When blood glucose falls, the central nervous system (CNS) can utilize nonglucose substrates to a variable extent for its metabolic needs, especially keto acids and intermediates of glucose metabolism, such as lactate, pyruvate, fructose, and other hexoses. In the neonatal brain, which has a higher glycogen reserve, keto acids provide a considerable proportion of cerebral energy requirements; this also happens after prolonged starvation. However, in the face of severe and sustained hypoglycemia, these alternative substrates are inadequate to preserve the structural integrity of neurons, and eventually adenosine triphosphate (ATP) is depleted as well. If convulsions occur, they usually do so during a period of confusion; the convulsions have been attributed to an altered integrity of neuronal membranes and to elevated NH3 and depressed GABA and lactate levels (Wilkinson and Prockop).
The brain is the only organ besides the heart that suffers severe functional and structural impairment under conditions of severe hypoglycemia. Beyond what is described above, the pathophysiology of the cerebral disorder has not been fully elucidated. It is known that hypoglycemia reduces O2 uptake and increases cerebral blood flow. As with anoxia and ischemia, there is experimental evidence that the excitatory amino acid glutamate is involved in the process. The levels of several brain phospholipid fractions decrease when animals are given large doses of insulin. However, the suggestion that hypoglycemia results in a rapid depletion and inadequate production of high-energy phosphate compounds has not been corroborated; some other glucose-dependent biochemical processes must be implicated.
The most common causes of hypoglycemic encephalopathy are (1) accidental or deliberate overdose of insulin or an oral diabetic agent; (2) islet cell insulin-secreting tumor of the pancreas; (3) depletion of liver glycogen, which occasionally follows a prolonged alcoholic binge, starvation, or any form of severe liver failure; (4) glycogen storage disease of infancy; (5) an idiopathic hypoglycemia in the neonatal period and infancy; and (6) subacute and chronic hypoglycemia from islet cell hypertrophy and islet cell tumors of the pancreas, carcinoma of the stomach, fibrous mesothelioma, carcinoma of the cecum, and hepatoma. Purportedly, an insulin-like substance is elaborated by these nonpancreatic tumors. In the past, hypoglycemic encephalopathy was a not infrequent complication of “insulin shock” therapy for schizophrenia. In functional hyperinsulinism, as occurs in anorexia nervosa and dietary faddism, the hypoglycemia is rarely of sufficient severity or duration to damage the CNS.
The initial symptoms appear when the blood glucose has descended to about 30 mg/dL, nervousness, hunger, flushed facies, sweating, headache, palpitation, trembling, and anxiety. These gradually give way to confusion and drowsiness or occasionally, to excitement, overactivity, and bizarre or combative behavior. Many of the early symptoms relate to adrenal and sympathetic overactivity and some of the manifestations may be muted in diabetic patients with neuropathy. In the next stage, forced sucking, grasping, motor restlessness, muscular spasms, and decerebrate rigidity occur, in that sequence. Myoclonic twitching and convulsions develop in some patients. Rarely, there are focal cerebral deficits, the pathogenesis of which remains unexplained; according to Malouf and Brust, hemiplegia, corrected by intravenous glucose, was observed in 3 of 125 patients who presented with symptomatic hypoglycemia.