Acta Neuropathologica

, Volume 64, Issue 3, pp 177–191 | Cite as

The distribution of hypoglycemic brain damage

  • R. N. Auer
  • T. Wieloch
  • Y. Olsson
  • B. K. Siesjö
Original Works


Rats were exposed to insulin-induced hypoglycemia resulting in periods of cerebral isoelectricity ranging from 10 to 60 min. After recovery with glucose, they were allowed to wake up and survive for 1 week. Control rats were recovered at the stage of EEG slowing. After sub-serial sectioning, the number and distribution of dying neurons was assessed in each brain region. Acid fuchsin was found to stain moribund neurons a brilliant red.

Brains from control rats showed no dying neurons. From 10 to 60 min of cerebral isoelectricity, the number of dying neurons per brain correlated positively with the number of minutes of cerebral isoelectricity up to the maximum examined period of 60 min.

Neuronal necrosis was found in the major brain regions vulnerable to several different insults. However, within each region the damage was not distributed as observed in ischemia.

A superficial to deep gradient in the density of neuronal necrosis was seen in the cerebral cortex. More severe damage revealed a gradient in relation to the subjacent white matter as well. The caudatoputamen was involved more heavily near the white matter, and in more severely affected animals near the angle of the lateral ventricle. The hippocampus showed dense neuronal necrosis at the crest of the dentate gyrus and a gradient of increasing selective neuronal necrosis medially in CA1. The CA3 zone, while relatively resistant, showed neuronal necrosis in relation to the lateral ventricle in animals with hydrocephalus. Sharp demarcations between normal and damaged neuropil were found in the hippocampus. The periventricular amygdaloid nuclei showed damage closest to the lateral ventricles. The cerebellum was affected first near the foramina of Luschka, with damage occurring over the hemispheres in more severely affected animals. Purkinje cells were affected first, but basket cells were damaged as well. Rare necrotic neurons were seen in brain stem nuclei. The spinal cord showed necrosis of neurons in all areas of the gray matter. Infarction was not seen in this study.

The possibility is discussed that a neurotoxic substance borne in the tissue fluid and cerebrospinal fluid (CSF) contributes to the pathogenesis of neuronal necrosis in hypoglycemic brain damage.

Key words

Hypoglycemia Cerebral damage Cerebrospinal fluid Interstitial fluid Neuronal necrosis 


