Pediatric Diabetes 2004: 5: 59—62
Printed in Denmark. All rights reserved
Editorial
Does moderately severe hypoglycemia cause
cognitive dysfunction in children?
Multiple case reports have demonstrated that clinically
significant brain damage may result following an
extended period of profound hypoglycemia — generally
characterized as blood glucose values below
1.5—1.0 mmol/L for several hours. Neuroimaging and
neuropathological studies show extensive neuronal loss
bilaterally in the cerebral cortex, particularly in mesial
temporal regions, as well as in the hippocampus, basal
ganglia, and brain stem (1). Although neurocognitive
assessments have been conducted only infrequently in
these cases, the extant data indicate that learning and
memory skills are most likely to be compromised, as
one would expect given the well-established association
between hippocampal/mesial temporal lobe damage
and memory dysfunction (2).
Most individuals with diabetes never experience an
episode of profound hypoglycemia, but a large propor-
tion of diabetic children and adults will experience one
or more moderate to severe hypoglycemic events (i.e.,
blood glucose values between 2.2 and 3.3 mmol/L)
(3). Remarkably, however, there is little compelling
evidence — particularly from studies conducted within
the past 10 yrs — that this degree of hypoglycemia leads
to significant brain dysfunction. For example, serum
markers of acute neuronal damage (neuron-specific
enolase and protein S-100) remain within normal limits
following a single episode of moderate to severe hypo-
glycemia in adults; in contrast, elevations of these
markers, consistent with brain cell death, are seen in
patients who experienced an episode of profound hypo-
glycemia accompanied by permanent neurological signs
or death (4). Positron emission tomography (5) and
Copyright # Blackwell Munksgaard 2004
Pediatric Diabetes
Corresponding author:
Christopher M. Ryan, PhD
Department of Psychiatry
University of Pittsburgh School of
Medicine
3811 O’Hara Street
Pittsburgh
PA 15213
USA
Tel: þ1-412-246-5392
e-mail: ryancm@upmc.edu
neurophysiological event-related potential (P300)
studies (6) have also failed to demonstrate brain dysfunc-
tion in adults who had one or more hypoglycemic comas,
whereas magnetic resonance imaging (MRI) studies have
been equivocal, with some (7), but not all (8) showing
cortical atrophy following recurrent hypoglycemia.
Longitudinal neuropsychological studies have similarly
failed to find robust evidence of cognitive deterioration
in older adolescents or adults following moderately
severe recurrent hypoglycemia (9), and learning and
memory skills are almost invariably reported to be
normal (10).
Is it possible that children are more susceptible to the
neurocognitive sequelae of hypoglycemia than adults?
Researchers have now identified at least one subgroup
that is particularly vulnerable: children with an early
onset of diabetes. Studies conducted over the past
20 yrs have repeatedly demonstrated that children and
adolescents diagnosed before 5 or 6 yrs of age have a
greatly elevated risk of experiencing severe hypoglyce-
mia and of manifesting significant brain dysfunction, as
evidenced by abnormalities on electroencephalograms
(EEGs) (11) and by poor performance on a variety of
cognitive tasks, including measures of learning and
memory (12). On the other hand, children who are
first diagnosed during elementary or high school and
who subsequently experience an episode of moderate to
severe hypoglycemia do not ordinarily manifest neuro-
cognitive sequelae (13, 14). Why is an early onset of
diabetes such a potent predictor of hypoglycemia-
induced cognitive dysfunction? It is now widely
believed that the first 5 yrs of life constitute an
59
Ryan
especially critical period for brain development (15),
and the occurrence of either hypoglycemia-associated
neuroglycopenia and/or chronic hyperglycemia during
that critical period may induce structural and
functional brain abnormalities that interfere with
normal cognitive function (16). As a corollary, when
diabetes onset occurs after that critical period, hypogly-
cemic events are unlikely to have any significant impact
on brain function unless the blood glucose levels fall
below 1.5 mmol and persist for an extended period of
time.
In this issue, Hershey and her associates provide
some very intriguing data suggesting that the view
outlined above may be incorrect. During a 15-month
observation period, children who experienced at least
one episode of severe hypoglycemia subsequently
performed less well on a spatial working memory task
regardless of their age at diagnosis, as compared to
their diabetic peers without intercurrent hypoglycemia.
Although multiple learning and memory tests were
administered, the only task adversely affected by a
hypoglycemic event was an unfamiliar, cognitively
demanding, non-verbal task known to tap mnemonic
skills that may be largely ‘hard-wired’ and dependent
on intact hippocampal systems.
Hershey’s group has now used this task with several
different groups of children and adults and has repeat-
edly demonstrated a link between conditions thought
to affect the hippocampus (e.g. temporal lobe epilepsy
and severe hypoglycemia) and spatial working memory
(17, 18). Thus, there is little doubt about the reprodu-
cibility of their observation. What remain unknown,
however, are the implications (if any) of this observa-
tion for the child with diabetes. After all, the magnitude
of this effect is quite small. For example, children who
experienced an episode of hypoglycemia did not show a
worsening of performance over time. Rather, they
showed no change, as compared to diabetic children
who did not experience hypoglycemia in the interim
and subsequently improved their accuracy on the task.
Moreover, performance decrements on this task were
not associated with declines on any other cognitive
tasks, raising questions about the validity of spatial
working memory as a meaningful measure of cognitive
function in children.
