Sunteți pe pagina 1din 6

Diabetic Ketoacidosis and Memory Dysfunction in Children with

Type 1 Diabetes
Simona Ghetti, PhD, Joshua K. Lee, BA, Clare E. Sims, BA, Dana M. DeMaster, BA, and Nicole S. Glaser, MD
Objective We tested the hypothesis that diabetic ketoacidosis (DKA) results in memory deficits typical of hypoxic/
ischemic injury because recent studies suggest that cerebral metabolic changes similar to those observed in hypoxic/ischemic cerebral injury are observed in children with DKA, even without symptoms suggesting cerebral injury.
Study design Thirty-three children with type 1 diabetes mellitus (T1DM) and a history of DKA and 29 children with
T1DM without a history of DKA were enrolled from an academic hospital pediatric endocrinology clinic. These
groups were comparable on demographic and disease-related variables. These groups ability to recall events in
association with specific details, the memory function most directly affected by mild hypoxia/ischemia, was compared on 2 tasks (ie, event-color associations and eventspatial position associations).
Results In multivariate analyses controlling for other critical variables, children with DKA history had significantly
lower rates of accurate memory on both tasks (mean, 0.34  0.13 on the color task and 0.57  0.15 on the spatial
task) than did children without DKA history (mean, 0.44  0.11 and 0.65  0.18, P < .01).
Conclusions DKA disrupts memory function, underscoring the importance of DKA prevention when T1DM is
known and prompt diagnosis of children with new onset of T1DM. (J Pediatr 2010;156:109-14).
hildren with type 1 diabetes mellitus (T1DM) are typically average in overall intellective abilities1,2 but exhibit deficits
on neuropsychological measures of memory.3-7 The origin of these deficits is not fully understood, in part because specific complications of T1DM, rather than T1DM per se, may place subsets of patients at increased risk. The effect of
complications of T1DM (eg, hypoglycemia) on memory has been evaluated,3-7 but the effect of diabetic ketoacidosis (DKA)
has not been reported.
DKA is a state of metabolic decompensation with high blood glucose concentrations and hepatic ketone production resulting in
acidosis.8 Twenty-five to forty percent of children with new onset of T1DM may present with DKA, and in established patients,
DKA may be the consequence of illness, poor compliance, or malfunction of diabetes care equipment (eg, insulin pumps). Newer
data suggest that DKA may cause subtle brain injury.9 Cerebral edema associated with severe disturbances in neurological function
and high mortality rates has long been recognized as a rare but serious complication of DKA in children.10,11 Overt manifestations
of cerebral edema may represent only the most severe cerebral injury caused by DKA. Subtle cerebral injury may occur in the
majority of children with DKA, even among those with minimal or no alterations in mental status.9,12-15 Further, studies using
magnetic resonance (MR) imaging in children and in an animal model demonstrate changes in cerebral water distribution, blood
flow, and metabolism during DKA similar to those often observed in hypoxic/ischemic cerebral injury.9,15,16
Cerebral hypoxia or ischemia associated with other conditions (eg, high-altitude exposure, cardiac arrest, and sleep-related
breathing disorders in childhood) has been linked to memory deficits.17-20 Research with animal models confirms a causal relation between mild hypoxia or ischemia and specific damage to the hippocampus,21 a brain structure that is responsible for
formation and retrieval of memories of the association between an event and the context in which it originally occurred.22,23 We
studied whether DKA is associated with such specific memory deficits in children with T1DM. We examined the effects of DKA
on memory for item-context associations while accounting for other variables that are related with memory impairment in
children with T1DM.3-7 We hypothesized that if DKA results in mild hypoxia or ischemia, then specific deficits in memory
functions mediated by the hippocampus should be expected.

