at some time with phenytoin.
Qualitative
Assessment
of the Images
All MR images were subjectively
who reviewed
Image
the films with
Quantification
Measurements
accordance
assessed
knowledge
by a neuroradiohogist
of the patients’
diagnoses.
Protocol
of the brain on sagittal
with our previous
report
images
[1 4]. Areas
were
were
made
calculated
in
by
using a method of computer-assisted
phanimetry in which magnified
images permitted differentiation of regions of interest from surrounding structures (Fig. i All sagittal measurements
were made on the
).
Control
Subjects
midsagittal
The control group consisted
of
and 27 years old (1 5.4 ± 7.5 years,
in the transverse
plane; eight were
None had a history of neurologic
or
1 0 female volunteers
between
6
mean ± SD). All 1 0 were imaged
imaged in the sagittal plane also.
systemic
illness.
MR Imaging Protocol
After
images
informed
were
consent
acquired
was obtained,
sagittal
with a 1 .5-T magnet
and transverse
(GE Signa,
MR
General
image.
The
measurements
included
the
area
of vermian
lobules l-V, vermian lobules VI-VIl, vermian lobules Vhhl-X, the fourth
ventricle, the ventral pons, the corpus callosum, and the pituitary
gland. The boundaries between the vermian lobules were assigned
in accordance
with
a previous
report
[1 5]:
the
boundary
between
vermian lobules h-V and VI-VIl was defined as the line joining the
anterior aspect of the primary fissure to the apex of the fourth
ventricle; the boundary between vermian lobules VI-VIl and Vlhh-.X
was defined as the line joining the anterior aspect of the prepyramidal
fissure to the apex of the fourth ventricle. The fourth ventricle was
designated
as the area of CSF extending
from
the inferior
aspect
of
Fig. 1.-A and B, Midsagittal
(A) and transverse (B) MR images from a 5-year-old with Rett
syndrome.
Areas measured
on A : cerebellar
vermian lobules l-V, vI-vll,
and Ul-X,
fourth yentricle (4), ventral
pens (P), pituitary
gland (black
arrow), and corpus callosum(CC).
Width of basal
ganglia (open arrows)
and lateral width of corebrum (white
arrows)
at level of basal ganglia
were measured on B.
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AJA:159,JuIy
MR OF RETT SYNDROME
1992
the quadrigeminal
plate to the obex, bounded
posterior aspect of the brainstem and posteriorly
anteriorly by the
by the medullary
velum, cerebellar
vermis,
and cerebellar
tonsils.
The area of the
ventral pons is bounded
anteriorly
by CSF and posteriorly
by the
ventral aspect of the medial lemniscus,
as described
by Carpenter
[1 6J, Hayakawa et al. [i 7J, and Hsu et al. [1 8]. The areas of the
pituitary
gland
and
the
corpus
callosum
(measured
from
rostrum
control
Midsagittal
subjects
observers
measurements
correlated
were
measurements
data presented
in
good
(r
well
=
agreement
All quantitative
of the cerebrum
width, as described
transverse dimension
The widths
bisecting
olives
were
the brainstem
the brainstem
determined
The cerebellar
by choosing
halves,
the
and measuring
the
distance from the midline to the lateral aspect of the brainstem
through the left and night inferior olives. The anteropostenor
length
of the brain was the greatest anteropostenior
dimension of the cerebrum shown on a single transverse image. The lateral width of the
basal ganglia was determined by first choosing the transverse slice
that best showed the putamen and globus palhidus and then measuring the distance perpendicular to the midline of the brain from the
lateral
aspect
of the putamen
of one hemisphere
to the lateral
aspect
This
“basal
ganghia”
line
begins
at the
lateral
aspect
of one
putamen, passes sequentially through that putamen, the corresponding globus pallidus, the midline of the brain adjacent to the mamillothalamic tracts, the globus pallidus of the opposite hemisphere, and
finally the putamen of the opposite hemisphere (Fig. 1). By dividing
the width of the basal ganglia by the cerebral width, we created
ratio of basal ganghia width to brain width. Transverse
measurements
were made by a single observer who knew the groups’ designations.
a
As cachexia is common in older patients
with Rett syndrome,
we
correlated our brain measurements
with several body measurements
(height, weight, head circumference)
in the patients with Aett syndrome.
Statistical
analysis
of the data
(statistical significance was p
analyses (statistical significance
included
two-tailed
.05) and simple
was p
.01).
