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Blood, Vol. 93 No. 1 (January 1), 1999:
pp. 71-79
By
From the Departments of Pediatrics, Radiology, Pathology and
Laboratory Medicine, and Neurology, the Divisions of
Hematology/Oncology and Biostatistics, University of Southern
California School of Medicine, Los Angeles; the Department of
Pediatrics, the Division of Hematology/Oncology, Long Beach Memorial
Hospital, Long Beach; the Ahmanson Pediatric Center, the Division of
Hematology/Oncology, Cedars Sinai Medical Center, Los Angeles; the
Department of Pediatrics, Hematology Division, Kaiser Foundation Health
Plan, Inc, Los Angeles; the Department of Pediatrics, City of Hope
Medical Center, Duarte, CA.
Children with sickle cell anemia (SS) have an increased risk for
cerebral vasculopathy with stroke (CVA) and cognitive impairment. The
present study examines the extent to which adding positron emission
tomography (PET) to magnetic resonance imaging (MRI) can improve the
detection of cerebral vasculopathy. Whereas MRI has been the prime
modality for showing anatomical lesions, PET excels at assessing the
functional metabolic state through glucose utilization 2-deoxy-2
[18F] fluoro-D-glucose (FDG) and microvascular blood flow
([15O]H2O). Forty-nine SS children were
studied. Among them, 19 had clinically overt CVA, 20 had
life-threatening hypoxic episodes or soft neurologic signs, and 10 were
normal based on neurological history and examination. For the entire
sample of 49 subjects, 30 (61%) had abnormal MRI findings, 36 (73%)
had abnormal PET findings, and 44 (90%) showed abnormalities on either
the MRI or the PET or both. Of the 19 subjects with overt CVA, 17 had abnormal MRI (89%), 17 had abnormal PET (89%), and 19 (100%) had either abnormal MRI or PET or both. Among the 20 subjects with soft
neurologic signs, 10 (50%) had abnormal MRI, 13 (65%) had abnormal
PET, and 17 (85%) had abnormal MRI and/or PET. Six (60%) of
the 10 neurologically normal subjects had abnormal PET. Among the 30 subjects with no overt CVA, 25 (83%) demonstrated imaging abnormalities based on either MRI or PET or both, thus, silent ischemia. Lower than average full-scale intelligence quotient (FSIQ) was associated with either overt CVA or silent
ischemic lesions. Four subjects who received chronic red blood
cell transfusion showed improved metabolic and perfusion
status on repeat PET scans. In conclusion, (1) the addition of PET to
MRI identified a much greater proportion of SS children with
neuroimaging abnormalities, particularly in those who had no history of
overt neurologic events. (2) PET lesions are more extensive, often
bihemispheric, as compared with MRI abnormalities. (3) PET may be
useful in management as a tool to evaluate metabolic improvement after
therapeutic interventions, and (4) the correlation of PET abnormalities
to subsequent stroke or progressive neurologic dysfunction requires
further study.
NEUROVASCULOPATHY in sickle cell anemia
(SS) is clinically manifested as cerebral infarction with paresis
during childhood and intracranial hemorrhage in older children and
adults.1-7 In addition to regional central nervous system
(CNS) infarction with overt stroke, a subclinical diffuse
cerebral microvasculopathy also occurs as best shown by regional or
global cerebral atrophy on computed tomography (CT) imaging scans. One
consequence of this microvasculopathy is a variety of cognitive
impairments, which usually becomes evident by middle school
age.8-14
At the present time, CT and magnetic resonance imaging (MRI) are the
accepted imaging modalities used to confirm a clinical diagnosis of
cerebral infarction, intracranial hemorrhage, or neuronal damage in SS
children.3,6,7,15-21 MRI provides high resolution
anatomical delineation, whereas positron emission tomography (PET) can
gauge the functional activity of the cerebral tissues by using
radioactive tracers to indicate glucose metabolism 2-deoxy-2 [18F] fluoro-D-glucose (FDG) and evaluate microvascular
blood flow ([15O]H2O) as demonstrated in a
normal PET study (Fig 1). Stenosis or occlusion of the large
intracranial vessels of the Circle of Willis, particularly the middle
cerebral artery (MCA),22-27 detected by transcranial
doppler (TCD)24-26,28,29 or magnetic resonance angiography
(MRA)19,25,29,30 can be used to predict an increased risk
of clinical infarctive stroke.