Methods
Patients with T1DM between the ages of 7 and 16 years were recruited from the
pediatric endocrinology clinic at the University of California, Davis, Medical

ANCOVA
DKA
GCS
MR
T1DM

Analysis of covariance
Diabetic ketoacidosis
Glasgow Coma Scale
Magnetic resonance
Type 1 diabetes mellitus

From the Department of Psychology (S.G., J.K.L.,


D.M.D.), Center for Mind and Brain (S.G., J.K.L., D.M.D.),
University of California, Davis, CA; the Department of
Psychology (C.E.S.), University of Colorado at Boulder,
Boulder, CO; and the Department of Pediatrics (N.S.G.),
Division of Endocrinology, School of Medicine, University
of California, Davis, CA
Supported by a Young Investigator Research Award from
the Childrens Miracle Network. The authors declare no
conflicts of interest.
0022-3476/$ - see front matter. Copyright 2010 Mosby Inc.
All rights reserved. 10.1016/j.jpeds.2009.07.054

109

THE JOURNAL OF PEDIATRICS

www.jpeds.com

Center. The study was approved by the University of California Davis Internal Review Board, and written consent was obtained from the parents or guardians. Patients were eligible
for participation if they did not have a history of attention
and learning disorders (eg, disorders such as attention
deficit hyperactivity disorder and dyslexia, which are not associated with hypoxic/ischemic injury), psychiatric conditions, history of head trauma, premature delivery (<36
weeks of gestation), low birth weight (<5.5 lb), color blindness, or were not English speaking. The patients blood glucose concentration was required to be within 70 to 300 mg/
dL just before participating. Participants were excluded
from analysis if their glucose concentration fell outside of
the desired range or if IQ scores were 2 standard deviations
below the mean.
After obtaining consent and blood glucose testing the
experimental procedure began. The experimenter was blinded
to DKA history at the time of testing. We included the 2 memory tasks described below to investigate memory deficits across
different types of contextual features. After the memory tasks,
a 5- to-10-minute break preceded the administration of the
Wechsler Abbreviated Scale of Intelligence, described below.
While participants were tested, their parents or guardians
provided demographic and disease-related information on
a questionnaire, which was integrated with information
from the medical records. Early onset of T1DM was defined
as diagnosis before age 7 years because children diagnosed
with diabetes within the first 6 years of life have been found
to have more extensive cognitive deficits than do children
who have diabetes later in life.3,7 A history of severe hypoglycemia (defined as hypoglycemia associated with loss of consciousness, seizure, or other severe alteration in mental
status) was obtained from the parent or guardian as well as
by review of the childs medical record. A history of DKA
was obtained by review of the medical record and by questioning the parent or guardian about any hospitalizations or
emergency department visits for DKA occurring at other facilities. Medical records were reviewed to determine whether
any child had clinically apparent DKA-related cerebral edema
(defined as deterioration in mental status during DKA with
radiographic evidence of cerebral edema and/or requiring
treatment with mannitol or hypertonic saline).
Hemoglobin A1c was measured on the day of participation
using a Bayer DCA 2000 HbA1c analyzer (Block Scientific,
Nutley, New Jersey). As an additional comparison of overall
blood glucose control among patients in each group, we
determined the percentage of glucose readings from the
patients meter either below 70 mg/dL or above 300 mg/dL
during the month before participation.

Memory Measures
Versions of published tasks were used.24 In the color task,
80 black-ink drawings on a white, square background were
presented on a computer screen with either a green, red, yellow, or blue border (20 of each color in a random order), and
participants were instructed to try to remember both the item
110

