Hypoglycemic brain damage

doi:10.1016/j.forsciint.2004.08.001

Forensic Science International

Volume 146, Issues 2–3, 16 December 2004, Pages 105-110

https://doi.org/10.1016/j.forsciint.2004.08.001 Get rights and content

Abstract

Hypoglycemia was long considered to kill neurons by depriving them of glucose. We now know that hypoglycemia kills neurons actively from without, rather than by starvation from within. Hypoglycemia only causes neuronal death when the EEG becomes flat. This usually occurs after glucose levels have fallen below 1 mM (18 mg/dl) for some period, depending on body glycogen reserves. At the time that abrupt brain energy failure occurs, the excitatory amino acid aspartate is massively released into the limited brain extracellular space and floods the excitatory amino acid receptors located on neuronal dendrites. Calcium fluxes occur and membrane breaks in the cell lead rapidly to neuronal necrosis. Significant neuronal necrosis occurs after 30 min of electrocerebral silence. Other neurochemical changes include energy depletion to roughly 25% of control, phospholipase and other enzyme activation, tissue alkalosis and a tendency for all cellular redox systems to shift towards oxidation. The neurochemistry of hypoglycemia thus differs markedly from ischemia. Hypoglycemia often differs from ischemia in its neuropathologic distribution, a phenomenon applicable in forensic practice. The border-zone distribution of global ischemia is not seen, necrosis of the dentate gyrus of the hippocampus can occur and a predilection for the superficial layers of the cortex is sometimes seen. Cerebellum and brainstem are universally spared in hypoglycemic brain damage. Hypoglycemia constitutes a unique metabolic brain insult.

Section snippets

Historical aspects of hypoglycemia

Manfred Sakel introduced hypoglycemia as a therapy in psychiatry [1], [2], publishing in the English literature in the late 1930s [3]. At that time, insulin was given to people for the treatment of schizophrenia and drug addiction. The desired period of coma, after some experience with this procedure, was 30 min, since, it was discovered, if the patient remained in coma for longer than 30 min coma would be transformed from a “reversible coma” to an “irreversible coma” [4], [5]. Our present day

The EEG in hypoglycemia

The electroencephalogram (EEG) is important in hypoglycemia because it determines the presence of brain damage. The EEG normally consists of waves in the alpha range of 8–13 Hz (α waves) and beta range of 13–25 Hz (β waves). Normally, the theta range of 4–8 Hz (θ waves) constitutes a very minor component of the EEG and delta activity in the range of 1–4 Hz (δ waves) is absent.

As the blood glucose levels progressively drop in hypoglycemia to the range of 1–2 mM, θ waves increase and coarse δ waves

Neurochemistry

Glycolytic flux through the Embden–Meyerhof pathway is obviously decreased in hypoglycaemia, contributing to a decreased cerebral metabolic rate for glucose (CMR_gl) [18]. Transamination reactions occur, and the aspartate–glutamate transaminase reaction is shifted to the left (Fig. 1).

Oxaloacetate increases due to the shortage of acetate with which it condenses to form citrate in the Krebs cycle. It is this primary increase in oxaloacetate that secondarily drives this reaction to the left,

Neuropathology

Once the EEG goes flat, neuronal necrosis appears over the ensuing minutes as aspartate floods the extracellular space [30]. These necrotic neurons can be stained with any acid histological stain, and the increased affinity for acid dyes will cause them to be acidophilic [31]. Since most histologic stains of the brain involve a pink or red acid dye, acidophilic neurons are invariably red in routinely stained tissue sections.

A conspicuous feature of hypoglycemic brain damage in the rat is

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Hypoglycemic brain damage

Abstract

Section snippets

Historical aspects of hypoglycemia

The EEG in hypoglycemia

Neurochemistry

Neuropathology

Brain Res.

Neue Behandlungsart Schizophreniker und verwirrter Erregter

Wien klin Wchnschr.

Schizophreniebehandlung mittels Insulin-Hypoglykämie sowie hypoglykämischen Schocks

Wien med Wchnschr.

The methodical use of hypoglycemia in the treatment of psychoses

Am. J. Psychiat.

Cerebral lesions in hypoglycemia. II. Some possibilities of irrevocable damage from insulin shock

Arch. Pathol.

Irreversible posthypoglycemic coma

Am. J. Med. Sci.

Hypoglycemic brain injury in the rat. Correlation of density of brain damage with the EEG isoelectric time: a quantitative study

Diabetes

Insulin coma therapy of schizophrenia: some critical remarks on Dr. Sakel's report

J. Ment. Sci.

Anatomische Befunde bei spontaner Hypoglykämie infolge multipler Pankreasinseladenome

Beitr z path Anat u allg Path.

Neurobehavioural deficit due to ischemic brain damage limited to half of the CA1 sector of the hippocampus

J. Neurosci.

Effect of severe hypoglycemia on the human brain

Acta Neurol. Scand.

The effect of pronounced hypoglycemia on monoamine metabolism in rat brain

Diabetes

Hypoglycemic brain injury. I. Metabolic and light microscopic findings in rat cerebral cortex during profound insulin-induced hypoglycemia and in the recovery period following glucose administration

Acta Neuropathol. (Berl.)

Influence of severe hypoglycemia on mitochondrial and plasma membrane function in rat brain

J. Neurochem.

Effect of insulin hypoglycemia upon cerebral energy metabolism and EEG activity in the rat

Brain Res.

Hypoglycemic brain injury: phospholipids, free fatty acids, and cyclic nucleotides in the cerebellum of the rat after 30 and 60 min of severe insulin-induced hypoglycemia

J. Cereb. Blood Flow Metab.

Hypoglycemic brain injury: metabolic and structural findings in rat cerebellar cortex during profound insulin-induced hypoglycemia and in the recovery period following glucose administration

J. Cereb. Blood Flow Metab.