The application of PET in SS subjects was published in 1988 when
investigators at the National Institutes of Health (NIH) reported a
preliminary study using FDG PET technology on six adults with sickle
cell anemia who had normal CT scans and no known neurological events.31 These subjects were found to have significant
hypometabolism in the frontal areas of the brain. A second study showed
that brain oxygen extraction ratios were normal in six nontransfused anemic adults along with lower oxygen consumption.32 In two subjects with abnormal CT scans, although blood flow was similar to the
level of normal children, blood perfusion seemed to be decreased. PET
studies have detected incipient stroke and identified risk regions of
the brain for subsequent infarction based on ipsilateral increased
cerebral oxygen extraction fraction in adults with carotid artery
stenosis.33 The combined use of PET and MRI should better identify the extent of the physiologic dysfunction in relation to
anatomic loss of neuronal tissue.34-36
We report findings on a group of 49 subjects with SS evaluated to
assess the combined use of MRI and PET in detecting cerebral dysfunction. The study hypothesis is that metabolic imaging would provide additional information on the neurophysiologic status of the
patient. The ultimate aim is to identify patients at high risk for
stroke or functional neurologic deficits, thus allowing for timely
therapeutic interventions.
Patient population.
Subjects with sickle cell anemia were recruited from a Southern
California regional consortium of pediatric hematologists investigating
stroke in SS children. Hemoglobinopathy diagnosis was based on
hemoglobin electrophoresis, column chromatography, or molecular
biologic techniques. Pediatric hematologists were the primary care
physicians for these patients and knew them essentially from birth.
Neurologic examinations were performed by consulting neurologists at
the participating institutions. Three groups of children were
recruited. The first group (Category I) included those who had clinical
neurologic events with overt cerebral vascular accidents (CVA). The
second group (Category II) was those subjects who had a prior hypoxic
illness requiring hospitalization or showed soft neurologic signs with
poorer fine motor coordination according to the Zurick Neuromotor
Examination or the Movement ABC Test Scale (modified for children),
similar to that compiled by Mercuri et al.37 A third
comparison group (Category III) was composed of those who had no
history of neurologic events including seizures and no soft neurologic
signs. The following patients were excluded from this study: (1) those
who had been hospitalized for head trauma, (2) those who could not stay
motionless inside the MRI imaging equipment, and (3) those who were
severely brain damaged after stroke and were in custodial care. Some
subjects were too cognitively impaired for complete neuropsychologic
testing.
Imaging methods.
PET scans were performed using the Siemens (ECAT, Knoxville, TN)
953/whole body scanner, located in the
University of Southern California PET Imaging Science Center, with
axial FOV of 10.4 cm, plane slice thickness of 3.375 mm and in-plane
resolution of 4 mm. Image reconstruction was done using the filtered
back projection technique with calculated attenuation correction. The radiopharmaceuticals used were FDG (maximum dose-10 mCi) for measuring glucose metabolism and ([15O] H2O) (maximum
dose 70 mCi) for measuring cerebral blood flow (CBF). Interpretation
was performed using multiple dimensional scan images in black and
white.
Figure
1 shows normal FDG and ([15O] H2O) PET scans.
PET scans were reviewed using visual inspection by two expert
neuroradiologists and results were reported without knowledge of the
clinical history, results of other imaging modalities, doppler studies,
or the findings of neuropsychologic testing. The criterion for
abnormalities was the decrease of neuronal function (glucose
utilization) or blood perfusion in the gray matter regions.
Neuropsychological assessment.
As part of a comprehensive neuropsychological battery of tests,
age-appropriate Wechsler scales were used to assess intelligence, including the Wechsler Pre-School and Primary Scales of
Intelligence-Revised (WPPSI-R) for ages 3 to 5 years,38 the
Wechsler Intelligence Scales for Children-third edition (WISC-III) for
ages 6 to 16 years,39 and the Wechsler Adult Intelligence
Scale-Revised (WAIS-R) for ages 17 to 19 years.40 Findings
on the full- scale intelligence quotient scores (FSIQ: normative mean,
100; standard deviation, 15) are presented in this report.
Statistical analysis.
Between group differences in proportions of subjects with abnormal
findings on the MRI, PET, or FSIQ scores were tested for significance
by the Subject characteristics.
A total of 49 subjects, 26 males and 23 females, with SS were included
in the study: 19 patients who had known CVA (Category I), 20 children
who had soft neurologic signs (Category II), and 10 children who had no
clinical indication of neurologic dysfunction (Category III).
Correlation of clinical status with MRI and/or PET findings.