Vol. 156, No. 1


and the color of the border that went with that item. Each
drawing was shown for 1 second, followed by a 1-second interval in which a fixation point was presented. Participants
then were given a self-paced recognition test including 80
studied drawings and 80 new drawings presented in random
order. No color border was presented. Participants first determined whether or not they had seen the drawing before.
When a drawing was recognized, participants reported the
color of the border previously presented with that drawing.
The spatial position task was identical to the color task,
except that the drawings did not vary in colored border
but in the spatial position in which they appeared (ie, 1
of the 4 quadrants of the computer screen; 20 items in
each quadrant in a random order). Thus, participants
were instructed to remember and then were tested on their
memory for the association between drawing and spatial
position. Each memory task took approximately 25 minutes, and a 30-minute break was given between them.
Drawings for each task were chosen from a set of 320 unambiguous line drawings; these materials are normed with
child participants for familiarity, visual complexity, and
name agreement.25 Use of these drawings in the color versus spatial position and task order were counterbalanced
across participants.
Each memory task provides 2 indices of memory performance. One is the item-context association rate (rate of
correct item-color and itemspatial positions associations
recollected over the total of previously viewed items correctly recognized). This index is the primary measure of interest for this report because it is thought to reflect the kind
of memory process that is most likely affected by episodes
of mild ischemia or hypoxia. The other index, d0 ,26 is
a well-established measure that corresponds to the normalized difference between hit rates (correct identification of
an item that was seen previously) and false-alarm rates (incorrect identification of an item as being seen previously
when it was not); this measure reflects the ability to discriminate between old and new items and varies from
0 (no ability to discriminate) to 4 (nearly perfect ability
to discriminate).
IQ Measure
The Wechsler Abbreviated Scale of Intelligence27 is a measure
of IQ designed for individuals ages 6 to 89 years. The Wechsler Abbreviated Scale of Intelligence includes 4 subtests; the
Block Design and Matrix Reasoning tests measure Performance IQ, and the Vocabulary and Similarities tests measure
Verbal IQ. Full-scale IQ was also computed. This test took
about 35 minutes to administer.
Statistical Analyses
Preliminary analyses to determine if there were any differences between patients with or without a history of DKA
were conducted with a series of univariate analysis of variance
(when comparing these groups for mean age, HbA1c, family
income, serum glucose concentration before participation,
IQ, and d0 ) and c2 analysis (when comparing these groups
Ghetti et al

ORIGINAL ARTICLES

January 2010

Table. Sample characteristics

Characteristics
Female participants, No. (%)
Age at testing, mean (SD), y
Family income, mean (SD), $1000
Early onset (before age 7), No. (%)
Severe hypoglycemia, No. (%)
HbA1c, mean % (SD)
Frequency of high and low glucose, % (SD)*
Frequency of ketosis resolved at home, No (%)
Glucose before testing, mg/dL(SD)
Total IQ, mean score (SD)
Verbal IQ, mean score (SD)
Performance IQ, mean score (SD)
Color task
d 0 , mean (SD)z
Spatial task
d 0 , mean (SD)z

Children with
DKA history
(n = 33)

Children without DKA history


(n = 29)

Total
(n = 62)

P
value

20 (55%)
12.4 (3.3)
65.9 (27.4)
12 (36%)
14 (42%)
8.1 (1.4)
27 (13%)
5 (17%)
199 (75)
106.0 (10.6)
104.5 (11.8)
106.6 (12.4)

16 (61%)
12.5 (2.4)
61.3 (29.2)
13 (45%)
9 (31%)
8.1 (1.7)
28 (16%)
7 (21%)
181 (79)
109.1 (11.0)
109.4 (13.2)
106.4 (9.4)

36 (58%)
12.4 (2.9)
63.53 (28.2)
25 (40%)
23 (37%)
8.1 (1.6)
.28 (15%)
12 (19%)
190 (77)
107.5 (10.8)
106.8 (12.6)
106.5 (11.0)

.80
.83
.53
.61
.43
.90
.86
.69
.37
.26
.13
.94

1.97 (.67)

1.96 (.79)

1.97 (.72)

.97

2.06 (.78)

2.34 (.79)

2.19 (.79)

.16

*This index of glucose variability was calculated as the percentage of all measured glucose values below 70 or above 300 mg/dL during the month participation.
This index refers to the number of patients with episodes of ketosis treated at home in consultation with the childs physician.
zd 0 is the normalized difference between hit rates and false-alarm rates; it may range from 0 to 4; higher scores indicate better performance.