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  1. 1.
    Abercombie M (1946) Estimation of nuclear population from microtome sections. Anat Rec 94:239–247Google Scholar
  2. 2.
    Agardh C-D, Folbergrová J, Siesjö BK (1978) Cerebral metabolic changes in profound, insulin-induced hypoglycemia and in the recovery period following glucose administration. J Neurochem 31:1135–1142Google Scholar
  3. 3.
    Agardh C-D, Kalimo H, Olsson Y, Siesjö BK (1980) 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) 50:31–41Google Scholar
  4. 4.
    Agardh C-D, Chapman AG, Nilsson B, Siesjö BK (1981) Endogenous substrates utilized by rat brain in severe insulin-induced hypoglycemia. J Neurochem 36:490–500Google Scholar
  5. 5.
    Agardh C-D, Kalimo H, Olsson Y, Siesjö BK (1981) 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 Cerebr Blood Flow Metabol 1:71–84Google Scholar
  6. 6.
    Andersen P, Bliss TVP, Skede KK (1971) Lamellar organization of hippocampal excitatory pathways. Exp Brain Res 13:222–238Google Scholar
  7. 7.
    Anderson JM, Milner RDG, Strich SJ (1966) Pathological changes in the nervous system in severe neonatal hypoglycemia. Lancet II:372Google Scholar
  8. 8.
    Auer RN, Fox AJ, Kaufmann JCE (1982) The histologic effect of intraventricular injection of Metrizamide. Arch Neurol 39:60–61Google Scholar
  9. 9.
    Auer RN, Olsson Y, Siesjö BK (1984) Hypoglycemic brain injury in the rat: Correlation of density of brain damage with the EEG isoelectric time. A quantitative study. Diabetes (in press)Google Scholar
  10. 10.
    Banker BQ (1967) The neuropathological effects of anoxia and hypoglycemia in the newborn. Dev Med Child Neurol 9:544–550Google Scholar
  11. 11.
    Blackstad TW, Brink K, Hem J, Jeune B (1970) Distribution of hippocampal mossy fibers in the rat. An experimental study with silver impregnation methods. J Comp Neurol 138:433–450Google Scholar
  12. 12.
    Bradbury MW (1979) The concept of the blood brain barrier. Wiley, Chichester New York Brisbane TorontoGoogle Scholar
  13. 13.
    Bradbury MWB, Cserr HF, Westrop RJ (1981) Drainage of cerebral interstitial fluid into deep cervical lymph of the rabbit. Am J Physiol 240:F329-F336Google Scholar
  14. 14.
    Bradbury MWB, Westrop RJ (1983) Factors influencing exit of substances from cerebrospinal fluid into deep lymph of the rabbit. J Physiol (Lond) 339:519–534Google Scholar
  15. 15.
    Brierley JB, Brown AW, Meldrum BS (1971) The nature and time course of the neuronal alterations resulting from oligemia and hypoglycemia in the brain ofMacaca mulatta. Brain Res 25:483–499Google Scholar
  16. 16.
    Brierley JB (1976) Cerebral hypoxia. In: Blackwood W, Corsellis JAN (eds) Greenfield's neuropathology, 3rd edn, Chapt 2, Arnold, London, pp 43–85Google Scholar
  17. 17.
    Brightman MW (1965) The distribution within the brain of ferritin injected into cerebrospinal fluid compartments. Am J Anat 117:193–220Google Scholar
  18. 18.
    Brightman MW (1968) The intracerebral movement of proteins injected into blood and cerebrospinal fluid of mice. Prog Brain Res 29:19–40Google Scholar
  19. 19.
    Cammermeyer J (1938) Über Gehirnveränderungen, entstanden unter Sakel'scher Insulintherapie bei einem Schizophrenen. Z Gesamte Neurol Psychiatr 163:617–633Google Scholar
  20. 20.
    Casley-Smith JR, Földi-Börcsök E, Földi M (1976) The prelymphatic pathways of the brain as revealed by cervical lymphatic obstruction and the passage of particles. Br J Exp Pathol 57:179–188Google Scholar
  21. 21.