Among the entire group of 49 subjects, 30 (61%) had MRI
white and/or gray matter lesions, 36 (73%) had abnormal PET
findings, and 44 (90%) had either an abnormal MRI or abnormal PET or
both (Table 1). Of the 19 CVA subjects
(Category I), 17 (89%) had abnormal imaging findings on MRI or PET
when considered independently, 19 (100% sensitivity) when considered
in combination. Performing MRI alone would have left two of 19 patients
(11%) who had overt clinical CVA undetected (normal MRI; abnormal
PET). Of the 20 patients in Category II, 10 (50%) had abnormal MRI, 13 (65%) had abnormal PET, and 17 (85%) had either abnormal MRI or PET
or both. Three (30%) of the 10 Category III patients had abnormal MRI, 6 (60%) had abnormal PET, and 8 (80%) had an abnormality on either MRI or PET or both.
Type of abnormal PET findings.
Of the 36 abnormal PETs, 28 (78%) had both hypoperfusion
and hypometabolism, 6 had only focal hypometabolism (FDG), and 2 had
only focal hypoperfusion (CBF) (Table 2).
The percentage of subjects with both hypoperfusion and hypometabolism
progressively increased with increasing severity of abnormal neurologic
findings: 2 of 6 (33%) in Category III, 10 of 13 (77%) in Category
II, and 16 of 17 (94%) in Category I. Overall, 14 of the 36 patients
with abnormal PETs (39%) had a normal MRI.
Correlation of PET findings with MRI gray and white matter lesions.
The concordance between abnormal PET and MRI scans where
abnormalities were found in both gray and white matter was 11 of 12 (91.7%) (Table 3). The concordance between
PET and MRI was 80.0% for MRI identified abnormal gray matter lesions.
Concordance was lower at 53.8% for abnormal white matter lesions on
MRI without gray matter involvement because of the low glucose
utilization in the white matter (corona radiata and watershed). A
normal PET was found in 6 of 13 subjects with MRI watershed
abnormalities. Among the non-CVA subjects (Categories II and III), PET
was abnormal in 4 of 9 (44%) of those with MRI watershed white matter
lesions. In our PET studies, we confirmed the observation by Steen et
al21 based on T1q MRI mapping and
T2 MRI by Moser et al15 of occasional dysfunction of the thalamus (n = 9). We also identified dysfunction of
the parahippocampal gyrus and uncus in one neurologically normal Category III patient. Figure 3 is a good example of the added information derived from FDG and ([15O]H2O)
PET images when correlated with the MRI. The FDG shows a large left
frontal lobe deficit much greater than seen on
([15O]H2O) perfusion, whereas perfusion is
markedly decreased in the right superior parietal lobe. MRI shows white
matter bright lesions in the frontal regions and in the corona radiata
slightly more on the left side. In all cases with abnormal MRI, the
abnormality identified on PET, as measured by glucose metabolism and
perfusion defects, was more extensive than indicated by MRI alone
(Fig 4).
Transfusion and PET.
Four of our study subjects who were placed on a chronic transfusion
program (HbS maintained at <30%)43-46 had improvement in glucose metabolism and perfusion on repeat PET scans. The first PET
scan was performed within a month of entry into the study. One of the
four was an asymptomatic patient with a normal MRI and an elevated
screening TCD. Her PET showed significant metabolic and perfusion
hypofunction. Repeat PET was used to monitor transfusion effect and
showed normalization after 16 months of transfusion therapy. The MRI
has been repeatedly normal and FSIQ was stable near the original 129. The second subject with sleep apnea and a normal MRI had hypometabolism
of the thalamus on PET. After a year of transfusion, all PET studies
had reverted to normal. The third patient had a fixed left hemiparetic
stroke with both MRI and PET evidence of infarction in the distribution
of the right middle cerebral artery (RMCA). After transfusion for 3 years, repeat PET showed improvement of both metabolism and perfusion in the contiguous anterior regions of the RMCA. Clinical status was
unchanged. The fourth subject had a normal MRI 2 years before an
encephalopathic episode. The PET scan performed during this comatose
episode showed left hemispheric multifocal areas of decreased glucose
metabolism and blood perfusion. During that same hospital admission, a
second MRI showed a small ill-defined anterior watershed abnormality on
the left. PET scans performed at 6-month intervals after the initiation
of a transfusion program showed near normalization in glucose
metabolism and improvement in perfusion (Fig 5). The patient has
significant cognitive deficiencies and poor adaptive behavior. In these
four patients, improvement in neuronal metabolic function and
microvascular perfusion was demonstrated by repeat PET imaging.
