Apart from the acute complication of hypoglycemia, patients often worry about whether multiple episodes of severe hypoglycemia will impair longterm cognitive ability and negatively affect their performance at school or work. In a follow-up of the DCCT study, patients with type 1 diabetes were followed for an average of 18 years and underwent a comprehensive battery of cognitive testing.^60,61 For the study, severe hypoglycemic events were limited to those that led to coma, seizures, or both. The study found no decline in cognitive ability despite multiple episodes of severe hypoglycemia, and no correlation between frequency of severe hypoglycemia and cognitive function was observed.^60,61 Interestingly, a recent study found that recurrent moderate episodes of hypoglycemia may protect the brain against severe hypoglycemia-induced neuronal damage.⁶² Thus, moderate episodes of hypoglycemia may pre-condition the brain and prevent neuronal damage and associated cognitive decline. If extrapolated to the clinical situation, this beneficial adaptation induced by recurrent moderate hypoglycemia could account for the discrepancy between episodes of recurrent hypoglycemia and cognitive decline in intensively treated individuals with diabetes. These data are reassuring, for although hypoglycemia can be acutely dangerous, it does not appear to have long-term adverse effects on cognition in adolescent and adult patients with type 1 diabetes.^60,61

The effect of hypoglycemia on cognition in infants and very young children is a topic that is under investigation. As the brain is still rapidly developing and thus has higher demand for glucose in young children, a child’s brain may be more sensitive to hypoglycemia than an adult brain.^63,64 Hershey found that in children between five and 16 years of age, hypoglycemia was associated with lower spatial intelligence and delayed memory.⁶⁵ A study that assessed cognition in children at the time of diagnosis of diabetes and seven years later found that children who experienced hypoglycemic seizures had a decline in verbal abilities and attention.⁶⁶ Other studies found deficits in memory⁶⁷ and processing speed^66,68 in children with a history of severe hypoglycemia. Although many studies suggest the adult brain to be resistant to cognitive decline due to hypoglycemia, the long-term cognitive effects of hypoglycemia in young children are still controversial.

Management and Prevention of Hypoglycemia
To minimize the frequency and severity of hypoglycemia, several precautions should be considered (see Table 3). First, an individualized insulin regime that includes basal insulin and mealtime bolus insulin should be established. Consistent monitoring should be performed before all meals and snacks, before and after exercise, at bedtime, and, if nocturnal hypoglycemia is a concern, occasionally during the middle of the night. The accuracy of carbohydrate intake or ‘carb counting’ can be improved using reference tables available in cookbooks concerning diabetes and online. During moderate-intensity exercise of 30 minutes or more, a predictable fall in blood sugar can be prevented by a reduction in the insulin dose prior to exercise or consideration of snacks taken during exercise.¹² Following a period of moderate- to high-intensity exercise, a delayed onset of hypoglycemia may occur up to 24 hours later, so adjustments in food and insulin may be warranted.¹² Finally, for individuals with HU who are at high risk for hypoglycemia, hypoglycemia should be avoided for three weeks in order to reverse HAAF.^11–13

Conclusions
Until a cure for diabetes is found, hypoglycemia will continue to be a major barrier to the achievement of long-term glucose control and will cause recurrent morbidity in individuals with diabetes. Numerous research studies have begun to uncover the mechanisms by which the CNS responds and adapts to hypoglycemia. Understanding these mechanisms will undoubtedly lead to better management and therapies that reduce the risk for hypoglycemia, while still allowing patients to achieve the benefits associated with tight glycemic control. Given this barrier of hypoglycemia for the treatment of diabetes, physicians should discuss hypoglycemia treatment and prevention strategies with their patients taking insulin so that they can have a better chance of achieving their glucose controls goals while avoiding the morbidity and mortality associated with hypoglycemia.