If, on the other hand, the spatial memory task is
conceptualized as a marker of hippocampal integrity —
consistent with both the animal literature and some of
Hershey’s earlier work (18), and if a single episode of
hypoglycemia can affect this brain system, then one
would expect recurrent episodes to produce extensive
and permanent hippocampal damage with resultant
profound memory problems. Yet, there is little evidence
to support that prediction: clinically significant memory
disorders are infrequent in diabetic children or adults
with recurrent hypoglycemia (19). Because learning
and memory skills are fundamental to acquiring new
60
information in the classroom and in the workplace,
one would also predict that children experiencing severe
and/or recurrent hypoglycemia to be at an academic
or vocational disadvantage. Again, there is little
evidence to support that prediction. We know that
over time, diabetic children do tend to manifest a relative
deterioration in performance on measures of verbal
intelligence or academic achievement, but that decline
seems more related to poor metabolic control and/or
duration of diabetes (14, 20); there is no compelling
evidence that recurrent hypoglycemia per se is associated
with cognitive decline.
In their report, Hershey and her associates have
focused on the occurrence of one or more episodes of
intercurrent hypoglycemia, and argued that it is the
hypoglycemic event that is likely to be responsible for
the very subtle performance differences seen on meas-
ures of spatial memory. But another interpretation
comes to mind: perhaps cognitive decline is largely
secondary to chronic hyperglycemia. A growing body
of literature on adults with type 2 diabetes has shown
clear evidence of cognitive deterioration in the
absence of severe hypoglycemia (21), and both cross-
sectional and longitudinal studies of adults with
juvenile-onset type 1 diabetes have also reported
cognitive differences (8) or decrements over time
(22) that are related to poor metabolic control and/or
to the development of complications, rather than
to recurrent hypoglycemia. Recent studies of children
with diabetes have also highlighted the possible adverse
effects of chronic hyperglycemia on cognitive function
(14, 23).
Indeed, it is noteworthy that as a group, the children
studied by Hershey et al. who had an episode of severe
hypoglycemia during follow-up also had nearly twice as
many episodes of severe hyperglycemia (6.5 vs. 3.4)
prior to baseline testing than those who experienced
no hypoglycemic episodes. While neither group differed
in hemoglobin A1c (HbA1c) levels at either the baseline
visit or at the follow-up visit, during the 15-month
observational period, those subjects who experienced
severe hypoglycemia also had higher HbA1c levels
(8.6% vs. 8.2%). Consistent with the link between
chronic hyperglycemia and cognitive dysfunction are
the between-group differences in performance at
baseline on several measures, including the magnitude
of the error made by the severe hypoglycemia group on
the spatial memory task (38.0 vs. 31.2 mm) and their
longer response times on the Grooved Pegboard test
(92.1 vs. 80.6 s).
Spatial working memory tasks, similar to the task
used by Hershey et al. have also been found to be
sensitive to chronic hyperglycemia — at least in rats
(24). Maze learning, which necessarily relies on spatial
memory, is also disrupted in diabetic animals, with the
magnitude of the effect associated with the duration of
diabetes. Importantly, animals with diabetes of longer
Pediatric Diabetes 2004: 5: 59—62

duration also showed a significant decline in neuronal
densities in the hippocampus, and these changes could
not be attributed to insulin-induced hypoglycemia (25).
Other animal research has demonstrated that during
the performance of a spatial maze, there is a 32%
decline in extracellular glucose levels in the hippo-
campus, suggesting that certain types of cognitive
tasks — particularly those with a spatial component —
can deplete hippocampal glucose (26). Diabetic individ-
uals in poor metabolic control may thus have more
difficulty performing those types of cognitive tasks,
particularly if chronic hyperglycemia triggers a down-
regulation of glucose transporters at the level of the
blood—brain barrier (27), thereby reducing the avail-
ability of glucose to hippocampal neurons. Healthy
non-diabetic adults with reduced glucose tolerance
also show an inverse relationship between glucose levels
during a 2-h intravenous glucose tolerance test, and
both the size of the hippocampus — as measured by
MRI, and performance on verbal memory tests (28).
Taken together, these studies argue for a link between
elevated glucose levels and poor cognition which may
be particularly evident on tests sensitive to hippo-
campal function.
Does a single episode of moderately severe hypogly-
cemia disrupt brain function in children with diabetes?
The excellent study of Hershey and her colleagues
makes it clear that those children who experienced
severe hypoglycemia are more likely to perform some-
what more poorly on spatial memory tasks, but as
should be evident from these comments, the patho-
physiological mechanism is by no means self-evident,
nor are the clinical implications. The ‘confound’ that
investigators need to be mindful of is that individuals
who experience severe hypoglycemia are also more
likely to have extended periods of chronic hyperglyce-
mia, as indexed by poor metabolic control, and this
variable is also known to be associated with neuro-
cognitive dysfunction. An additional issue that is
sometimes, but not invariably, taken into account
by researchers is the fact that severe hypoglycemia
is also more common in individuals with an early onset
of diabetes, who may as a consequence have diabetes-
associated abnormalities in brain development.
Until all of these issues are sorted out and we are in a
position to make accurate attributions of causality,
patients should be counseled to prevent the occurrence
of hypoglycemia but at the same time maintain their
blood glucose levels as close to the normal range as
possible. Individualized therapy, with frequent blood
glucose monitoring, remains the only way to reduce
the likelihood that children (or adults) with diabetes
will develop cognitive complications.
Christopher M. Ryan
Department of Psychiatry, University of Pittsburgh
School of Medicine, Pittsburgh, PA, USA
Pediatric Diabetes 2004: 5: 59—62
Editorial
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