Children Experience Cognitive Decline Despite Reversal of Brain Atrophy One Year
Following Resolution of Cushing Syndrome
Deborah P. Merke, MD, MS,* Jay N. Giedd, MD, Margaret F. Keil, MS, CRNP, Sarah L.
Mehlinger, M.A., EA Wiggs, PhD, Stuart Holzer, BS, Erin Rawson, BS, A. Catherine Vaituzis, AA,
Constantine A. Stratakis, MD, DSci, George P. Chrousos, MD
From the Pediatric and Reproductive Endocrinology Branch (DPM, MFK, SM, EAW, SH, ER,
GPC) and Section on Endocrinology of Genetics (CAS), Developmental Endocrinology Branch,
National Institute of Child Health and Human Development, the Warren Grant Magnuson Clinical
Center (DPM) and the Child Psychiatry Branch, National Institute of Mental Health (ACV, JNG),
*Commissioned Officer in the United States Public Health Service
Address correspondence and reprint requests to:
Deborah P. Merke, M.D.
Bldg10 Room 13S260
10 Center Dr MSC 1932
Bethesda MD 20892-1932
Tel: (301) 496-0718
Fax: (301) 402-5618
Running title: Cognitive Decline in Pediatric Cushing
Word Count: 3398
Key terms: Pediatric Cushing syndrome, Pediatric Cushing disease, Cushing and psychopathology
Journal of Clinical Endocrinology & Metabolism. First published March 1, 2005 as doi:10.1210/jc.2004-2488
Copyright (C) 2005 by The Endocrine Society
Adults with Cushing syndrome frequently develop brain atrophy, memory impairment and
depression, with partial to complete resolution after cure. The effect of excess glucocorticoid
exposure on the brain of children has not been systematically studied. Eleven children (6 girls, 5
boys; ages 8-16 years) with endogenous Cushing syndrome seen at the National Institutes of Health
Clinical Center from 1999-2000 and 10 healthy age- and sex-matched control subjects were studied.
Cognitive and psychologic evaluations and magnetic resonance imaging of the brain were done prior
to and one year after cure for patients with Cushing syndrome and once for controls. The estimated
duration of Cushing syndrome was 4.4 ± 1.2 years. When compared to control subjects, children
with Cushing syndrome had significantly smaller cerebral volumes (P<0.001), larger ventricles
(P=0.02), and smaller amygdala (P=0.004). At baseline, there were no significant differences in IQ
between the two groups and no psychopathology was identified. Despite reversal of cerebral
atrophy one year after surgical cure (total cerebral volume: 947 ± 94 vs.1050 ± 74, P<0.001;
ventricular volume 21.4 ± 12.5 vs. 14.5 ± 11.6; P<0.001), children with Cushing syndrome
experienced a significant (P<0.05) decline in Wechsler IQ scores (Full Scale: 112 ± 19 vs 98 ± 14)
and a decline in school performance, without any associated psychopathology. The effect of
glucocorticoid excess on the brain of children appears to be different from adults. Despite rapid
reversibility of cerebral atrophy, children experience a significant decline in cognitive function one
year after correction of hypercortisolism.
The assumption that children respond similarly to adults with respect to disease
processes and medication efficacy and side effects is often erroneous (1). Cushing disease and
other endogenous causes of excess cortisol secretion are rare in children. Patients with
endogenous causes of Cushing syndrome represent a model in which to study the effects of
hypercortisolism, although the degree to which the effects of excess endogenous and exogenous
glucocorticoids are comparable is unknown. Moreover, many effects may be dose-related.
Prolonged exposure to excess glucocorticoid from an endogenous or exogenous source causes
growth retardation and obesity in children (2), but mental changes secondary to exposure to excess
glucocorticoid have not been systematically studied in pediatric patients. Studies of adult patients
with Cushing syndrome have found that, in the majority of patients, prolonged exposure to excess
cortisol results in cognitive and memory impairment and significant psychopathology, most
commonly, depression (3, 4). Significant recovery of depressive symptoms and improvement in
concentration (5-7), and partial reversibility of cerebral atrophy have been observed in adult
patients with Cushing syndrome following remission (8, 9).