for frequency of males versus females, early versus late T1DM


onset, history of severe hypoglycemia, and frequency of ketosis episodes resolved at home). Univariate analyses of variance were also conducted to examine differences between
children who participated and children who were eligible
but declined to participate.
The central hypothesis that DKA history resulted in specific
memory deficits was tested by entering the item-color association rates and the itemspatial position association rates as
repeated dependent measures in the following 3 multivariate
analyses of the covariance (ANCOVA): (1) a 2 (DKA history
versus no DKA history)  2 (early versus late onset of T1DM)
 (sex) mixed ANCOVA in which age at testing and history of
hypoglycemia were entered as covariates; this analysis allowed
for an examination of the main effect of DKA as well as interactive effects with 2 variables, sex and disease onset, identified
as critical for memory development in children with T1DM,
while controlling for the effects of other covariates; (2) a 2
(DKA history versus no DKA history)  2 (early T1DM onset
versus late T1DM onset)  2 (age at testing: 7 to 11 years versus 12 to 16 years) mixed ANCOVA with sex and hypoglycemia entered as covariates; this analysis allowed for the
examination of the additional interactive effects of DKA
with early diagnosis and current age, allowing for the identification of periods of increased risk or resilience for the effects
of DKA; and (3) a 2 (DKA history versus no DKA history)  2
(early T1DM onset versus late T1DM onset)  2 (severe hypoglycemia versus no severe hypoglycemia) mixed ANCOVA
in which age at testing and sex were entered as covariates. This
analysis allowed for the examination of the additional interactive effects of DKA with hypoglycemia, another variable that is
critical for memory performance in this T1DM. Finally, we
conducted correlational analyses to explore whether the timing of DKA during development was associated with altered
memory function.

Results
Sixty-six children with T1DM enrolled in the study; 3 were
excluded from the analyses because their pretest blood glucose concentrations were above the specified range (n = 2)
or because the IQ score was more then 2 standard deviations below the mean. One additional patient was excluded
because his parents elected to end participation before
completion of the memory tasks. Descriptive data for the
remaining 62 children who comprised the study sample
are presented in the Table. None of the children had clinically apparent cerebral edema. None of the participants exhibited clinically relevant mental status deterioration as
measured by the Glasgow Coma Scale (GCS) scores obtained roughly hourly during DKA treatment. A few patients had minimal abnormalities in GCS scores. One
patient had a decline in GCS score to 13, and 5 patients
had GCS scores decline to 14. GCS information was missing for 3 patients, but there was no indication in their clinical records that would suggest concern about clinically
apparent cerebral edema or brain injury.
Thirty-seven additional eligible patients declined to participate in the study. These patients did not significantly differ
from the study sample in mean age at first contact (12.2 
2.4 years; P = .61), sex (62% females, P = .58), frequency of
early T1DM onset (35% early onset, P = .52), HbA1c (8.4
 1.9, P = .30), frequency of DKA (36% had a history of
DKA, P = .14), and severe hypoglycemic episodes recorded
in the medical record (14% versus 22% in patients who participated, P = .30; this comparison is based on the information included in the medical records alone, given that
parental reports were not available for patients who declined
to participate).
Children with and without a history of DKA did not significantly differ in any demographic or T1DM-related variables

Diabetic Ketoacidosis and Memory Dysfunction in Children with Type 1 Diabetes

111

THE JOURNAL OF PEDIATRICS

www.jpeds.com

(Table). Consistent with our hypothesis that children with


DKA would exhibit selective deficits in the ability to remember
events in association with specific contextual details, we found
comparable d0 in both the color and the spatial position task.
The next set of analyses directly investigated whether children with a history of DKA demonstrated selective deficits in
memory for item-context associations controlling for the effect
of other variables that might affect performance. In the first
ANCOVA analysis examining main and interactive effects of
DKA, sex, and early T1DM onset adjusting for age at testing
and history of severe hypoglycemia, the effect of DKA was significant [F (1, 52) = 11.30, P < .001]. Although the color task
was more challenging than the spatial position task, as indicated by lower levels of overall performance in the former
than the latter [F (1, 52) = 6.52, P < .05], poorer performance
of DKA patients was observed across both tasks (Figure 1).
Furthermore, DKA significantly interacted with T1DM onset
and sex [F (1, 52) = 6.07, P < .05], such that males who had
DKA and had an early T1DM onset had disproportionately
lower memory scores (Figure 2). We note that the main effect
of sex was significant [(F (1, 52) = 18.28, P < .001] and was not
fully accounted for by the interaction. Age at testing was a significant covariate [F (1, 52) = 9.19, P < .01]; as is typical in development, older age was associated with better memory
performance.24 History of severe hypoglycemia was not a significant covariate [F (1, 52) = .49, P = .49].
In the second ANCOVA analysis examining main and interactive effects of DKA, early T1DM onset, and current age
(divided at the median for the purpose of these analyses
thereby resulting in 2 groups of children currently ages 7 to
11 or 12 to 16 years), adjusting for sex and hypoglycemia,
the effect of DKA was significant [F (1, 52) = 12.75, P <
.001]. A significant interaction between DKA, early T1DM
onset, and current age was found [F (1, 52) = 7.00, P = .01
(Figure 3)]: Children who had early T1DM onset were at
elevated risk for detrimental effects of DKA. Among patients

