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Frequency and Timing of Severe Hypoglycemia Affects Spatial Memory
CITATION:  Hershey, T., Perantie, D., Warren, S., Zimmerman, E., Sadler, M.R, White, N. (2005).  Frequency and timing of severe hypoglycemia affects spatial memory in children with type 1 diabetes.  Diabetes Care 28:2372-2377.


Objective:  Repeated severe hypoglycemia has been reported to reduce long-term spatial memory in children with type 1 diabetes. Early exposure to hypoglycemia may be more damaging to cognitive function than later exposure. Our goal was to determine whether the age at which severe hypoglycemia occurs modulates the impact of severe hypoglycemia frequency on long-term spatial memory. 

Research Design and Methods:  We combined data from three independent studies to obtain a sample of children aged 6–18 years with type 1 diabetes (n = 103) and nondiabetic control subjects (n = 60). Each study evaluated previous severe hypoglycemia and tested short (5 s)- and long (60 s)-delay spatial memory with the spatial delayed response task. Type 1 diabetic participants were categorized as having zero, one to two, or three or more severe hypoglycemic episodes and as having their first severe hypoglycemic episode before or after 5 years of age. Information on chronic hyperglycemia (HbA1c values) was also collected. 

Results:  We found that repeated severe hypoglycemia (more than three episodes) reduced long-delay spatial delayed response performance, particularly when severe hypoglycemic episodes began before the age of 5 years. Age of type 1 diabetes onset and estimates of chronic hyperglycemia did not influence performance. 

Conclusions:  High frequency of and early exposure to severe hypoglycemia during development negatively affects spatial long-term memory performance. 


Davis EA, Keating B, Byrne GC, Russell M, Jones TW: Hypoglycemia: incidence and clinical predictors in a large population-based sample of children and adolescents with IDDM. Diabetes Care 20:22–25, 1997[Abstract]

Ryan C, Vega A, Drash A: Cognitive deficits in adolescents who developed diabetes early in life. Pediatrics 75:921–927, 1985[Abstract/Free Full Text]

Ack M, Miller I, Weil WB: Intelligence of children with diabetes mellitus. Pediatrics 28:764–770, 1961[Abstract/Free Full Text]

Wolters CA, Yu SL, Hagan JW, Kail R: Short-term memory and strategy use in children with insulin-dependent diabetes mellitus. J Consult Clin Psych64:1397–1405, 1996

Holmes CS, Richman LC: Cognitive profiles of children with insulin-dependent diabetes. J Dev Behav Pediatr 6:323–326, 1985[Medline]

Bjorgaas M, Gimse R, Vik T, Sand T: Cognitive funciton in type 1 diabetic children with and without episodes of severe hypoglycemia. Acta Paediatr 86:148–153, 1997[Medline]

Rovet JF, Ehrlich RM: The effect of hypoglycemic seizures on cognitive function in children with diabetes: a 7-year prospective study. J Pediatr 134:503–506, 1999[Medline]

Hershey T, Lillie R, Sadler M, White NH: Severe hypoglycemia and long-term spatial memory in children with type 1 diabetes mellitus: a retrospective study. J Int Neuropsychol Soc 9:740–750, 2003[Medline]

Hershey T, Bhargava N, Sadler M, White NH, Craft S: Conventional vs. intensive diabetes therapy in children with type 1 diabetes mellitus: effects on memory and motor speed. Diabetes Care 22:1318–1324, 1999[Abstract]

Ryan CM: Does moderately severe hypoglycemia cause cognitive dysfunction in children? Pediatr Diabetes 5:59–62, 2004[Medline]

Ryan CM: Memory and metabolic control in children. Diabetes Care 22:1239–1241, 1999[Free Full Text]

Wechsler D: Wechsler Intelligence Scale for Children. 3rd Revision. Cleveland, OH, The Psychological Corporation, 1991

Naglieri JA, Das JP: Planning, attention, simultaneous, and successive (PASS) cognitive processes as a model for intelligence. Journal of Psychoeducational Assessment 8:303–337, 1990

McGrew KS, Woodcock RW: Technical Manual for the Woodcock-Johnson III. Itasca, IL, Riverside Publishing, 2001

Hershey T, Craft S, Glauser TA, Hale S: Short-term and long-term memory in early temporal lobe dysfunction. Neuropsychology 12:52–64, 1998[Medline]

Hershey T, Lillie R, Sadler M, White N: Prospective report of severe hypoglycemia explains changes in delayed response (Abstract). J Int Neuropsychol Soc 7:240, 2001

Murphy BL, Arnsten AF, Goldman-Rakic PS, Roth RH: Increased dopamine turnover in the prefrontal cortex impairs spatial working memory performance in rats and monkeys. Proc Natl Acad Sci U S A 93:1325–1329, 1996[Abstract/Free Full Text]

Williams GV, Goldman-Rakic PS: Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 376:572–575, 1995[Medline]

Funahashi S, Bruce CJ, Goldman-Rakic PS: Dorsolateral prefrontal lesions and oculomotor delayed-response performance: evidence for mnemonic "scotomas." J Neurosci 13:1479–1497, 1993[Abstract]