    Chii E, Wilmes F, Sotelo JE, Horie R, Fujiwara K, Suzuki R, Klatzo I (1981) Immunocytochemical studies on extravasation of serum proteins in cerebrovascular disorders. Cerebral microcirculation and metabolism. Raven Press, New York, pp 121–127Google Scholar
  22. 22.
    Courville CB (1957) Late cerebral changes incident to severe hypoglycemia (insulin shock): Their relation to cerebral anoxia. Arch Neurol Psychiatry 78:1–14Google Scholar
  23. 23.
    Coyle P (1978) Spatial features of the rat hippocampal vascular system. Exp Neurol 58:549–561Google Scholar
  24. 24.
    Coyle JT (1983) Neurotoxic action of kainic acid. J Neurochem 4:1–11Google Scholar
  25. 25.
    Cserr HF, Cooper DN, Milhorat TH (1977) Flow of cerebral interstitial fluid as indicated by the removal of extracellular markers from rat caudate nucleus. Exp Eye Res [Suppl] 25:461–473Google Scholar
  26. 26.
    Cserr HF, Cooper DN, Suri PK, Patlak CS (1981) Efflux of radiolabeled polyethylene glycols and albumin from rat brain. Am J Physiol 240:F319-F328Google Scholar
  27. 27.
    Erzurumlu RS, Rose G, Lynch GS, Killackey HP (1981) Selective uptake and anterograde transport of horseradish peroxidase by hippocampal granule cells. Neuroscience 6:897–902Google Scholar
  28. 28.
    Fenstermacher JD, Bradbury MWB, duBoulay G Kendall BE, Radu EW (1980) The distribution of125I-diatrizoate between blood, brain and cerebrospinal fluid in the rabbit. Neuroradiology 19:171–180Google Scholar
  29. 29.
    Finley KH, Brenner C (1941) Histologic evidence of damage to the brain in monkeys treated with Metrazol and insulin. Arch Neurol Psychiatry 45:403–438Google Scholar
  30. 30.
    Folbergrová J, MacMillan V, Siesjö BK (1972) The effect of moderate and marked hypercapnia upon the energy state and upon cytoplasmic NADH/NAD+ ratio of the brain. J Neurochem 19:2497–2505Google Scholar
  31. 31.
    Gaarskjaer FB (1981) The hippocampal mossy fiber system of the rat studied with retrograde tracing techniques. Correlation between topographic organization and neurogenetic gradients. J Comp Neurol 203:717–735Google Scholar
  32. 32.
    Graybiel AM, Ragsdale CW, Jr (1983) Biochemical anatomy of the striatum. In: Emson PC (ed) Chemical neuroanatomy. Raven Press, New York, pp 427–504Google Scholar
  33. 33.
    Grayzel DM (1934) Changes in the central nervous system due to convulsions due to hyperinsulinism. Arch Int Med 54:694–701Google Scholar
  34. 34.
    Harris RJ, Wieloch T, Symon L, Siesjö BK (1984) Cerebral extracellular calcium activity in severe hypoglycemia: Relation to extracellular potassium and energy state. J Cerebr Blood Flow Metabol 4:187–193Google Scholar
  35. 35.
    Hirano A, Zimmermann HM, Levine S (1967) Fine structure of cerebral fluid accumulation. In: Klatzo I, Seitelberger F (eds) Brain edema. Springer, New York, pp 569–589Google Scholar
  36. 36.
    Hjorth-Simonson A, Jeune B (1972) Origin and termination of the hippocampal perforant path in the rat studied by silver impregnation. J Comp Neurol 144:215–232Google Scholar
  37. 37.
    Ito U, Spatz M, Walker JT, Jr, Klatzo I (1975) Experimental cerebral ischemia in Mongolian gerbils. I. Light-microscopic observations. Acta Neuropathol (Berl) 32:209–223Google Scholar
  38. 38.
    Jones EL, Smith WT (1971) Hypoglycaemic brain damage in the neonatal rat. In: Brierley JB, Meldrum BS (eds) Brain hypoxia, chapt 23. Heinemann, London, pp 231–241Google Scholar
  39. 39.
    Kalimo H, Olsson Y (1980) Effect of severe hypoglycemia on the human brain. Acta Neurol Scand 62:345–356Google Scholar
  40. 40.