Vol. 156, No. 1

Figure 2. Significant interaction effect on rates of item-context associations between DKA history, early T1DM onset,
and sex [F (1, 52) = 6.07, P < .05]: Males who had DKA and an
early T1DM onset had disproportionately lower memory
scores.

with late onset, those who at the time of testing were 12 years
of age or older seemed resilient to the effects of DKA. Sex was
a significant covariate [F (1, 52) = 13.99, P < .001].
In the third ANCOVA analysis examining main and interactive effects of DKA, early T1DM onset, and hypoglycemia
adjusting for age at testing and sex, the effect of DKA was
confirmed to be significant [F (1, 52) = 8.74, P < .01]. Although a main effect of severe hypoglycemia was not found,
there was a significant interaction with age at T1DM onset,
such that lower performance was observed in participants
who had a history of hypoglycemia and early T1DM onset
[F (1, 52) = 4.15, P < .05]. Age and sex were significant covariates [Fs (1, 52) $ 7.76, Ps # .01].
All of the main and interactive effects of DKA reported
above retained significance even after controlling for IQ
[Fs (1, 51) $ 5.56, Ps < .05], HbA1c [Fs (1, 51) $ 5.93,
Ps < .05], and glucose levels at time of testing [Fs (1, 51) $
4.69, Ps < .05]. These effects were also retained when the
DKA group was modified to include only patients who
had 1 DKA episode that occurred at the time of diagnosis
[Fs (1, 42) $ 4.29, Ps < .05].
Finally, we examined the correlation between time in years
since DKA (average 2.54 years and varied from 0.11 to 14.54
years) and current memory for item-context associations in
patients who only had 1 DKA episode at diagnosis. After controlling for current age, we found a significant correlation
(r = .37, P < .05), such that memory performance was
worse in children whose DKA was in the more distant past.

Discussion
Figure 1. Rates of item-context associations as a function of
DKA history and type of task: Children with DKA history had
significantly lower rates of accurate memory on both tasks
than did children without DKA history [F (1, 52) = 11.30,
P < .001].
112

The ability to remember specific events along with information about the context in which these events occurred is a fundamental capacity, supporting mundane yet crucial abilities
as well as more complex senses such as continuity of self.
Our study demonstrated that this capacity is significantly
Ghetti et al

ORIGINAL ARTICLES

January 2010

Figure 3. Significant interaction effect on rates of item-context associations between DKA history, early T1DM, and age
at testing [F (1, 52) = 7.00, P = .01]. Performance was most
strongly affected by DKA in children with early diabetes onset;
children with late onset and who at the time of testing were 12
years of age or older appeared protected from the effects of
DKA.