Goldman-Rakic PS: Circuitry of primate prefrontal cortex and regulation of behavior by representational memory. In Handbook of Physiology: The Nervous System. Mills J, Mountcastle VG, eds. Baltimore, MD, Williams and Wilkins, 1987, p. 373–417

Hershey T, Barr WB, Richards K, Newcomer JW, Miller JW: Delayed response performance in temporal lobe epilepsy (Abstract). J Int Neuropsychol Soc5:122, 1999

Alvarez P, Zola-Morgan S, Squire LR: The animal model of human amnesia: long-term memory impaired and short-term memory intact. Proc Natl Acad Sci U S A 91:5637–5641, 1994[Abstract/Free Full Text]

Cave C, Squire LR: Intact verbal and nonverbal short-term memory following damage to the human hippocampus. Hippocampus 2:151–164, 1992[Medline]

Correll RE, Scoville WB: Performance on delayed match following lesions of medial temporal lobe structures. J Comp Physiol Psychol 60:360–367, 1965[Medline]

Kowalska DM: Effects of hippocampal lesions on spatial delayed responses in dog. Hippocampus 5:363–370, 1995[Medline]

Rains GD, Milner B: Right-hippocampal contralateral-hand effect in the recall of spatial location in the tactual modality. Neuropsychologia 32:1233–1242, 1994[Medline]

Sidman M, Stoddard LT, Mohr JP: Some additional quantitative observations of immediate memory in a patient with bilateral hippocampal lesions. Neuropsychologia 6:245–254, 1968

Smith ML, Milner B: The role of the right hippocampus in the recall of spatial location. Neuropsychologia 19:781–793, 1981[Medline]

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. Pediatric Diabetes 5:63–71, 2004[Medline]

Auer RN, Hugh J, Cosgrove E, Curry B: Neuropathological findings in three cases of profound hypoglycemia. Clin Neuropath 8:63–68, 1989

Auer RN, Olsson Y, Siesjo BK: Hypoglycemic brain injury in the rat: correlation of density of brain damage with the EEG isoelectric time: a quantitative study. Diabetes 33:1090–1098, 1984[Abstract]

Auer RN, Siesjo BK: Biological differences between ischemia, hypoglycemia, and epilepsy. Ann Neurol 24:699–707, 1988[Medline]

Chalmers J, Risk MTA, Kean DM, Grant R, Ashworth B, Campbell IW: Severe amnesia after hypoglycemia: clinical, psychometric, and magnetic resonance imaging correlations. Diabetes Care 4:922–925, 1991

Saykin AJ, Gur RC, Sussman NM, O’Conner MJ, Gur RE: Memory deficits before and after temporal lobectomy: effect of laterality and age of onset. Brain Cogn 9:191–200, 1989[Medline]

Lipska BK, Halim ND, Segal PN, Weinberger DR: Effects of reversible inactivation of the neonatal ventral hippocampus on behavior in the adult rat. J Neurosci22:2835–2842, 2002[Abstract/Free Full Text]

Ryan CM, Williams TM: Effects of insulin-dependent diabetes on learning and memory efficiency in adults. J Clin Exp Neuropsychol 15:685–700, 1993[Medline]

Ryan CM, Williams TM, Orchard TJ, Finegold DN: Psychomotor slowing is associated with distal symmetrical polyneuropathy in adults with diabetes mellitus. Diabetes 41:107–113, 1992[Abstract]

Holmes CS: Neuropsychological profiles in men with insulin-dependent diabetes. J Consult Clin Psychol54:386–389, 1986[Medline]

Rovet J, Alvarez M: Attentional functioning in children and adolescents with IDDM. Diabetes Care 20:803–810, 1997[Abstract]

Northam EA, Anderson PJ, Werther GA, Warne GL, Andrewes D: Predictors of change in the neuropsychological profiles of children with type 1 diabetes 2 years after disease onset. Diabetes Care 22:1438–1444, 1999[Abstract]

Kaufman FR, Epport K, Engilman R, Alvorson M: Neurocognitive functioning in children diabetes with diabetes before age 10 years. J Diabetes Complications 13:31–38, 1999[Medline]

Northam EA, Anderson PJ, Jacobs R, Hughes M, Warne GL, Werther GA: Neuropsychological profiles of children with type 1 diabetes 6 years after disease onset. Diabetes Care 24:1541–1546, 2001[Abstract/Free Full Text]

Ferguson SC, Blane A, Wardlaw J, Frier BM, Perros P, McCrimmon RJ, Deary IJ: Influence of an early-onset age of type 1 diabetes on cerebral structure and cognitive function. Diabetes Care 28:1431–1437, 2005[Abstract/Free Full Text]

Ferguson SC, Blane A, Perros P, McCrimmon RJ, Best JJ, Wardlaw J, Deary IJ, Frier BM: Cognitive ability and brain structure in type 1 diabetes: relation to microangiopathy and preceding severe hypoglycemia. Diabetes 52:149–156, 2003[Abstract/Free Full Text]

Hagen JW, Barclay CR, Anderson BJ, Feeman DJ, Segal SS, Bacon G, Goldstein GW: Intellective functioning and strategy use in children with insulin-dependent diabetes mellitus. Child Dev 61:1714–1727, 1990[Medline]