Neuropsychological findings.
Impairments were found in several areas including intelligence, school
achievement, motor and psychomotor speed, and adaptive behavior. In the
present communication, findings on the FSIQ are presented to illustrate
the impairment of Category I, Category II, Category III, and the silent
ischemia group. The mean (± SD) of FSIQ scores was significantly
different among the three patient groups 82 (±13) for Category I,
78 (±19) for Category II, and 99 (±23) for Category III.
Pair-wise comparison of the means by one-tailed t-test showed
that the difference was significant (P < .01) between
Categories I or II and III. The proportion of subjects below the normal
mean of 100 was similar for Categories I (CVA) and II (soft
neurological) children, but significantly lower among Category III (no
neurological signs) subjects: 14 of 15 (93%) for Category I, 15 of 16 (94%) for Category II, and 4 of 9 (44%) for Category III. Among the
25 subjects in Categories II and III who had silent ischemia on the MRI
or PET or both, 20 participated in neuropsychological assessment. Their
mean FSIQ score was 84 (±23), and 16/20 (80%) of the IQs were
below 100; these values were not significantly different from those of
Category I (CVA group). In those whose silent ischemic lesions were
diagnosed by an abnormal PET in the face of a normal MRI (n = 11), the
mean FSIQ was 86 (±22) and 8 of 11 (73%) were below the normal
mean.
Forty-nine children with sickle cell anemia were studied by a
combination of PET and MR imaging techniques, which identified a high
percentage of anatomical and/or functional brain abnormalities across a spectrum of clinically identified neurologic states. All 19 of
the subjects with overt CVA showed at least one imaging abnormality,
while 85% of patients who were clinically identified with soft signs
of neurologic impairment and 80% of subjects with no CVA or soft
neurologic signs did also. The addition of PET to MRI evaluation of the
CNS in these SS subjects clearly demonstrated that PET imaging can
identify both overt and subtle loss of cerebral neuronal metabolic
function when MRI studies show no clear anatomic lesion. Fourteen of
the 19 subjects with normal MRIs (74%) were abnormal on PET, five of
these identified in the neurologically normal group. This study
confirms the original observation of Rodgers et al31 of
silent neuronal dysfunction in adults based on abnormal FDG-PET. The
high sensitivity of PET for CNS dysfunction is consistent with recent
PET studies in subjects with acute traumatic head injuries. These show
that areas of functional abnormality are usually greater than the
structural neuronal loss defined by MRI or CT and can be found
associated with a normal MRI or CT.47,48 In like manner,
PET showed more extensive bilateral hemispheric dysfunction than was
demonstrated by MRI in our SS subjects with known clinical ischemic
events. This may account for the high risk of extension of the cerebral
vasculopathy into previously presumed nonaffected areas. We suggest
that the definition of the MRI identified silent infarction status be
extended to include unexpected metabolic or perfusion ischemic lesions
on PET.
PET imaging techniques offer additional and detailed delineation of
both (1) regional infarction and (2) diffuse cerebral disease.33,50,54,55 The addition of PET to MRI identified a
greater proportion of SS children with neuroimaging abnormalities than
MRI alone (90% v 61%). The majority (63%) of these SS
children with no overt neurologic events had abnormal PET studies. The prevalence of silent ischemic lesions was much higher than the reported
10% frequency of overt CVA in SS children would imply.2 PET lesions were also shown to be more extensive, often bihemispheric as compared with MRI. These findings may be helpful in understanding the development of cerebral vascular disease in SS children.
We thank Dr Cage Johnson, Director, USC Comprehensive Sickle Cell
Center for his advice and encouragement. We greatly appreciate the
efforts of the neuroradiology staff and the pediatric neurology staff
of the cooperating institutions who forwarded their reports to the
principal investigator coupled with copies of the MRI and MRA. We are
grateful for the secretarial efforts of Debra Johnson in the
preparation of this manuscript.
Submitted January 5, 1998;
accepted September 1, 1998.
Address reprint requests to Darleen R. Powars, MD, LAC+USC Medical
Center, Department of Pediatrics, 1240 N Mission Rd, Room L911, Los
Angeles, CA 90033.
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Top
Abstract
Introduction
2 test. Between group differences in mean FSIQ
scores were tested by analysis of variance with Bonferroni adjustment
for multiple paired comparisons.
Revised. San Antonio, TX, The Psychological Corporation, 1989.