Mild hypoglycemia associated with deterioration of mental efficiency in children with insulin-dependent diabetes mellitus

Mild hypoglycemia associated with deterioration of mental efficiency in children with insulin-dependent diabetes mellitus Christopher M. Ryan, PhD, Joy Atchison, MD, Sandy Puczynski, MSN, Mark Puczynski, MD, Silva Arslanian, MD, a n d Dorothy Becker, MBBCh From the Departments of Psychiatry, Pediatrics, and Nursing, University of Pittsburgh School of Medicine, and the Department of Pediatrics, Allegheny General Hospital, Pittsburgh, Pennsylvania To assess the effects of mild hypoglycemia on cognitive functioning in diabetic children, we used an insulin glucose clamp technique to induce and maintain a hypoglycemic state. Eleven patients, 11 to t8 years of age, completed a series of cognitive tests during a baseline euglycemic state (t00 m g / d l [5.5 mmol/L]) and repeated those measures at the beginning and end of a hypoglycemic plateau (55 to 65 m g / d l (3.t to 3.6 retool/L]), and again at restoration of euglycemia. At plasma glucose levels of 60 to 65 mg/dl (3.3 to 3.6 retool/L), a significant decline in mental efficiency was found. This was most apparent on measures of mental "flexibility" (Trail Making Test) and on measures that required planning and decision making, attention to detail, and rapid responding. Moreover, complete recovery of cognitive function was not contemporaneous with restoration of euglycemia, particularly on those tests requiring rapid responding and decision making (choice reaction time). Not all subjects showed evidence of cognitive impairment during hypoglycemia. The very high degree of intersubject variability suggests that, in addition to plasma glucose values, unknown physiologic variables are responsible for triggering cognitive impairments in school-aged youngsters with diabetes during an episode of mild

hypoglycemia. (J PEDIATR1990;117:32-38)

Children and adolescents with insulin-dependent diabetesmeilitus have an increased risk of the development of cognitive impairment. Children in whom diabetes is diagnosed before 4 or 5 years of age may show cognitive impairments in a wide range of neuropsychologic tests, particularly in

those measuring visuospatial skills.l-4 The most potent predictors of deficit in this population of diabetic children are age at diagnosis and number of episodes of severe hypoglycemia. Although less attention has been directed to children in whom diabetes developed after the age of 5 years, several RT

Supported in part by U.S. Public Health Service grant No. M01 RR-00084 to the General Clinical Research Center, Children's Hospital of Pittsburgh. Supplemental funding provided by the Allegheny Singer Research Institute. Submitted for publication Nov. 29, 1989; accepted Jan. 29, 1990. Reprint requests: Christopher Ryan, PhD, Western Psychiatric Institute and Clinic, 3811 O'Hara St., Pittsburgh, PA 15213. 9/20/]9716

32

Reaction time

[

studies have demonstrated that they, too, may manifest subtle decrements on certain types of intellectual tests, especially on measures of verbal intelligence and academic achievement. In this group of adolescents with later-onset diabetes, the best predictor of performance is duration of disease. 5