Student’s
t tests
linear regression
Results
Subjective
with
volumes
(Fig.
and pituitary
cerebellar
inferior
and pituitary
olives,
vermian
gland.-Measunements
of cenlobules l-V, fourth ventricle,
gland
were
all significantly
smaller
(by i 3-45%) in the patients with Rett syndrome than in the
control subjects (see statistical results in Table 1). Measurements
of the areas
of the ventral
pons
and vermian
lobules
gland. Conversely,
changes
structures
with increasing
age the
patients
reduction
with Rett syndrome
showed a statistically
significant
in the area of vermian lobules I-V, VI-VIl, and VIIIx (for each area; n = 1 2, r
.738, p
.005) and a trend
toward
enlargement
in the area of the fourth ventricle
(n =
i i , r = .665, p = .024). For example, the area (mean ± SD)
of vermian
lobules VI-VIl
in the younger
patients
with Rett
syndrome (5-iO years old, n = 8) was 265.5 ± 38.1 mm2
whereas
in the older patients
with Rett syndrome
(i 3-25
years old, n = 4) this area was 188.2 ± 46.3 mm2. The ventral
pons,
inferior
olives,
changes
and
and pituitary
gland
had no significant
in the patients with Rett syndrome.
basal
gang/ia-Quantitative
analyses
showed that measurements
of cerebral width and length,
basal ganghia width, and corpus callosum area were all significanthy smaller(by i 0-27%) in the patients with Rett syndrome
than in the control
The widths
subjects
(see statistical
results
of the basal ganghia and cerebrum
in Table
1).
were similarly
reduced in the patients with Rett syndrome
(see basal ganghia
ratio in Table 1). No significant
age-related
changes
were
found
in any measurement
of supratentonial
structures
in
either the Rett or the normal group.
Anthropometric
data.-No
statistically
significant
(p
.Oi)
linear correlations
were found between
any of the measurements of the posterior
fossa, pituitary
gland, and supratentonal structures
made on MR images and any of the anthropometnic measurements
(height, weight, head circumference).
Discussion
Assessment
Nearly all measurements
The MR data for the patients
qualitatively
fossa
ebellan width,
age-related
Cerebrum
of the putamen of the opposite hemisphere, with the measurement
line crossing the midline adjacent to the mamillothalamic
tracts (Fig.
i).
a 23-year-old
Measurements
and the pituitary
at the level of the inferior olivary
into lateral
and
and hemispheric
cant.
In the control
group,
no significant
age-related
were found in measurements
of posterior
fossa
in a previous report [i4], was the greatest
of the cerebellum shown on a transverse image.
of the inferior
image that showed
nuclei,
at the level of the basal ganglia.
Objective
volume
vermian
VI-VIl and VIII-X also were smaller in the patients with Rett
syndrome, but these differences were not statistically
signifi-
Measurements made on transverse images included the cerebellar
width, the widths of the inferior olives, the anteroposterior
dimension
of the cerebrum, the lateral width of the basal ganglia, and the lateral
width
vermian
decreased
Posterior
of the two observers for the
.923-994).
Likewise, the two
(r = .956-991
) on all seven
in the patients with Rett syndrome.
here are from one observer.
decreased
severely
3).
to
splenium)
were measured
by using a previously
described
method
[i 7]. Sagittal measurements
were made independently
by two observers.
The observers
were not blinded to the subjects’
group
designations.
mildly
i79
assessed
with
Rett syndrome
by a neuroradiologist
who
knew
were
the
patients’ diagnoses when viewing the films. His impressions
of the MR images from the 13 patients with Rett syndrome
were (i) normal findings in eight cases (Fig. 2); (2) decreased
cerebral volume, primarily in the frontal lobe, in three patients
6, i 2, and 14 years old but not in any of the older patients;
and (3) decreased cerebellan volume without cerebral abnormahity in the two oldest patients, but not in any of the younger
patients. The two oldest patients were a 25-year-old
with
of length and area of the cerebel-
hum, brainstem,
basal ganglia, and cerebrum
smaller than normal in our 5- to 25-year-old
syndrome
neural
(Table i). This evidence
structures
are
similarly
were significantly
patients with Rett
suggests
affected
that a variety of
and
that
Rett
syn-
drome may involve widespread
brain hypophasia. In addition,
the area of the cenebellan vermis decreased with age and the
area of the fourth ventricle increased with age. These findings
indicate
a progressive
loss
(i.e.,
atrophy)
of the
cenebellar
parenchyma
with age; measurement
of other brain regions
did not show age-related loss. Unlike the finding of widespread
MURAKAMI
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i80
ET AL.
AJR:159,
July 1992
Fig. 2.-A-D,
Midsagittal and transverse MR
images from an 8-year-old
patient with Rett syndrome (A and B) and a 6-year-old
control subject
(C and D) show no qualitative
differences,
but
quantitative
differences
exist (Table 1).
