Hypoglycaemia: brain neurochemistry and neuropathology.

The widespread use of insulin and oral hypoglycaemic agents has increased the incidence of hypoglycaemic brain damage due to accidental, suicidal, or homicidal overdose. Hypoglycaemia is capable of damaging the brain in the face of intact cardiac function, but neuronal necrosis occurs only when the electroencephalogram (EEG) becomes isoelectric. Neurochemical changes are distinct from ischaemia, and cerebral blood flow is actually increased, in contrast to cerebral ischaemia. Salient neurochemical changes include an arrest of protein synthesis in many but not all brain regions, a shift of brain redox equilibria towards oxidation, incomplete energy failure, loss of ion homeostasis, cellular calcium influx, intracellular alkalosis, and a release of neuroactive amino acids, especially aspartate, into the extracellular space of the brain. The metabolic release of aspartate, and to a lesser extent glutamate, into the interstitial space of the brain produces histopathological patterns of neuronal death that can be distinguished from ischaemic brain damage in experimental brain tissue and, occasionally, in brains from human autopsies after hypoglycaemic brain damage. The excitatory amino acids released during profound hypoglycaemia bind to neuronal dendrites and perikarya, but not to other cell types in the nervous system, thus giving rise to selective neuronal death. The absence of acidosis, and an adequate blood supply during hypoglycaemia, protect the brain against pan-necrosis or infarction. However, the neurons die more quickly during hypoglycaemic brain damage than after cerebral ischaemia. Hypoglycaemic brain damage thus falls into the newly defined class of cerebral 'excitotoxic' neuropathologies, where neurons are selectively killed by an extracellular overflow of excitatory amino acids produced by the brain itself. The pathogenesis of hypoglycaemic brain damage is thus rather more novel and intriguing than was thought even a decade ago, when it was believed that glucose starvation and simple energy failure resulted directly in neuronal catabolism.