Volume 1t 7 Number 1, Part 1

Duration of disease may function as a surrogate or marker of some biologic or psychosocial process that disrupts performance on certain cognitive measures. One psychosocial variabte that could account for these declines is absence of the child from school. 6, 7 An alternative (or complementary) explanatory variable is transient hypoglycemia. If even mild levels of hypoglycemia reduce mental efficiency for a significant period, the diabetic child with mild hypoglycemia may be less attentive to classroom activity and may therefore fail to acquire the kinds of knowledge that are measured by tests of verbal intelligence and by academic achievement. When a moderate level of hypoglycemia is induced in adults with or without diabetes, decrements appear on a wide range of standardized neurobehavioral tests of cognitive functioning, s l ~ Adults with less severe experimentally induced hypoglycemia may also manifest transient cognitive deficits, although there is considerably less consensus in the literature. Although clinicians have speculated that children may respond differently from adults to hypoglycemia, no one has yet examined the neurobehavioraI effects of experimentally induced hypoglycemia in that population. This study was undertaken to address four issues: (1) Does mild hypoglycemia disrupt mental efficiency in diabetic children and adolescents? (2) Are any decrements limited to those tests tapping "more complex" cognitive processes, or are they found on both cognitively simple and complex tasks? (3) Does recovery of mental functioning occur when euglycemia is reached, or is there a temporal lag? (4) Are all children equally affected, or are some youngsters more sensitive than others to hypoglycemia? METHODS Subjects. The study included 11 children with insulin-dependent diabetes who were being followed at Children's Hospital of Pittsburgh (CHP) and were admitted for routine diabetes education and assessment of complications and control. Five of the children were girls; one of the 11 was black. All were between 11 and 18 years of age (mean _+ SD, 14.4 _+ 2.7 years), had had the diagnosis of diabetes since they were between 2 and 10 years of age (mean 6.9 _+ 2.0 years), and had had the disease for 2 to 15 years at the time of this assessment (mean 7.7 _+ 3.4 years). Their glycosytated hemoglobin values ranged from 9.0% to 13.5% (mean 10.6 _+ 1.5%) in the year before this evaluation. These values are similar to those from the CHP clinic population (mean 10.48 + 1.7%). At the time of admission these subjects were receiving two subcutaneous injections per day of a mixture of regular and intermediate-acting insulin. In addition, two subjects were taking L-thyroxine for autoimmune thyroiditis and were euthyroid at the time of evaluation. All children were of at least average intelligence, as

Hypoglycemia and mental efficiency

33

ascertained by their Wechsler Full Scale IQ (mean 106.0 _+ 13.5). This research protocol was approved by the CHP Human Rights Committee. Informed consent and assent were obtained from the parents and the patients, respectively. Procedures. Twenty-four hours before the study began, intermediate-acting insulin was withdrawn and only regular insulin was given before meals. In the evening before the study, two intravenous catheters, one for blood sampling (dorsal hand vein) and one for infusion of glucose and insulin (antecubital vein), were inserted in the patients' nondominant arm. Starting at 10 PM, a variable rate intravenous infusion of regular insulin (without glucose) was given to maintain nocturnal euglycemia at 5.0 to 6.7 m m o l / L (90 to 120 mg/dl). All studies were performed in the postabsorptive state after 10 to 12 hours of overnight fasting. On the morning of the study, at 8 AM, a constant intravenous infusion of regular insulin was started at a rate of 0.1 U / kg/hr, resulting in the maintenance of plasma-free insulin concentration at a mean of 107 #U/ml. Plasma glucose was clamped at the desired level with the use of a variable rate intravenous infusion of 10% glucose. At the beginning of the study, plasma glucose was clamped to achieve a stable level of euglycemia (5.5 retool/ L [100 mg/dl]) for at least 45 minutes. Baseline cognitive tests were administered during the last 15 minutes of that period (session 1). After this, plasma glucose concentration was dropped to approximately 3.6 mmol/L (65 mg/dl) by decreasing the intravenous glucose infusion during a 20minute period; this level was maintained for at least 15 minutes before the cognitive tests were repeated (session 2). For the first five subjects studied, plasma glucose was lowered further during a 20-minute period and clamped at approximately 3.1 mmol/L (55 mg/dl) for 15 minutes before cognitive tests were readministered (session 3). For the remaining six subjects, the plasma glucose level was not dropped further but was held at 3.6 mmol/L for an additional 50 minutes; the cognitive tests were repeated during the last 15 minutes. All patients were returned to euglycemia during a 15-minute period by increasing the glucose infusion rate. Cognitive tests were repeated (session 4) as soon as plasma glucose reached 5.0 mmol/L (90 mg/dl) and again after glucose levels had been maintained at 5.6 m m o l / L (100 mg/dl) for 15 minutes (session 5). Throughout the study, blood was obtained from a heated nondominant hand vein at 5-minute intervals for determination of artcrialized plasma glucose concentration. Measurements of free insulin concentrations were made every 15 minutes. Assessment measures. Mental efficiency was assessed by repeatedly administering three neuropsychologic tests. Subjects were given extensive practice with each measure before beginning the study, in an effort to bring them to an opti-

