Hypoglycemic Encephalopathy

Roger F Butterworth.
Correspondence to Roger F. Butterworth, Clinical Research Center, University of Montreal, Campus Saint-Luc, 1058 Rue Saint
Denis, Montreal, Quebec H2X 3J4, Canada.

Go to:
Hypoglycemia usually results from insulin overdose, hepatic disease resulting
in decreased hepatic gluconeogenesis or renal disease
Hypoglycemia is sometimes encountered in other medical conditions, such as malignancies
and chronic alcoholism. Early clinical signs in hypoglycemia reflect the appearance of
physiological protective mechanisms initiated by hypothalamic sensory nuclei [1]. Such
symptoms include sweating, also termed diaphoresis, tachycardia, anxiety and hunger. If
unheeded, these symptoms give way to a more serious CNS disorder progressing through
confusion, lethargy and delirium followed by seizures and coma. Prolonged hypoglycemia
may lead to irreversible brain damage.
During the progression of hypoglycemic encephalopathy, as blood glucose falls below 2.5
mM, a stage at which confusion and delirium occur, the cerebral metabolic rate for glucose
(CMRglc) falls more rapidly than does the cerebral metabolic rate for oxygen (CMRO2), a
finding which signifies the utilization of substrates other than glucose by the brain. Such
substrates include tricarboxylic acid cycle (TCA) intermediates as well as amino acids,
particularly glutamine and glutamate. However, these substrates are quickly used up and
support cerebral energy requirements for only a few minutes in the absence of glucose. As
blood glucose concentrations fall below 2 mM, the electroencephalogram (EEG) initially
shows increased amplitude and decreased frequency, followed by decreased amplitude and
frequency as blood glucose concentrations approach 1 mM. Below 1 mM blood glucose
concentrations, brain ATP levels become depleted [2] (Fig. 38-2), the EEG becomes
isoelectric and coma develops. Similar conclusions have been drawn from 31P nuclear
magnetic resonance spectroscopic experiments with brain slices, in which perfusion of guinea
pig slices in buffered medium containing various concentrations of glucose revealed that
lowering of glucose concentrations from 10 to 0.2 mM was necessary before the ATP and
phosphocreatine (PCr) contents of the slices were significantly reduced [3].

Figure 38-2
Neocortical concentrations of phosphocreatine (PCr) and ATP in rats subjected to graded
hypoglycemia. Samples of frozen neocortex were used for these measurements.
,
EEG non-isoelectric;

, EEG isoelectric for 3 min prior to freezing brain; , (more...)

Clinically, hypoglycemia results in depression of CNS function, with rostral brain regions
being affected before more caudally situated regions. For example, in severe hypoglycemia
associated with isoelectric EEG tracings, cerebral cortical activity is absent but medullary
function persists, as indicated by the maintenance of effective respiratory and cardiovascular
activity.
Go to:
Reduced synthesis of neurotransmitters rather than a global cerebral energy
deficit explains the neurological symptoms and EEG changes in moderate
hypoglycemia
Regional susceptibility to hypoglycemic insult is not reflected in selective regional changes in
glucose, glycolytic orTCA cycle intermediates, pyruvate, lactate or ATP. However, glucose
oxidation by the brain not only provides energy in the form of the anhydride bonds of ATP
but also provides precursors for the synthesis of some neurotransmitters, including
acetylcholine (ACh), -amino-butyric acid (GABA) and glutamate (Fig. 38-1). Most evidence
now suggests that the neurological symptoms characteristic of hypoglycemic encephalopathy
prior to isoelectric EEG stages result from neurotransmission failure involving one or more
of these neurotransmitter systems.
Pyruvate derived from glucose is the major precursor of the acetyl group of ACh (Fig. 38-1).
Inhibition of pyruvate oxidation results in reduced ACh synthesis both in vitro and in
vivo. Incorporation of [14C]choline into ACh in brain in vivo is decreased in rats with insulininduced hypoglycemia [4]. That hypoglycemia results in decreased synthesis of the
neurotransmitter pool of ACh is supported by the observation that administration of
the CNS cholinesterase inhibitor physostigmine to hypoglycemic animals delays the onset of
seizures and coma.
Similar findings of an adverse effect of hypoglycemia on the synthesis of the amino acid
neurotransmitters GABA and glutamate have also been reported. Utilization of amino acids
such as glutamate and glutamine as alternative energy substrates in moderate to severe
hypoglycemia results in accumulation of aspartate and ammonia in the brain [5].
Hypoglycemia also produces a transient but substantial increase in extracellular
concentrations of glutamate, GABA and dopamine, as measured using in vivo cerebral
microdialysis [6]. Alterations of neurotransmission mediated by ACh, glutamate, GABA
and/or dopamine (DA) could therefore contribute to the neurological signs and symptoms that
characterize moderate hypoglycemia.
As hypoglycemia progresses below 1mM, the EEG becomes isoelectric and neuronal cell
death ensues. As is the case in some other metabolic encephalopathies, cell death is not global
in distribution; rather, certain brain structures, in particular hippocampal and cortical
structures, are selectively vulnerable to hypoglycemic insult. Pathophysiological mechanisms
responsible for neuronal cell death in hypoglycemia include the involvement of glutamate
excitotoxicity. Severe and prolonged hypoglycemia results in increased release of glutamate

in the brain, leading to membrane depolarization. This is followed by cerebral energy failure
and neuronal cell death, particularly in the hippocampus. Glutamate neurotoxicity is thus
implicated in the pathogenesis of hypoglycemiainduced neuronal death, and Ca2+calmodulindependent protein kinase II appears to be one of the intracellular targets for glutamate
neurotoxicity in hypoglycemia [7].