To assess the effect of hypercortisolism on the developing child brain, we performed clinical,
cognitive, psychologic and magnetic resonance brain imaging studies in children with Cushing
syndrome at diagnosis and at one-year after a return to eucortisolism and in age-and sex-matched
Subjects and Methods
Eleven children (6 females, ages 8 to 16 years; 5 males, ages 9 to15 years) with endogenous
Cushing syndrome seen at the National Institutes of Health Clinical Center from 1999-2000 and 10
healthy age- and sex-matched control subjects (6 females, ages 8 to 16 years; 4 males, ages 9 to 16
years) were studied. Children with Cushing syndrome were evaluated prior to surgery and one-year
post-surgery. Ten children were diagnosed with Cushing disease and underwent transsphenoidal
surgery for removal of a pituitary adenoma. Of these ten patients, two female patients with Cushing
disease had prior transsphenoidal surgery without remission and were referred to the National
Institutes of Health for a possible second surgery. One child (8 year old female) was diagnosed with
primary pigmented nodular adrenocortical disease, not associated with Carney Complex, and a
bilateral adrenalectomy was performed. Magnetic resonance imaging (MRI) of the brain and
psychologic testing of healthy subjects were obtained from a parallel study of normal brain
development using subjects recruited from the community (10).
All subjects underwent physical and neurologic examinations. Retrospective growth data for
the patients with Cushing syndrome was obtained from their pediatricians’ medical records. Control
subjects with physical, neurologic, and personal or familial psychologic abnormalities (one first
degree relative, or greater than 20% of second degree relatives with psychiatric diagnosis) were
excluded. Tanner staging of patients with Cushing syndrome was determined by breast development
(females) (11) or testicular size (males) (12), and by a self-administered questionnaire in control
The study was approved by the institutional review boards at the National Institute of Child
Health and Human Development and the National Institute of Mental Health. Each parent gave
written informed consent, and children over the age of seven years gave their assent.
Cognitive and Psychologic Studies
All children were evaluated by a neuropsychologist (EAW). Psychologic evaluation
included the 12 handedness items from the Physical and Neurologic Examination for Subtle Signs
(PANESS) inventory (14) and the Behavioral Assessment System for Children (BASC) (15). The
Wechsler Intelligence Scale for Children was administered to subjects under 16 years of age (16).
The Wechsler Adult Intelligence Scale (17) was used to evaluate subjects 16 years of age or older.
Evaluation of the patients with Cushing syndrome also included the California Verbal Learning Test
– C (18), the reading and math clusters of the Woodcock-Johnson Psychoeducational Battery
Revised: Test of Achievement (19) and questions regarding school performance.
Magnetic Resonance Imaging
We examined the hippocampus and amygdala, areas of the brain known to be affected by
hormones of the hypothalamic-pituitary-adrenal (HPA) axis (20-22). Volumes of the cerebrum,
ventricles, and temporal lobes also were evaluated.