34

Ryan et al.

mal "steady state" performance level before the baseline assessment. This strategy eliminates, or minimizes, the improvement in performance that is normally associated with repetition of any task (i.e., "learning to learn"). The same test stimuli were administered at each test session, with one exception. Four alternate versions of part B of the Trail Making Test were used to reduce practice effects further. A fixed order of test administration was used such that each session began with the reaction time assessment and ended with the Stroop test. The alternate versions of Trail Making part B were randomly distributed across test sessions. Reaction time. Simple and Choice visual RTs were measured with a Lafayette Instruments Reaction Time Apparatus. For the Simple RT task, an auditory warning signal was followed by the onset of a colored light. The subject's task was to press the button under the stimulus light as quickly as possible. The subject was told that the stimulus would always be blue during the first set of 10 test trials and would always be green during the second set. This task provides a measure of vigilance. For the Choice RT task, subjects were not informed in advance as to the color of the stimulus; when the stimulus appeared, they were to press the appropriate button. Ten trials with a blue stimulus were randomly intermixed with 10 green stimulus trials. This task provides a measure of simple decision-making efficiency. The median RT in milliseconds was calculated from the 20 Simple RT trials and from the 20 choice RT trials. Trail Making Test. The Trail Making Test is a wellknown clinical measure of psychomotor efficiency and mental flexibility that has been found to be sensitive to subtle brain dysfunction.ll On part A, the subject is presented with a series of numbers randomly arrayed across the page and is told to connect the numbers in order as quickly as possible. On part B, both numbers and letters are presented and the subject is required to alternate sequentially between the two (e.g., 1-A-2-B). The principal response measure is the time (in seconds) taken to complete each part. Stroop Color-Word Test. On the first part of this test (Read Words), the subject reads a page of words ("red," "green," and "blue") printed in black ink. On the second part (Name Colors), the subject sees a series of • marks printed in different colors and names the color of the ink. On the third part (Interference), the subject is presented with names printed in different colors (the word "red" printed in green ink) and is told to name the color of the ink. In each subtest the number of correct responses made in 45 seconds is the variable of interest) 2 Both the Word Reading and Color Naming subtests measure sustained attention; the Interference subtest measures the ability to inhibit a highly overlearned response (read the word) and replace it with a relatively novel response (name the ink color). Hypoglycemic symptoms. Adrenergic and neuroglyco-

The Journal of Pediatrics" July 1990

penic symptoms of hypoglycemia were ascertained before each cognitive test. Seven symptoms were assessed, including sweating, feeling shaky, heart pounding, hunger, sleepiness, "feeling low," and light-headedness. Statistical methods. Repeated-measures multivariate analysis of variance techniques were used to determine whether statistically significant differences appeared across time on each of the three cognitive tests. If the overall multivariate F value was significant, we computed univariate F values for each of the subtests and then conducted a series of single-df comparisons 13 in which baseline scores were compared with scores obtained at the beginning (session 2) and end (session 3) of the hypoglycemic period and at the euglycemic recovery stage (sessions 4 and 5). RESULTS Plasma glucose levels. At the baseline euglycemic assessment (session 1), mean plasma glucose concentration ( _+SEM) was 5.4 _+ 0.15 mmol/L (97 _+ 2.6 mg/dl) for at least 45 minutes. During session 2 plasma glucose concentration was 3.6 +_ 0.10 mmol/L (64 _+ 1.6 mg/dl) and clamped at that level for a minimum of 30 minutes. During session 3, six of the subjects remained at that plateau for an additional 50 minutes, whereas the plasma glucose concentration of five subjects was lowered further to a mean value of 3.1 mmol/L (55 mg/dl). Because there were no differences between those two subgroups on the cognitive tests, their data were combined, yielding a mean plasma glucose concentration for the entire group of 3.3 +_ 0.10 mmol/L (60 +_ 1.7 mg/dl). During session 4, at euglycemic recovery, mean plasma glucose concentrations were 5.0 _+ 0.06 mmol/L (96 _+ 1.1 mg/dl) and rose to 5.7 mmol/L _+ 0.17 (102.8 __ 3.1 mg/dl) by session 5. Reaction time. Raw scores for this and all other cognitive tests are presented in the Table. Reaction times changed as plasma glucose levels were modified (F[6,60] = 2.64; p <0.025). These changes were apparent on both the Simple (F[3,30] = 5.36; p <0.01) and Choice (F[3,30] = 3.11; p <0.05) RT tasks, although the two tasks showed somewhat different sensitivities to the glycemic manipulation. The Simple RT was significantly slowed, relative to the euglycemic baseline, only at the end of the hypoglycemic period (session 3: F[1,10] = 27.36;p <0.0001). In contrast, Choice RT was significantly slowed at both hypoglycemic assessment points (session 2:F[1,10] = 8.37; p <0.025; session 3: F[1,10] = 11.04; p <0.01 and did not recover to the euglyeemic baseline level when euglycemia was restored (session 4: F[1,10] = 6.18; p <0.05). Trail Making Test. Trail Making Test performance changed significantlyover time(F[6,60] = 5.39;p<0.0001) for both part A (F[3,30] = 4.49; p <0.01 and part B (F[3,30] = 9.16; p <0.0001). The processes underlying