    Kastein GW (1938) Insulinvergiftung. II. Neurologische und anatomisch-histologische Beschreibung. Z. Gesamte Neurol Psychiatr 163:342–361Google Scholar
  41. 41.
    Kiessling M, Weigel K, Gartzen D, Kleihues P (1982) Regional heterogeneity ofl-(3-3H) tyrosine incorporation into rat brain proteins during severe hypoglycemia. J Cerebr Blood Flow Metabol 2:249–253Google Scholar
  42. 42.
    Kirino T, Sano K (1984) Selective vulnerability in the gerbil hippocampus following transient ischemia. Acta Neuropathol (Berl) 62:201–208Google Scholar
  43. 43.
    Klatzo I, Wisniewski H, Steinwall O, Streicher E (1967) Dynamics of cold injury edema. In: Klatzo I, Seitelberger F (eds) Brain edema. Springer, New York, pp 554–563Google Scholar
  44. 44.
    Lawrence RD, Meyer R, Nevin S (1942) The pathological changes in the brain in fatal hypoglycemia. Q J Med 11:181–201Google Scholar
  45. 45.
    Lee JC, Olszewski J (1960) Penetration of radioactive bovine albumin from cerebrospinal fluid into brain tissue. Neurology 10:814–822Google Scholar
  46. 46.
    Leppien R, Peters G (1937) Todesfall infolge Insulinschockbehandlung bei einem Schizophrenen. Z Gesamte Psychiatr 160: 444–454Google Scholar
  47. 47.
    Milhorat TH, Clark RG, Hammock MK, McGrath PP (1970) Structural, ultrastructural, and permeability changes in the ependyma and surrounding brain favoring equilibration in progressive hydrocephalus. Arch Neurol 22:397–407Google Scholar
  48. 48.
    Moersch FP, Kernohan JW (1938) Hypoglycemia and neuropathologic studies. Acta Neurol Psychiatry 39:242–257Google Scholar
  49. 49.
    Myers RE, Kahn KJ (1971) Insulin-induced hypoglycemia in the non-human primate. II. Long-term neuropathological consequences. In: Brierley JB, Meldrum BS (eds) Brain hypoxia, chapt 20. Heinemann, London, pp 195–206Google Scholar
  50. 50.
    Nadler JV, Evenson DA, Cuthbertson GJ (1981) Comparative toxicity of kainic acid and other acidic amino acids toward rat hippocampal neurons. Neuroscience 6:2505–2517Google Scholar
  51. 51.
    Norberg K, Siesjö BK (1976) Oxidative metabolism of the cerebral cortex of the rat in severe insulin induced hypoglycemia. J Neurochem 26:345–352Google Scholar
  52. 52.
    Paxinos G, Watson C (1982) The rat brain in stereotaxic coordinates. Academic Press, Sydney New York Paris San Diego San Francisco Sao Paulo Tokyo TorontoGoogle Scholar
  53. 53.
    Pelligrino D, Almquist L-O, Siesjö BK (1981) Effects of insulin-induced hypoglycemia on intracellular pH and impedance in the cerebral cortex of the rat. Brain Res 221:129–147Google Scholar
  54. 54.
    Pulsinelli WA, Brierley JB, Plum F (1982) Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol 11:491–498Google Scholar
  55. 55.
    Ratcheson R, Blank AC, Ferrendelli JA (1981) Regionally selective metabolic effects of hypoglycemia in brain. J Neurochem 36:1952–1958Google Scholar
  56. 56.
    Rosenberg GA, Kyner WT, Estrada E (1980) Bulk flow of brain interstitial fluid under normal and hyperosmolar conditions. Am J Physiol 238:F42-F49Google Scholar
  57. 57.
    Schwarcz R, Scholz D, Coyle JT (1978) Structure-activity relations for the neurotoxicity of kainic acid derivatives and glutamate analogues. Neuropharmacology 17:145–151Google Scholar
  58. 58.
    Shapiro WR, Chernik NL, Posner JB (1973) Necrotizing encephalopathy following intraventricular instillation of methotrexate. Arch Neurol 28:96–102Google Scholar
  59. 59.
    Siesjö BK (1981) Cell damage in the brain: A speculative synthesis. J Cerebr Blood Flow Metabol 1:155–185Google Scholar
  60. 60.