All subjects were scanned on the same GE 1.5 Tesla Signa Advance scanner (GE Signa
version 5.4). Axial slices 1.5-mm-thick and coronal slices of 2 mm were acquired using a 3D
spoiled gradient recalled echo in the steady state, with standard head positioning, as previously
described (23). All persons involved in the process of obtaining brain measurements were blinded to
subject characteristics including age, sex and diagnosis. The volumes of the cerebrum, ventricles,
temporal lobe, hippocampus, and amygdala were quantified using techniques previously validated
(10, 23). Total cerebral volume was quantified using an automated program that employs a
mathematically modeled template brain to calculate volumetric measurements based on MRI signal
intensity characteristics. Each axial slice of the brain was edited by experienced raters to remove
artifacts. Lateral ventricular volumes were measured in the coronal plane on all slices on which they
were visible using an operator-supervised thresholding technique that segmented cerobrospinal fluid
from brain tissue. This analysis was carried out using an image analysis program, the NIH Image
Measurements of the temporal lobe, amygdala and hippocampus were done by manually
tracing in the coronal plane by a single experienced operator (SM) who was blind to any subject
characteristics. Our measurement of the temporal lobe, hippocampal formation and amygdala has
been previously described (10, 23). Reliabilities for the quantification of each of the structures were
established by having two raters (ACV and SM) initially measure ten subjects to determine inter-
rater intraclass correlation coefficients (ICCs). After completion of image analysis for the study, ten
previously measured subjects were redone in order to account for possible drifts in rater assessment
and establish intra-rater ICCs. Inter-rater ICCs were .98 for the temporal lobe, .74 for the amygdala
and .70 for the hippocampus, and intra-rater ICCs were .99 for the temporal lobe, .96 for the
amygdala and .94 for the hippocampus.
Height standard-deviation score and body mass index (BMI) standard-deviation score were
determined using anthropometric reference data for US children (25). Demographic and clinical
measures were compared between Cushing syndrome patients and age- and sex-matched controls
using two sample two-sided Student’s t-test for continuous measures or Chi square test for nominal
measures. The comparison between Cushing syndrome patients at baseline and at one year follow-up
was assessed by using the paired two-sided Student’s t-test. Statistical significance was accepted
for P < 0.05. All values are the mean plus-minus standard deviation unless otherwise specified.
There were no significant differences between children with Cushing syndrome and the
healthy control group with respect to age, gender, pubertal stage, percent right-handedness and IQ
(Table 1). Both children with Cushing syndrome and the control children had average to above-
average pro-rated Wechsler Full Scale IQ (Table 1). No significant learning disabilities were
identified in either group.
At baseline, children with Cushing syndrome had impaired growth velocity (1.2 ± 0.9 cm per
year), short stature, younger bone age (up to 3.8 years delayed) and significantly greater body mass
index (27.5 ± 3.9 vs. 21.9 ± 4.4 kg/m2, P<0.001) than the healthy age-matched controls (Table 1).
All of the patients with Cushing syndrome had biochemically confirmed hypercortisolism (urinary
free cortisol: 198 ± 75 microgram/24 hours (546 ± 206 nmol/day), normal range: 8-77 microgram/24
hours (22-212 nmol/day); urinary free cortisol corrected for body surface area: 147 ± 69
microgram/m2/24 hours (405 ± 190 nmol/ m2/day), normal < 68 microgram/m2/24 hours (<188
nmol/ m2/day))(26) and lacked diurnal variation in plasma cortisol concentrations (AM cortisol 19.1
± 9.5 microgram/dl (526 ± 262 nmol/L), midnight cortisol 18.7 ± 8.8 microgram/dl (515 ± 242
nmol/L)). The average duration of Cushing syndrome based on onset of decreased growth velocity
was 4.4 ± 1.2 years (range 1.0 to 4.5 years). Three patients had secondary hypothyroidism in the
immediate postsurgical period and were placed on thyroid hormone replacement therapy. No other
pituitary dysfunction was identified.