Volume 117 Number 1, Part I

Hypoglycemia and mental efficiency

35

Table. Raw scores from each cognitive measure at each of five test sessions Session I

Blood glucose (mmol/L) Reaction time (msec) Simple Choice Trail Making (sec) Part A Part B Stroop (No. correct) Read Words Name Colors Interference

2

3

4

5

5.4 • 0.4

3.6 _+ 0.3

3.3 + 0.3

5.0 -+ 0.2

5.7 • 0.5

389.4 • 39.4 442.3 -+ 52.0

396.9 -+ 40.5 473.4 +_ 58.7

430.8 _+ 48.2 502.1 + 82.9

408.7 _+ 57.6 483.0 +_ 77.7

408.4 -+ 57.4 457.0 -+ 90.8

17.8 -+ 4.8 38.6 -+ 9.7

16.6 _+ 3.7 53.7 _+ 21.9

19.2 _+ 4.3 64.9 • 23.4

15.2 _+ 3.3 38.8 _+ 8.6

15.9 -+ 3.9 31.7 -+ 11.7

99.6 -+ 11.6 75.2 + 6.6 46.1 _+ 6.6

94.6 • 12.8 64.9 +_ 8.6 44.7 +_ 5.3

84.6 _+ 16.3 62.3 _+ 8.2 44.4 _ 9.3

95.2 _+ 21.2 70.9 • 10.1 45.3 _+ 8.9

97.8 • 19.8 68.7 _+ 10.4 44.6 _+ 4.1

Values are expressed as mean + SD.

these changes differed for the two subtests (Table). In general, performance improved somewhat over time on part A - - t h a t is, the changes were primarily a consequence of repeated practice with the test, although there was a decrement in functioning at the end of the hypoglycemic plateau (session 3). On the other hand, performance on part B declined significantly at the beginning of the hypoglycemic plateau (session 2" F[ 1,10] = 7.53;p <0.025), stayed at that level for the duration of hypoglycemia (session 3: F[1,10] = 17.32;p <0.001), and then recovered completely as euglycemia was restored (session 4: F[1,10] = 0.18; p >0.10). This decrement in functioning during hypoglycemia was clinically significant. If one defines clinical impairment as a score of 60 or more (>2 SD beyond the mean), 6 of the 11 children met criteria for impairment when mean plasma glucose level was 3.4 m m o l / L (60 mg/dl). All those scores returned to the normal range immediately after restoration of euglycemia. Stroop Color-Word Test. The multivariate F for this test was highly significant (F [9,81 ] = 3.03;p <0.01 ); univariate F values were significant for only the Read Words (F[3,30] -- 5.09; p <0.01) and Name Colors (F[3,30] = 10.86; p <0.0001) subtests. Relative to baseline, color-naming scores were significantly lower at both the beginning (session 2: F[1,10] = 15.0l; p <0.01) and end (session 3: F[1,10] = 19.57; p <0.01) of hypoglycemia. In contrast, word-reading scores were significantly poorer than baseline scores only at the end of the hypoglycemic period (session 3: F[1,10] = 12.33;p <0.01). Performance on both subtests did not differ from baseline when euglycemia was restored. Hypoglycemia did not disrupt performance on the interference subtest (F[3,30] = 0.29; p >0.10). Individual variability. Because of our impression that some subjects were very sensitive to the effects of hypoglycemia whereas others were relatively insensitive, we exam-