    Siesjö BK, Wiesloch T (1984) Brain injury: Neurochemical aspects. In: Povlischock I, Becker D (eds) Central nervous system trauma — status report. William Byrd Press, Inc, Richmond, USAGoogle Scholar
  61. 61.
    Silfverskiöld BP (1946) Polyneuritis hypoglycemia. Late peripheral paresis after hypoglycemic attacks in two insulinoma patients. Acta Med Scand 125:502–504Google Scholar
  62. 62.
    Smith M-L, Auer RN, Siesjö BK (1984) Neuronal damage in the rat brain following 2–10 min of forebrain ischemia. Acta Neuropathol (Berl) (in press)Google Scholar
  63. 63.
    Spielmeyer W (1925) Zur Pathogenese örtlicher elektiver Gehirnveränderungen. Z Gesamte Neurol Psychiatr 99:756–776Google Scholar
  64. 64.
    Stern J, Hochwald GM, Wald A, Gandhi M (1977) Visualization of brain interstitial fluid movement during osmotic disequilibrium. Exp Eye Res [Suppl] 25:475–482Google Scholar
  65. 65.
    Stief S, Tokay L (1932) Beitrag zur Histopathologie der experimentellen Insulinvergiftung. Z Gesamte Neurol Psychiatr 139: 434–461Google Scholar
  66. 66.
    Stief A, Tokay L (1935) Weitere experimentelle Untersuchungen über die cerebrale Wirkung des Insulins. Z Gesamte Psychiatr 153:561–572Google Scholar
  67. 67.
    Suzuki R, Yamaguchi T, Kirino T, Orzi F, Klatzo I (1983) The effects of 5-minute ischemia in Mongolian gerbils. I. Blood-brain barrier, cerebral blood flow, and local cerebral glucose utilization changes. Acta Neuropathol (Berl) 60:207–216Google Scholar
  68. 68.
    Suzuki R, Yamaguchi T, Li C-L, Klatzo I (1983) The effects of 5-minute ischemia in Mongolian gerbils. II. Changes of spontaneous neuronal activity in the cerebral cortex and CA1 sector of the hippocampus. Acta Neuropathol (Berl) 60:217–222Google Scholar
  69. 69.
    Tannenberg J (1939) Comparative experimental studies on symptomatology and anatomical changes produced by anoxic and insulin shock. Proc Soc Exp Biol Med 40:94–96Google Scholar
  70. 70.
    Tom MI, Richardson JC (1951) Hypoglycemia from islet cell tumor of pancreas with amyotrophy and cerebrospinal nerve cell changes. J Neuropathol Exp Neurol 10:57–66Google Scholar
  71. 71.
    Vogt C, Vogt O (1937) Sitz und Wesen der Krankheiten im Lichte der topistischen Hirnforschung und des Variierens der Tiere. J Psychol Neurol 47:237–457Google Scholar
  72. 72.
    Weil A, Liebert E, Heilbrunn G (1938) Histopathologic changes in the brain in experimental hyperinsulinism. Arch Neurol Psychiatry 39:467–481Google Scholar
  73. 73.
    Wieloch T, Harris RJ, Symon L, Siesjö BK (1984) Influence of severe hypoglycemia on brain extracellular calcium and potassium activities, energy and phospholipid metabolism. J Neurochem 43:160–168Google Scholar
  74. 74.
    Winkelman NW, Moore MT (1940) Neurohistopathologic changes with metrazol and insulin shock therapy. Arch Neurol Psychiatry 43:1108–1137Google Scholar
  75. 75.
    Zelman IB, Wierzba-Bobrowicz T (1980) Structural picture of brain damage in the rat in relation to insulin-induced hypoglycemia. Neuropatol Pol 18:301–311Google Scholar
  76. 76.
    Zimmer J (1971) Ipsilateral afferents to the commissural zone of the fascia dentata, demonstrated in decommissurated rats by silver impregnation. J Comp Neurol 142:393–416Google Scholar

Copyright information

© Springer-Verlag 1984

Authors and Affiliations

  • R. N. Auer
    • 1
  • T. Wieloch
    • 1
  • Y. Olsson
    • 2
  • B. K. Siesjö
    • 1
  1. 1.Laboratory of Experimental Brain ResearchUniversity HospitalLundSweden
  2. 2.Neuropathology Laboratory, Dept. of PathologyUniversity of UppsalaUppsalaSweden

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