A
B
F-:--
hypoplasia,
in
the
hatter
Rett syndrome
Cerebellar
results
and Brainstem
MR imaging
suggest
may be localized
indicated
that
significant
atrophy
to the posterior
fossa.
Findings
that
two
processes
seem
to affect
the cerebellum in Rett syndrome: hypophasia and late-onset
atrophy. On MR images, hypoplasia (undergrowth)
was evidenced
by the significantly
reduced width of the cerebellan
hemispheres
and
reduced
midsagittal
area
of the
anterior
vermis; the posterior venmis also was insignificantly
smaller.
These size reductions appeared in young patients who had
no sign of atrophy (e.g., no increased sulcal widening) and in
older patients. These quantitative
MR findings are consistent
with
those
of qualitative
autopsy
reported
that the cerebellum
year-old
patients
studies:
appeared
with Rett syndrome,
Ohdfors
et al. [19]
small in their 7- to 30and Bauman
and Kem-
per [20] reported
increased
cell packing
density
(a sign of
arrested
development)
in the cerebellum
in one 12-year-old
patient. In the youngest
of the autopsy
cases in the study by
Ohdfors
et al., no atrophy
of the cerebellum
was visible on
macroscopic
examination.
In the olden patients
with Rett syndrome
but not in the
younger ones, atrophy (evidenced
by large increases
in sulcal
width) was shown on MR images of the cerebellar
venmis and
hemispheres
(Fig. 3). Measurement
of the venmis and fourth
ventricle confirmed
the presence
of an age-related
decline in
the size of the cerebellum.
These MR results
parallel
the
autopsy data of Oldfors et al. [i 9], who reported
macroscopic
evidence
tients
cases
molecular,
matter,
of cenebellar
with
Rett
atrophy
syndrome.
with the most
Purkinje,
accompanied
in older but not younger
Autopsy
severe
atrophy,
data
indicate
that
pain the
ghiosis was found
in
and granular
layers and in the white
by loss of neurons in the molecular
and
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AJR:159,
MR OF RETT
July 1992
i8i
SYNDROME
Fig. 3.-A-F,
Representative
sagittal MR images
from a 9-year-old
(A-C)
and a 23-year-old
(0-F)
with Rett syndrome. In older patient,
vermian
and hemispheric
fissures
are markedly
widened
(thought
to represent
cerebellar
atrophy);
arrowheads
point to several such widened
and D are midsagittal
images, B and E are 7.5 mm lateral to midsagittal, and C and F are 15 mm lateral to midsagittal.
Purkinje
cell layers
Kemper
[20] did not report
year-old
patient.
apparently
and in the dentate
Thus,
begins
in
nucleus.
loss of neurons
in Rett
childhood
Bauman
and
in their one i 2-
syndrome,
loss
or adolescence
of neurons
and pro-
gnesses for many years.
The cenebellar
atrophy found in Rett syndrome
may be an
integral part of the disorder
and would be consistent
with the
degeneration
of the motor
system
with stage 3-4 Rett syndrome.
to the poor nutritional
status
seven of our 13 patients
weight).
However,
seen clinically
in patients
Alternatively,
it may be related
typical of these patients
(e.g.,
were less than the fifth percentile
in the patients
no significant (p
with
Rett
syndrome
for
in the
present study,
.Oi ) correlations
between
height, weight, and head circumference
and cerebellar measurements were found. This does not rule out poor nutrition
as a contributing
factor in the cerebellar atrophy, but this
factor seems less likely to be one of the more important
factors. The cerebellan neuronal loss and ghiosis and attendant
atrophy
might instead be related to the presence
of seizure
disorders,
which is also typical of patients with Rett syndrome
(e.g., seen in 1 i of our i3 patients)
or to the use of anticon-
vulsant medications
(1 i of our i 3 patients
convulsants;
four have received
phenytoin).
cenebellar atrophy warrants
further study.
These characteristics
of cerebellar
cerebellar
fissures. A
have taken antiThis age-related
abnormalities
distinguish
Rett syndrome
from several other developmental
disorders
involving
the cerebellum,
such as infantile
autism,
fragile X
syndrome,
and Down’s
syndrome.
For example,
in infantile
autism,
hypoplasia
occurs
but later atrophy
does not; hypephasia is limited to posterior
vermis and hemispheres
(including
the flocculonodular
lobe) and does not involve the anterior
vermis; loss of Purkinje
neurons
is prenatal
or perinatal,
not
hate in childhood
or adolescence;
no cerebellar
cortical ghiosis
or gliosis
and loss of myehin in white matter occurs;
and no
loss of neurons in the dentate nucleus occurs [21 , 22]. Thus,
although
patients
with early stages of Rett syndrome
have
some of the behavioral
features of classic infantile autism, the
radiologically
and microscopically
observed
spectra
of cenebellar involvement
in these two groups
of patients
differ
markedly.