ined the raw scores of individual subjects. To illustrate the degree of variability, we selected the first six subjects and graphed their performance on the Color N a m i n g subtest from the Stroop test (Figure). This degree of variability was seen on virtually all the cognitive tests. Biomedical variables. Simple Pearson correlation coefficients were computed to assess the relationship between diabetes-related variables and neurobehavioral test performance. For each cognitive variable the percent change between baseline and the end of the hypoglycemic period (session 3) was first determined. Those change scores were correlated with the subjects' age, age at diagnosis of diabetes, duration of diabetes, and glycosylated hemoglobin value. None of the diabetes-related variables were significantly associated with the cognitive change scores. Intelligence test scores, The relationship between performance on several subtests from the Wechsler Intelligence Scale and the percentage of change between baseline and hypoglycemic plateau was also assessed for each of the neuropsychologic tests. Correlation coefficients were computed between the seven change score variables and the Information, Arithmetic, Comprehension, Vocabulary, Picture Completion, and Block Design subtests from the Wechsler Intelligence Scale for Children--Revised or Wechsler Adult Intelligence Scale--Revised (for subjects 16 or more years of age). Despite a number of relatively large correlation coefficients, few values actually reached statistical significance. It is likely that this reflects the very low level of statistical power associated with this small a sample. Symptoms of hypoglycemia. Nonparametric analyses (Cochran Q value) demonstrated that hypoglycemia was associated with an increased incidence of all symptoms except light-headedness. Hunger, sleepiness, and "feeling low" were the earliest symptoms, with statistically signifi-

36

Ryan et al.

The Journal of Pediatrics July 1990

90-

I-O

LU n,IZ 0

80-

70-

L) nr tlJ m

60-

Z

50-

40

=

i

i

i

i

5.4 mM

3.6 mM

3.3 mM

5.0 mM

5.7 mM

PLASMA Figure.

BLOOD

GLUCOSE

Mean number of correct responses on Stroop Color Naming subtest for six subjects at five plasma blood glucose

levels.

cant changes from baseline appearing for each of them (Q = 5.0; p <0.025 for each symptom) at the beginning of the hypoglycemic period. Only at the end of the hypoglycemic period did the number of subjects describing symptoms of shakiness (Q = 7.0; p <0.01) and heart pounding (Q = 4.0; p <0.05) differ significantly from baseline values. All symptoms remitted immediately on restoration of euglycemia. There was no strong relationship between the presence of symptoms and the presence of cognitive impairment. For example, when we compared those subjects who met criteria for clinically significant impairment on part B on the Trail Making Test with those subjects who did not, we found no difference in the number of symptoms described. DISCUSSION This study demonstrates that a transient episode of experimentally induced hypoglycemia was associated with a marked reduction in the mental efficiency of diabetic children and adolescents. These cognitive changes were not limited to one or two measures but appeared on virtually all the neurobehavioral tasks. Moreover, these changes were often apparent at relatively "mild" levels of hypoglycemia. On three frequently used measures of cognitive efficiency, statistically significant decrements in functioning first appeared shortly after the initiation of hypoglycemia, when the mean plasma glucose value was 3.7 mmol/L (66 rag/ dl). As duration of hypoglycemia increased and plasma glucose levels dropped somewhat, performance on two additional cognitive measures deteriorated significantly. The various neurobehavioral tasks were differentially affected by hypoglycemia. Trail Making part B, a task that measures planning ability and mental "flexibility," was ex-