One year after surgery, all patients with Cushing syndrome showed biochemical evidence of
cure with normal urinary free cortisol levels (17.9 ± 14.5 microgram/24 hours (49 ± 40 nmol/day;
corrected for body surface area: 11.8 ± 9.3 microgram/m2/24 hours (33 ± 26 nmol/ m2/day). Ten
patients had normalization of their hypothalamic-pituitary-adrenal axis based on a normal
cosyntropin stimulation test (cortisol > 18 microgram/dl (496 nmol/L) 60 minutes after cosyntropin
administration) while one patient remained on physiologic doses of hydrocortisone. All patients
were euthyroid and two patients remained on thyroid hormone replacement. During the year
following surgery, patients with Cushing syndrome also experienced a significant increase in growth
velocity (standard-deviation score, -3.8 ± 1.1 vs. 5.2 ± 4.1; P<0.001) and height (standard-deviation
score, -1.1 ± 0.9 vs. -0.6 ± 0.8; P=0.002) and a decrease in weight (standard-deviation score, 1.3 ±
1.6 vs. 0.1 ± 1.3; P<0.001) and body mass index (standard-deviation score, 3.2 ± 2.2 vs. 0.6 ± 1.3;
P<0.001), all indicative of resolution of their hypercortisolism. Overall, their physical appearance
improved; they became leaner and more age-appropriate (Figure 1); and puberty progressed in an
Cognitive and Psychologic Findings
At baseline, there were no significant differences between the children with Cushing
syndrome and the healthy control group with respect to Full Scale, Verbal and Performance IQ;
however, scores tended to be lower in the patients with Cushing syndrome (Wechsler IQ: Cushing
vs. control: Full Scale: 112 ± 18 vs. 120 ± 13; Verbal: 108 ± 16 vs. 127 ± 8; Performance: 112 ± 19
vs. 112 ± 8). One year after surgery and a return to eucortisolism, patients experienced a significant
(P<0.05) decrease in IQ (Figure 2). Similarly, Woodcock Johnson achievement scores declined,
with a statistically significant decline in mathematics only (reading: 115.5 ± 19.0 vs. 108.8 ± 15.8,
P=0.08; mathematics: 110.9 ± 19.9 vs. 99.5 ± 19.2; P=0.02). Overall, scores that were in the high-
average range at baseline declined to the average range at one-year follow-up evaluation. There were
no significant changes in memory measured by the California Verbal Learning test (57.3 ± 8.1 vs.
55.6 ± 13.0, P=0.68). The BASC did not identify any clinically significant psychologic disturbance.
All patients with Cushing syndrome were average to above-average students and the majority
reported a decline in school performance one year after surgery. At the time of diagnosis, six
patients described themselves as “A” students and taking accelerated classes. One year after
surgery, five of the six “A” students had become “B” or “C” students, with a decrease in the number
of honors classes. Two patients reported “no change” in school performance and no patient reported
an improvement in school performance. One of the eleven patients reported missing a significant
number of school days in the year following surgery and none of the patients reported a significant
change in social activities.
When compared to the age-matched control subjects, children with Cushing syndrome had
significantly smaller total cerebral volumes (P<0.001), larger ventricles (P=0.02), and smaller
amygdala volumes (P=0.004) (Table 2). Hippocampal volumes were smaller in the patients with
Cushing syndrome but differences between the two groups were not significant (Table 2).
A significant (P<0.001) increase in total cerebral volume and decrease in ventricular size was
observed one-year following surgical cure of Cushing syndrome (Table 2, Figure 3). Moreover, the
total cerebral volume and ventricular size was comparable to age-matched controls at one year
follow-up. Although an increase in the size of the hippocampus was also observed, this increase was
not statistically significant. In contrast to other measurements of the brain, no changes over time
were observed in the size of the amygdala after correction of hypercortisolism (Table 2).
In this study, we found that children with endogenous Cushing syndrome had average to
above-average intelligence despite having significant cerebral atrophy. One year after surgery and
a return to eucortisolism, they experienced a significant decline in cognitive function despite
almost complete reversal of the cerebral atrophy. This is in contrast to the adult experience.
Adults with Cushing syndrome have cognitive and memory impairment and significant
psychopathology during hypercortisolism, with significant recovery of symptoms (5-7) and partial
reversal of cerebral atrophy after a return to eucortisolism (8, 9). A decline in cognitive function
following cure appears to be unique to the pediatric population.
Children with Cushing syndrome present with symptoms that are somewhat different
from those seen in adults (2, 27, 28). The most sensitive indicator of excess glucocorticoid
secretion in children is growth retardation, which often precedes other manifestations (28). Other
most common clinical characteristics of Cushing syndrome in children are weight gain, obesity,
and facial plethora (2), which were present in all of our patients. Biochemical features of Cushing
syndrome are similar in pediatric and adult patients (27-29).