reduced in children with T1DM who had DKA. The nearly


identical mean HbA1c levels and frequency of high and low
glucose episodes between children with and without a history
of DKA suggest that these differences in memory capacity are
not attributable to differences in chronic blood glucose control. Differences in memory function in children with and
without DKA history also remained significant after adjusting for these and other variables associated with memory
function in other studies. Our findings lend support to recent
evidence suggesting that even when DKA does not result in
clinically apparent cerebral edema, subtle cerebral injury
may occur. Moreover, the similarity of the observed memory
deficits with those observed in studies of hypoxic/ischemic
cerebral injury19 is consistent with the possibility that reduced cerebral blood flow causes cerebral injury during
DKA. Our findings also suggest that memory impairment
in children with a history of DKA is permanent because we
did not observe better, but worse, memory performance in
children whose DKA episodes were more distant.
Several studies have examined memory deficits in children
with T1DM,3-7 but a coherent picture has yet to emerge. The
current results may be an important contribution in 2 ways.
First, because a history of DKA may be more critical than
other T1DM-related factors in determining memory deficits,
the frequency of DKA in the populations studied may affect
the results. Second, previous studies have assessed patients
using batteries of neuropsychological tests that do not fully
reflect current theoretical distinctions among types of memory. The current study focused on the ability to recollect past
events in association with information about features of the
context surrounding the event.22-24 This specific memory
function is mediated by the hippocampus, a brain region
that is highly sensitive to hypoxic/ischemic injury.19,21 Our
results, therefore, suggest that brain injury related to DKA
may be specific to the hippocampus. A recent study found
a high frequency of structural brain abnormalities in children
with early onset of T1DM.28 Mesial temporal sclerosis was

the most frequent abnormality, again suggesting hippocampal involvement. Although the authors did not find an association between mesial temporal sclerosis and DKA episodes,
their study included relatively few participants with DKA,
and the investigators recorded only moderate or severe
DKA episodes rather than all episodes of DKA. The lack of
association between mesial temporal sclerosis and DKA
may therefore reflect these methodological and sample size
differences from our report.
Mild cerebral edema is present in at least 50% of children
during DKA treatment.12 These findings are observed consistently despite use of different imaging techniques including MR imaging, CT, or MR diffusion weighted imaging.14,15
Alterations in levels of cerebral metabolites typically observed during hypoxic/ischemic cerebral injury have also
been demonstrated in children with DKA evaluated with
MR spectroscopy during treatment.9 Measurements of apparent diffusion coefficient values using MR diffusion
weighted imaging suggest that untreated DKA is associated
with cytotoxic cerebral edema (cell swelling) but that vasogenic cerebral edema, with increased extracellular fluid accumulation, develops during DKA treatment.15,29 These data
imply not only that untreated DKA is associated with cerebral injury but that further cerebral injury may result during
DKA treatment, as cerebral tissues are reperfused. The current data are consistent with these studies and with the occurrence of subtle but permanent cerebral injury in
children with DKA. Future research should examine directly
how brain injury mediates the relationship between DKA
and memory deficits.
In the current study, several variables other than DKA were
associated with differences in memory function. We found
that male sex, young age at onset of diabetes, and severe hypoglycemia were associated with reduced memory performance either directly or in interaction. Previous studies
have similarly reported that males are more likely than females to show detrimental effects of T1DM on intellectual
development and memory specifically,6 suggesting sex-specific vulnerabilities with regard to the consequences of diabetes for cognitive development. Earlier studies also suggest
that children who are diagnosed with T1DM earlier in life exhibit more extensive cognitive deficits (in memory, attention,
and executive functioning) than do children who had diabetes later in childhood.3,7 Our results further suggest that DKA
in early age may be particularly detrimental for memory
function. Finally, severe hypoglycemia has also been related
to damage to the hippocampus through an excitotoxic process.3,5 Although we did not find an overall effect of hypoglycemia on memory function, our data suggest that a subgroup
of children diagnosed with T1DM at an early age may be
more vulnerable to hypoglycemic injury.
The current study has some limitations. First, we relied on
medical record reviews and parents or guardians recollections of DKA episodes and hypoglycemic events to classify patients according to these variables. It is possible that some
episodes of DKA or severe hypoglycemia may have been
missed because the child received treatment at an outside