tremely sensitive to glycemic changes in these patients. The magnitude of these changes was very large--an average of 70% change from baseline to session 3. Smaller, albeit statistically reliable, changes appeared on the other cognitive tests. Were one to rank their sensitivity to hypoglycemia, one would probably follow Trail Making part B with Color Naming, Word Reading, Choice RT, and Simple RT. Although both cognitively simple and cognitively complex tasks were disrupted, it appears that the tasks that were most sensitive to hypoglycemia were those that required planning and decision making, attention to detail, visual scanning, and rapid responding. A similar pattern of results has been reported in adults, but these changes typically occurred at much lower plasma glucose levels. Statistically rehable decrements were most likely to appear when plasma glucose levels were maintained at or below 2.1 mmol/L (38 mg/dl). As did our diabetic children, both diabetic and nondiabetic adults showed a significant slowing in RTs, 9, 14 and performed in the impaired range on the Trail Making Test. 1517 Again, the magnitude of the effect appeared to be inversely related to the degree of hypoglycemia. Results from this study indicate that complete recovery of cognitive functioning is not invariably contemporaneous with restoration of euglycemia in children and adolescents. This is most apparent on measures of RT. Although few studies, including our own, were designed explicitly to map out the temporal process of cognitive recovery after a hypoglycemic event, several other reports support our view that, depending on the type of task used, the complete recovery of mental efficiency may lag behind restoration to euglycemia. 9 A review of data from our study also demonstrates a great

Volume 117 Number 1, Part 1

deal of variability from subject to subject. Our analyses suggest that these individual differences in sensitivity to hypoglycemia cannot be explained by degree of prior metabolic control, duration of diabetes, age at onset, age at assessment, or gender. Similarly, Herold et al. 9 were unable to attribute the very high variability found in their adult subjects to either the duration or severity of hypoglycemia or to the release of counterregulatory hormones. They speculated that differences in sensitivity to hypoglycemia may be related to variability in subjects' capacity to maintain a normal rate of cerebral glucose uptake at relatively low plasma glucose levels. During experimentally induced hypoglycemia, cerebral blood flow normally increases in adults without and those with diabetes who have no microangiopathy. 18 Recent work with chronically hypoglycemic rats suggests that prior hypoglycemia increases glucose transport across the blood brain barrier, w If one can extrapolate those findings to human beings, one might hypothesize that those children and adults who show little cognitive change during a transient episode of experimentally induced hypoglycemia may be those who have had multiple previous episodes of hypoglycemia. Unfortunately, we have not yet been able to test that hypothesis because of the difficulty in documenting chronic mild hypoglycemia retrospectively. Several investigators have examined the relationship between awareness of hypoglycemia (as indexed by adrenergic and neuroglycopenic symptoms) and the occurrence of cognitive impairment. Studies of adults have indicated that symptoms often, but not invariably, accompany hypoglycemia.9, 17, 20 Results from our study are consistent with those findings. Although not all of our subjects reported the presence of symptoms, 80% of them had at least two by the end of the hypoglycemic plateau. Hunger, sleepiness, and the recognition of "feeling low" appear to be the most salient symptoms in children. Not only do they tend to occur shortly after the induction of hypoglycemia, but they tend to be the most frequently reported. Whereas the majority of children also had shakiness--although only at the end of the hypoglycemic plateau--fewer reported sweatiness or pounding heart. Feelings of light-headedness were rarely reported in this sample. Moreover, there was no obvious relationship between the occurrence of hypoglycemic symptoms and changes in mental efficiency, as indexed by performance decrements on the cognitive tests. These results suggest that cognitive impairment cannot be readily predicted by the presence or absence of symptoms of hypoglycemia. One important goal of this study was to test the hypothesis that the severity of hypoglycemia-induced cognitive dysfunction is associated with decrements in performance on measures of verbal intelligence and academic achieveraent. Although those children who showed the greatest de-