As another
bellan hypoplasia
childhood
and
example,
without
adolescence;
in Down’s
progressive
granule
syndrome,
atrophy
cell
is seen
dysgenesis
cereduring
occurs
MURAKAMI
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182
TABLE
1: Quantitative
Rett Syndrome
Measurements
ET AL.
on MR Images
AJR:159,
in Control
Subjects
and in Patients
July 1992
with
% Size
Reduction
Control
Subjects
Measurement
Patients with Rett
Syndrome
in
Patients
Value
with Rett
Syndrome
Posterior
fossa
Venmis I-V (mm2)
Vermis
VI-VIl
(mm2)
Vermis VlIl-X
(mm2)
393.9
276.5
± 36.4 (8)
± 53.1 (8)
287.9 ± 43.0 (6)
i0i.0
± 3.1 (iO)
i78.6 ± 59.4 (8)
325.2 ± 35.1 (8)
Cerebehlar width (mm)
Fourth ventricle (mm)
Ventral pons (mm2)
Inferior olive width (right) (mm)
7.8
Inferior olive width (heft) (mm)
Supratentorium
Cerebral anteroposterior
length
343.1
239.8
24i.4
89.6
122.1
294.0
0.9 (8)
±
±
±
±
±
±
±
51.4
54.4
68.9
6.4
30.7
32.8
±
0.8 (1 3)
17
.003
6.6 ± 0.6 (1 3)
13
.012
6.5
7.6 ± 0.8 (8)
(12)
(1 2)
(ii)
(13)
(1 1)
(i2)
13
i 3
16
12
31
10
.027
.152
.157
<.001
.034
.058
1 63.6 ± 5.0 (9)
1 44.8
± 7.0 (1 3)
12
<.OOi
1 16.6
589.9
1 03.0
430.9
54.6
0.53
25.5
±
±
±
±
±
11
27
10
<.OOi
.002
<.001
.286
.012
(mm)
Cerebral lateral width (mm)
Corpus callosum (mm2)
Basal ganglia width
Basal ganglia ratio
Pituitarygland(mm2)
(mm)
± 6.4 (8)
± 93.5 (8)
60.7 ± 2.5 (8)
0.52 ± 0.02 (8)
46.2 ± 17.6(8)
6.0 (1 3)
102.6 (12)
3.0 (13)
0.02 (13)
5.1 (10)
45
Note-Measurements
are presented
as mean ± SD, followed in parentheses
by the number of subjects.
The p
values were calculated
from pooled variances
when Levene’s
F-test showed
variances
to be insignificantly
different
(p
.1) and from separate variances
when variances
were shown to be significantly
different
(p
.1).
but not dysgenesis
or later loss of Purkinje cells. As a last
example, in fragile X syndrome the posterior vermis is reduced
in size but the anterior
vermis
is not [23].
Measurements
of the transverse
width of the cerebellar
hemispheres
and measurements
of brainstem structures
interconnected
with the cerebellum (ventral pens and inferior
olives) did not closely reflect the amount of cerebellar atrophy
seen in the patients with Rett syndrome.
A lack of such
correlations has been noted in other disorders. For example,
in a patient
even though
reduced
with
progressive
the vermis
in size by 85%
cerebellar
and cerebellar
and 42%,
degeneration
[24],
hemispheres
were
respectively,
the width
the cerebellum,
the widths of the inferior olives,
midsagittal
area of the ventral pons were reduced
4%, 2%, and i 3%, respectively.
Supratentorial
of
and the
by only
Findings
MR imaging showed clean evidence of hypoplasia of the
cerebrum and the basal ganglia in Rett syndrome
but no
evidence of atrophy. For instance, cerebral length and width
and measurements
of the corpus callosum were reduced 10-
27%, but no evidence
head circumference
is usually normal at birth, but its growth
rate decelerates
after the age of 5-6 months
[26, 27]. This
deceleration
occurs in the midst of a rapid and critical phase
of human postnatal
brain growth:
for instance,
from birth to
2 years, the number of synapses
in the cerebrum
nearly
doubles [28], and the weight of the human brain normally
more than doubles, from 384 to 96i g (see Table i i i in
Bhinkov and Glazer [29]) [30]. The rate of growth thereafter
is significantly
shower,
but
growth
continues
into
the
third
decade of life [29].