Diabetic Ketoacidosis and Memory Dysfunction in Children with Type 1 Diabetes

113

THE JOURNAL OF PEDIATRICS

www.jpeds.com

medical facility and the patients parent or guardian did not


recall the event. Second, our exclusion of children with low
IQ or learning disabilities prevents us from drawing conclusions about the effects of DKA in patients who may be even
more vulnerable to alteration of cognitive development resulting from T1DM complications. Third, our data were collected after T1DM and DKA occurred; thus we cannot exclude
that memory differences between children with and without
a DKA history preexisted T1DM diagnosis and DKA or that
the occurrence of DKA in certain children could reflect underlying differences in cognitive abilities between families.
The reported substantial similarity between the DKA and
the non-DKA group on several variables that might affect
memory, however, assuage this concern. In addition, 72%
of children in the DKA group had DKA at the time of diabetes
diagnosis, and 90% had only 1 DKA episode. Thus, the majority of DKA episodes did not appear to be caused by inadequate
understanding of diabetes management. Finally, our study
did not include a group of children without a history of
T1DM (eg, siblings of patients); thus, no conclusions can be
drawn on general consequences of T1DM for cognitive function. Nevertheless, this approach is justified by the evidence
that complications of T1DM may be better predictors of altered memory function than the disease per se.
These data emphasize the importance of preventing DKA
in children with known T1DM and the importance of
prompt diagnosis of children with new onset of T1DM, before the development of DKA. Programs to educate the community, especially school personnel and primary care health
personnel, about the early signs of T1DM have been proven
successful in markedly reducing the frequency of DKA at onset and must be widely instituted.30 n
Submitted for publication Feb 6, 2009; last revision received Jun 23, 2009;
accepted Jul 24, 2009.
Reprint requests: Dr Simona Ghetti, Department of Psychology and Center for
Mind and Brain, One Shields Avenue, Davis, CA 95616. E-mail: sghetti@
ucdavis.edu.

References
1. Kovacs M, Goldston D, Lyengar S. Intellectual development and academic performance of children with insulin-dependent diabetes mellitus: a longitudinal study. Dev Psychol 1992;28:676-84.
2. Hagen J, Barclay CR, Anderson BJ, Feeman DJ, Segal SS, Bacon G, et al.
Intellective functioning and strategy use in children with insulin-dependent diabetes mellitus. Child Dev 1990;61:1714-27.
3. Hershey T, Perantie DC, Warren SL, Zimmerman EC, Sadler M,
White NH. Frequency and timing of severe hypoglycemia affects spatial
memory in children with type 1 diabetes. Diabetes Care 2005;28:
2372-7.
4. Perantie DC, Lim A, Wu J, Weaver P, Warren SL, Sadler M, et al. Effects
of prior hypoglycemia and hyperglycemia on cognition in children with
type 1 diabetes mellitus. Pediatr Diabetes 2008;9:87-95.
5. Hershey T, Lillie R, Sadler M, White NH. A prospective study of severe hypoglycemia and long-term spatial memory in children with
type 1 diabetes. Pediatr Diabetes 2004;5:63-71.
6. Fox MA, Chen RS, Holmes CS. Gender differences in memory and learning in children with insulin-dependent diabetes mellitus (IDDM) over
a 4-year follow-up interval. J Pediatr Psychol 2003;28:569-78.
114