Mental changes have not been systematically evaluated in children with Cushing
syndrome. However, school performance was reported as satisfactory (2), and children with
Cushing syndrome were described to have compulsive behavior with overachievement in school
(27, 30). This is in contrast to the poor job performance of adults with Cushing syndrome. These
observations are in agreement with our findings of average to above-average IQ scores and
excellent school performance in our pediatric patients with Cushing syndrome prior to treatment.
In children, long-term psychologic effects of excess glucocorticoid exposure are also unknown.
The depressive symptomatology associated with Cushing syndrome in adults is that of
the atypical type (3, 5). Atypical depression is characterized by irritability, hyperphagia,
hypersomnia and increased fatigue, in contrast to melancholic depression which is associated with
hyperarousal, hypervigilance, insomnia and anorexia. None of our pediatric patients had
symptoms of depression. In fact, the overachievement previously noted in pediatric patients with
Cushing syndrome might be a sign of a paradoxic hyperarousal state with compulsive features.
Our psychologic evaluation was based on the BASC, a standardized, validated, parent-report
which assesses emotional and behavioral problems in children. Although formal psychologic
interpretation and clinical diagnoses are possible based on the BASC, it is possible that more
extensive psychiatric evaluation would have revealed some psychopathology in our children with
Cushing syndrome. Undetected depression, or the psychosocial aspects of experiencing a dramatic
change in physical appearance, may have been contributing factors.
Autopsy (31, 32) and brain imaging studies have found significant cerebral atrophy in
adults with endogenous Cushing syndrome (8, 33). The pathogenesis of this loss of brain volume
due to chronic exposure to excess glucocorticoid is unknown. Loss of brain volume may be due to
a loss of cell volume, inhibition of the genesis of new neurons or glial cells, the loss of preexisting
neurons or glial cells, or some combination of these mechanisms (8, 20). A decrease in brain
water volume and ventricular enlargement with resulting tissue compression may also be
contributing factors. The occupation of glucocorticoid receptors by supraphysiologic doses of
glucocorticoid leads to decreased cell excitability and a reversible phase of atrophy of neurons in
culture (34, 35). If exposure to excess glucocorticoid persists, neuronal cell death may occur.
Glucocorticoids have been shown to increase synaptic accumulation of the excitotoxic glutamate,
which may lead to increased susceptibility to cell injury and death (8, 20, 34, 35). Glucocorticoids
also inhibit neurogenesis (36) and inhibit glucose utilization by the brain (37). The reversible
nature of the cerebral atrophy that characterizes Cushing syndrome suggests that the decrease in
brain volume is not merely due to neuronal or glial cell death, and a transient increase in
neurogenesis may occur following return to eucortisolism.
Sequential imaging studies have shown a progressive increase in brain volume after
correction of hypercortisolism in adult patients with endogenous Cushing syndrome (8). However,
after 39 months, brain volume did not reach the expected normal range (8). To the contrary, our
patients experienced a rapid increase in brain volume, which reached that of the normal controls
within a year following surgical cure. Longitudinal brain imaging data on children has shown
developmental changes in some brain structures and an increase in total cerebral volume with
increasing age (38). However, significant volumetric changes in one year have not been observed
in healthy children (38). The dramatic increase in brain volume observed in our patients with
Cushing syndrome is clearly different from previously reported subtle developmental changes and
is much greater than the increase in brain volume previously reported in adult patients with
Cushing syndrome following cure. Thus, rates of cell recovery and neurogenesis may differ
according to age and developmental stage.