Autopsy evidence is also consistent with MR evidence of
cerebral hypoplasia and arrest of development
without significant age-related
global atrophy in patients with Rett syndrome. For example, recent autopsy findings in a i 2-year-old
patient with Rett syndrome
[20] included
signs of developmental arrest such as increased
cell packing density throughout the cerebral
cortex,
basal ganghia, thalamus,
hippocampus, amygdaha,
and cerebellum.
In addition,
the mean weight
of the brain in 1 4 6- to 30-year-old
patients
with Rett syn-
drome
from three
studies
[i 9, 20, 3i]
is 945 g, a weight
comparable
to the normal weight
in 2-yean-olds
smaller than the normal weight in 6- to 30-year-old
and 26%
females
widening was found. In a recent MR report, Casanova et al.
[25] also found the cerebral hemispheres
and caudate nuclei
[29, Table i i i]. Moreover, the mean brain weight of the three
youngest patients reported in the literature (6, 7, and 8 years
old [i9, 3i]) differs by only 4% from the brain weight of the
in patients
three
with
Rett
of abnormal
syndrome
signal
intensities
to be smaller
than
or sulcal
those
in
control subjects. However, they did not find a difference in a
measurement
of the corpus callosum, perhaps because their
control subjects were patients rather than healthy volunteers.
These abnormal measurements
of the cerebrum and basal
ganghia from MR images are consistent with the microcephaly
seen in other studies of Rett syndrome [2, 5, 6, 1 0-i 2] and
in most
of our patients.
In patients
with
Rett
syndrome
the
oldest
old [1 9, 3i]).
youngest
patients
in the literature
Additionally,
Rett cases
(i 8, 20, and
the mean brain weight
reported
in the autopsy
30 years
of the eight
literature
(6-i
2
years old) is only slightly smaller than that of the six oldest
cases (i 3-30 years old) (920 vs 978 g) [1 9, 31].
It is uncertain
if atrophy
of the cerebral
cortex occurs
in
Rett syndrome.
Some autopsy
and imaging
studies
of the
brain have stated
that in a minority
of patients
with Rett
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AJA:159,July
syndrome,
[2, 5-7,
MR OF RETT
1992
the cerebral
9-i 2, 3i].
cortex
show signs of “slight”
Unfortunately,
these
studies
atrophy
generally
failed to maintain a clinically meaningful distinction
between
hypoplasia, defined as incomplete development
or underdevelopment, and atrophy, defined as a wasting away, loss, or
dimunition
of previously
developmental
established
disorders,
of some parenchymal
hypoplasia
element
brain
parenchyma.
In
can result from atrophy
(e.g., during
early development,
previously established Purkinje neurons may die, which then
leads to cerebellan hypoplasia, as in infantile autism). None of
the brain imaging or autopsy studies that did report atrophy
in Rett syndrome provided the evidence necessary to draw
this conclusion. On the contrary, the weight of evidence leans
toward hypoplasia (e.g., arnest of brain weight, increased cell
packing density, no age-related increase in sulcal width, no
age-related changes in cerebral width or length, mild to absent
evidence of cortical or white matter ghiosis in the cerebrum)
Ii 9, 29, 3i , this study].
The abnormality
of the basal ganghia detected with MR
imaging [25, this study] and at autopsy in patients with Rett
syndrome is compatible with other indexes of dysfunction
of
the basal
ganglia
in this disorder.
For example,
patients
with
Rett syndrome have dysfunction
of the extrapyramidal
motor
system,
including
abnormal
hand-wringing
behavior,
gait
apraxia, and truncal ataxia [4, 32]. Moreover, positron emission
tomography
showed
evidence
of decreased
D2-dopa-
mine receptor binding in the caudate nucleus of a 25-year-old
patient with Rett syndrome [33]. Finally, “isolated abnormal
neunites and reactive
been seen at autopsy
Rett syndrome
or degenerative
in the caudate
axonal
nucleus
swellings”
of patients
have
with
[3i].
A final implication
clinical neuroradiologic
of the present
examination
study has to do with the
of neurohogically
or de-
velopmentahhy impaired patients. Findings on neunoimaging
studies of patients with Rett syndrome are commonly interpreted as normal [6-9]. A neunonadiologist
interpreted quahitative findings on MR images as normal in eight of our patients
with Rett syndrome. However, the quick, accurate, and simple
quantitative
analyses used in this study revealed that these
normal images were markedly abnormal in all supratentorial
and posterior fossa regions measured. Quantitative
analyses
are an important complement
to routine radiologic interpretation
of neunoimaging
studies,
particularly
in children.
ACKNOWLEDGMENT
We thank Jeanne
Townsend
for assistance
with the statistical
analyses.
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