Vol. 156, No. 1


7. Strudwick SK, Carne C, Gardiner J, Foster JK, Davis EA, Jones TW. Cognitive functioning in children with early onset type 1 diabetes and severe
hypoglycemia. J Pediatr 2005;147:680-5.
8. Sperling MA. Diabetic ketoacidosis. Pediatr Clin North Am 1984;31:
591-610.
9. Wootton-Gorges SL, Buonocore MH, Kuppermann N, Marcin JP,
Barnes PD, Neely EK, DiCarlo J, McCarthy T, Glaser NS. Cerebral proton magnetic resonance spectroscopy in children with diabetic ketoacidosis. AJNR Am J Neuroradiol 2007;28:895-9.
10. Glaser N, Barnett P, McCaslin I, Nelson D, Trainor J, Louie J, et al. Risk
factors for cerebral edema in children with diabetic ketoacidosis. N Engl J
Med 2001;344:264-9.
11. Rosenbloom AL. Intracerebral crises during treatment of diabetic ketoacidosis. Diabetes Care 1990;13:22-33.
12. Glaser NS, Wooton-Gorges S, Buonocore M, Marcin JP, Rewers A,
Strain J, et al. Frequency of sub-clinical cerebral edema in children
with diabetic ketoacidosis. Pediatr Diabetes 2006;7:75-80.
13. Krane EJ, Rockoff MA, Wallman JK, Wolfsdorf JI. Subclinical brain
swelling in children during treatment of diabetic ketoacidosis. N Engl
J Med 1985;312:1147-51.
14. Hoffman WH, Steinhart CM, el Gammal T, Steele S, Cuadrado AR,
Morse PK. Cranial CT in children and adolescents with diabetic ketoacidosis. AJNR Am J Neuroradiol 1988;9:733-9.
15. Glaser NS, Marcin JP, Wootton-Gorges SL, Buonocore MH, Rewers A,
Strain J, et al. Correlation of clinical and biochemical findings with
DKA-related cerebral edema in children using magnetic resonance diffusion weighted imaging. J Pediatr 2008;153:541-6.
16. Yuen N, Anderson SE, Glaser NS, ODonnell ME. Cerebral blood flow and
cerebral edema in rats with diabetic ketoacidosis. Diabetes 2008;57:2588-94.
17. Suratt PM, Peruggia M, DAndrea L, Diamond R, Barth JT, Nikova M,
et al. Cognitive function and behavior of children with adenotonsillar
hypertrophy suspected of having obstructive sleep-disordered breathing.
Pediatrics 2006;118:771-81.
18. Virues-Ortega J, Garrido E, Javierre C, Kloezeman KC. Human behaviour
and development under high-altitude conditions. Dev Sci 2006;9:400-10.
19. Yonelinas AP, Kroll NE, Quamme JR, et al. Effects of extensive temporal
lobe damage or mild hypoxia on recollection and familiarity. Nat Neurosci 2002;5:1236-41.
20. de Haan M, Mishkin M, Baldeweg T, Vargha-Khadem F. Human memory development and its dysfunction after early hippocampal injury.
Trends Neurosci 2006;29:374-81.
21. Raman L, Tkac I, Ennis K, Georgieff MK, Gruetter R, Rao R. In vivo
effect of chronic hypoxia on the neurochemical profile of the developing
rat hippocampus. Brain Res Dev Brain Res 2005;156:202-9.
22. Eichenbaum H, Yonelinas AP, Ranganath C. The medial temporal lobe
and recognition memory. Annu Rev Neurosci 2007;30:123-52.
23. Fortin NJ, Wright SP, Eichenbaum E. Recollection-like memory retrieval
in rats is dependent on the hippocampus. Nature 2004;431:188-91.
24. Ghetti S, Angelini L. The development of recollection and familiarity in
childhood and adolescence: evidence from dual process signal detection.
Child Dev 2008;79:339-58.
25. Cycowicz YM, Friedman D, Snodgrass JG, Rothstein M. Picture naming
by young children: norms for name agreement, familiarity and visual
complexity. J Exp Child Psychol 1997;65:171-237.
26. MacMillan NA, Creelman CD. Signal Detection Theory: A Users Guide.
New York: Cambridge University Press; 1991.
27. Wechsler D. The Wechsler Abbreviated Scale of Intelligence. San Antonio, TX: The Psychological Corporation; 1999.
28. Ho MS, Weller NJ, Ives FJ, Carne CL, Murray K, Vanden Driesen RI,
et al. Prevalence of structural central nervous system abnormalities in
early-onset type 1 diabetes mellitus. J Pediatr 2008;153:385-90.
29. Lam TI, Anderson SE, Glaser NS, ODonnell ME. Bumetanide reduces
cerebral edema formation in rats with diabetic ketoacidosis. Diabetes
2005;54:510-6.
30. Vanelli M, Chiari G, Ghizzoni L, Costi G, Giacalone T, Chiarelli F.
Effectiveness of a prevention program for diabetic ketoacidosis in children: an 8-year study in schools and private practices. Diabetes Care
1999;22:7-9.

Ghetti et al

S-ar putea să vă placă și