Hypoglycemia and mental efficiency

37

cline on the neuropsychologic measures during hypoglycemia often had a tendency to earn somewhat lower scores on several of the intelligence subtests, those relationships were rarely statistically reliable. Our relatively small sample size provides insufficient statistical power to answer that question at this time. We conclude that diabetic children and adolescents may have a significant decline in mental efficiency during an experimentally induced episode of hypoglycemia. At plasma glucose levels of 3.3 to 3.6 mmol/L (60 to 65 mg/dl), performance o n a number of neuropsychologic measures-cognitively simple as well as complex--deteriorates significantly. The degree of deterioration is highly variable and reflects in part the differential sensitivity of particular cognitive tests to hypoglycemia as well as the differential (and yet unknown) physiologic sensitivity of the individual child to glycemic manipulations. These cognitive decrements are transient, but complete recovery of mental efficiency may lag behind the restoration of the euglycemic state. These findings have important implications for the school-aged child with diabetes, because they indicate that after an episode of hypoglycemia, the child may not function optimally for a time despite correction of hypoglycemia. We thank Ms. Theresa Williams for data management and statistical analyses. REFERENCES

1. Ryan C, Vega A, Drash A. Cognitive deficits in adolescents who developed diabetes early in life. Pediatrics 1985;75:921-7. 2. Rovet J, Ehrlich R, Hoppe M. Intellectual deficits associated with early onset of insulin-dependent diabetes mellitus in children. Diabetes Care 1987;10:510-5. 3. Holmes C, Richman L. Cognitive profiles of children with insulin-dependent diabetes. Dev Behav Pediatr 1985;6:323-6. 4. Golden M, Ingersoll G, Brack C, et al. Longitudinal relationship of asymptomatic hypoglycemia to cognitive function in IDDM. Diabetes Care 1989;12:89-93. 5. Ryan C, Vega A, Longstreet C, Drash A. Neuropsychological changes in adolescents with insulin-dependent diabetes. J Consult Clin Psychot 1984;52:335-42. 6. Ryan C, Longstreet C, Morrow L. The effects of diabetes mellitus on the school attendance and school achievement of adolescents. Child Care Health Dev 1985;11:229-40. 7. Weitzman M, Klerman L, Lamb G, et al. School absence: A problem for the pediatrician. Pediatrics 1982;69:739-46. 8. Pramming S, Thorsteinsson B, Theilgaard A, et al. Cognitive function during hypoglycaemia in type I diabetes mellitus. Br Med J 1986;292:647-50. 9. Herold K, Polonsky K, Cohen R, et al. Variable deterioration in cortical function during insulin-induced hypoglycemia. Diabetes 1985;34:677-85. 10. Kerr D, Macdonald I, Tattersall R. Adaptation to mild hypoglycaemia in normal subjects despite sustained increases in counter-regulatory hormones. Diabetologia 1989;32:24954. 11. Boll T, Barth J. Neuropsychology of brain damage in children.

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In: Filskov S, Boll T, eds. Handbook of clinical neuropsychology. New York: John Wiley & Sons, 1981. Golden C. Stroop Color and Word Test. Chicago: Stoelting Co, 1978. Keppel G, Zedeck S. Data analysis for research designs. New York: WH Freeman, 1989. Holmes C, Koepke K, Thompson R. Simple versus complex performance impairments at three different glucose levels. Psychoneuroendocrinology 1986;11:353-7. Ipp E, Forster B. Sparing of cognitive function in mild hypoglycemia: dissociation from the neuroendocrine response. J Clin Endocrinol Metab 1987;65:806-10. Hoffman R, Speelman D, Hinnen D, et al. Changes in cortical functioning with acute hypoglycemia and hyperglycemia in type I diabetes. Diabetes Care 1989;12:193-7.

17. Stevens A, McKane W, Bell P, et al. Psychomotor performance and counterregulatory responses during mild hypoglycemia in healthy volunteers. Diabetes Care 1989;12:t2-7. 18. Neil HAW, Gale EAM, Hamilton SJC, et al. Cerebral blood flow increases during insulin-induced hypogtycaemia in type 1 (insulin-dependent) diabetic patients and control subjects. Diabetologia 1987;30:305-9. 19. McCall AL, Fixman LB, Fleming N, et al. Chronic hypoglycemia increases brain glucose transport. Am J Physiol 1986;251 :E442-7. 20. Heller S, Macdonald I, Herbert M, et al. Influence of sympathetic nervous system on hypoglycaemic warning symptoms. Lancet 1987;2:359-63.

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