Studies of the effect of excess glucocorticoid on the brain have focused mostly on the
hippocampus, the brain structure critical for learning and memory (39). The hippocampus plays
also an important role in the fine-tuning of the hypothalamic-pituitary-adrenal axis by participating
in its glucocorticoid negative feedback regulation. Animal studies (40) and human studies of adult
patients with chronic hypercortisolemia (41) have shown that prolonged exposure to
glucocorticoid excess results in hippocampal atrophy and memory impairment (42). An
association between reduced hippocampal volume and lower scores for learning and memory has
been shown in adult patients with Cushing syndrome, and memory impairments observed were
specific to verbal learning and delayed verbal recall (41). Appropriate treatment of the underlying
Cushing syndrome tends to reverse this cognitive impairment in adults (41, 43). Our children with
Cushing syndrome had hippocampal volumes smaller than those of the controls, and Verbal IQ
scores were somewhat lower than the normal controls. An increase in the volume of the
hippocampus was observed one year following remission, while paradoxically Verbal IQ scores
declined, and memory scores did not change. This increase in hippocampal volume failed to reach
statistical significance, most likely due to limitations in our sample size. Thus, in children, despite
normalization of total brain and hippocampal volume with time that corresponded to resolution of
hypercortisolism, verbal scores declined while memory testing was unchanged. These findings are
based on limited evaluation of memory in a small sample size.
The amygdala is the brain structure that plays a central role in the processing of fear (44).
Glucocorticoids and corticotropin-releasing-hormone (CRH) are important in the regulation of
amygdala function (21, 22, 45, 46). Changes in amygdala function have been implicated in the
pathophysiology of anxiety and depressive disorders in both adults (47-49) and children (50). The
effect of hypercortisolism on the amygdala has not been systematically studied, however, patients
with classic congenital adrenal hyperplasia, who have prenatal glucocorticoid deficiency with
possible postnatal iatrogenic glucocorticoid excess, have smaller amydala volume than healthy
age- and sex-matched controls (23). In our children with Cushing syndrome, we observed
significantly smaller amygdala volumes than those of healthy controls. Unlike the hippocampus,
no correction in the size of the amygdala was observed one year after cure.
Several secondary hormonal imbalances occur with hypo- and hyper- cortisolemia.
Patients with Cushing disease have markedly decreased cerebrospinal fluid CRH levels (51) and
hyposecretion of CRH may play a role in the pathogenesis of the atypical depression characteristic
of adult patients with Cushing syndrome (5). Region-specific changes in dopamine activity occur
with chronic hypercortisolemia (52, 53). Chronic hypercortisolism also inhibits sympathoadrenal
activity (54, 55) and gonadotropin secretion. Removal of the source of excess endogenous or
exogenous glucocorticoid and the institution of physiologic glucocorticoid replacement typically
results in normal functioning of the hypothalamic-pituitary-adrenal axis within 6 months to one
year. The time course to normalization of other hormonal imbalances is unknown. The
mechanism responsible for the observed cognitive decline in our patients is unknown, but the
multiple hormonal imbalances characteristic of Cushing syndrome may play a role.
Our findings suggest that chronic glucocorticoid excess followed by normalization of
cortisol results in cognitive decline in children, despite reversal of cerebral and hippocampal, but
not amygdala, atrophy. This observed cognitive decline may be due to the prior cortisol excess,
the removal of cortisol excess, a relative cortisol deficiency following cure of Cushing syndrome,
or a combination of these factors. Studies regarding cognitive changes in other populations with
abnormal HPA axis function, such as children with primary or secondary adrenal insufficiency or
those receiving pharmacologic glucocorticoid therapy for immunosuppression or respiratory
disease, have not been done. Excess glucocorticoid, from an endogenous or exogenous source, not
only significantly impacts the height, weight and development of children, but also may have long
lasting effects on the brain and cognition. It is possible that further follow-up of our patients will
show positive cognitive changes. However, our findings indicate that differences between adults
and children exist in the cognitive effects of excess glucocorticoid. Further cognitive, psychiatric
and imaging studies in pediatric patients with iatrogenic and/or endogenous Cushing syndrome are
needed to elucidate the long-lasting effects of exposure to abnormal levels of glucocorticoid on the
developing brains of children.
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