Skip to main content

Advertisement

SpringerLink
Log in

Neurological Counterparts of Hyponatremia: Pathological Mechanisms and Clinical Manifestations

  • Neurology of Systemic Diseases (J Biller, Section Editor)
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Hyponatremia, defined as a serum sodium concentration <135 mEq/L, represents the most frequent electrolyte disorder in older hospitalized patients. Early recognition of hyponatremia is mandatory, since it represents an independent risk factor that increases hospital mortality by 40 %. Delayed correction of hyponatremia may worsen brain edema, resulting in different degrees of neural damage. However, an overly rapid correction of serum sodium levels can lead to osmotic demyelination syndrome (ODS), a dreadful neurological picture. In recent years, hyponatremia and ODS have received growing attention both in terms of clinical management and pathophysiology, leading to the discovery of new drugs and treatment algorithms. In this review, we recapitulate the pathogenetic background, clinical manifestations, and treatment guidelines of hyponatremia, focusing on the neurological alterations. Neurological symptoms may be neglected when they manifest as early signs of mild hyponatremia, while brain damage can irremediably affect patients’ conditions in the context of ODS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Anderson RJ, Chung HM, Kluge R, et al. Hyponatremia: a prospective analysis of its epidemiology and the pathogenetic role of vasopressin. Ann Intern Med. 1985;102(2):164–8.

    Article  CAS  PubMed  Google Scholar 

  2. DeVita MV, Gardenswartz MH, Konecky A, et al. Incidence and etiology of hyponatremia in an intensive care unit. Clin Nephrol. 1990;34(4):163–6.

    CAS  PubMed  Google Scholar 

  3. Bennani SL, Abouqal R, Zeggwagh AA, et al. Incidence, causes and prognostic factors of hyponatremia in intensive care. Rev Med Interne. 2003;24(4):224–9.

    Article  PubMed  Google Scholar 

  4. Ayus JC, Achinger SG, Arieff A. Brain cell volume regulation in hyponatremia: role of sex, age, vasopressin, and hypoxia. Am J Physiol Ren Physiol. 2008;295(3):F619–24.

    Article  CAS  Google Scholar 

  5. Nase G, Helm PJ, Enger R, et al. Water entry into astrocytes during brain edema formation. Glia. 2008;56(8):895–902.

    Article  PubMed  Google Scholar 

  6. King JD, Rosner MH. Osmotic demyelination syndrome. Am J Med Sci. 2010;339(6):561–7.

    PubMed  Google Scholar 

  7. Nagelhus EA, Lehmann A, Ottersen OP. Neuronal-glial exchange of taurine during hypo-osmotic stress: a combined immunocytochemical and biochemical analysis in rat cerebellar cortex. Neuroscience. 1993;54(3):615–31.

    Article  CAS  PubMed  Google Scholar 

  8. Pasantes-Morales H, Vazquez-Juarez E. Transporters and channels in cytotoxic astrocyte swelling. Neurochem Res. 2012;37(11):2379–87.

    Article  CAS  PubMed  Google Scholar 

  9. Manley GT, Fujimura M, Ma T, et al. Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med. 2000;6(2):159–63.

    Article  CAS  PubMed  Google Scholar 

  10. Amiry-Moghaddam M, Xue R, Haug FM, et al. Alpha-syntrophin deletion removes the perivascular but not endothelial pool of aquaporin-4 at the blood–brain barrier and delays the development of brain edema in an experimental model of acute hyponatremia. FASEB J. 2004;18(3):542–4.

    CAS  PubMed  Google Scholar 

  11. Faraci FM, Mayhan WG, Heistad DD. Effect of vasopressin on production of cerebrospinal fluid: possible role of vasopressin (V1)-receptors. Am J Physiol. 1990;258(1 Pt 2):R94–8.

    CAS  PubMed  Google Scholar 

  12. Sterns RH, Silver SM. Brain volume regulation in response to hypo-osmolality and its correction. Am J Med. 2006;119(7 Suppl 1):S12–6.

    Article  CAS  PubMed  Google Scholar 

  13. Kim J, Jung Y. Increased aquaporin-1 and Na+ -K+ -2Cl-cotransporter 1 expression in choroid plexus leads to blood-cerebrospinal fluid barrier disruption and necrosis of hippocampal CA1 cells in acute rat models of hyponatremia. J Neurosci Res. 2012;90(7):1437–44.

    Article  CAS  PubMed  Google Scholar 

  14. Pasantes-Morales H, Franco R, Ordaz B, et al. Mechanisms counteracting swelling in brain cells during hyponatremia. Arch Med Res. 2002;33(3):237–44.

    Article  CAS  PubMed  Google Scholar 

  15. Jalonen T. Single-channel characteristics of the large-conductance anion channel in rat cortical astrocytes in primary culture. Glia. 1993;9(3):227–37.

    Article  CAS  PubMed  Google Scholar 

  16. Pasantes-Morales H, Morales MS. Influence of calcium on regulatory volume decrease: role of potassium channels. Nephron. 2000;86(4):414–27.

    Article  CAS  PubMed  Google Scholar 

  17. Sterns RH, Thomas DJ, Herndon RM. Brain dehydration and neurologic deterioration after rapid correction of hyponatremia. Kidney Int. 1989;35(1):69–75.

    Article  CAS  PubMed  Google Scholar 

  18. Lien YH, Shapiro JI, Chan L. Effects of hypernatremia on organic brain osmoles. J Clin Invest. 1990;85(5):1427–35.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Haskew-Layton RE, Rudkouskaya A, Jin Y, et al. Two distinct modes of hypoosmotic medium-induced release of excitatory amino acids and taurine in the rat brain in vivo. PLoS ONE. 2008;3(10):e3543.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Hyzinski-Garcia MC, Vincent MY, Haskew-Layton RE, et al. Hypo-osmotic swelling modifies glutamate-glutamine cycle in the cerebral cortex and in astrocyte cultures. J Neurochem. 2011;118(1):140–52. Hyzinski-Garcia et al. demonstrated that an hypo-osmotic medium causes the inhibition of glutamine synthetase in rat primary astrocyte culture. The glutamate-glutamine cycle disruption that follows may partially explain the neural hyperexcitability observed in hyponatremia.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Arundine M, Tymianski M. Molecular mechanisms of glutamate-dependent neurodegeneration in ischemia and traumatic brain injury. Cell Mol Life Sci. 2004;61(6):657–68.

    Article  CAS  PubMed  Google Scholar 

  22. Pasantes-Morales H, Tuz K. Volume changes in neurons: hyperexcitability and neuronal death. Contrib Nephrol. 2006;152:221–40.

    Article  CAS  PubMed  Google Scholar 

  23. Benvenuti S, Deledda C, Luciani P, et al. Low extracellular sodium causes neuronal distress independently of reduced osmolality in an experimental model of chronic hyponatremia. Neruomol Med. 2013;15(3):493–503. Benvenuti et al. reported the results of cell culture exposure to chronic hyponatremia at different osmolarity. The authors found that hyponatremia influenced cellular viability and stress through the alteration of pathways involved in cellular death and survival, in a fashion independent of reduced osmolarity. This original research paper may partially explain the detrimental effects of chronic hyponatremia, supporting the need of correction even in mild forms.

    Article  CAS  Google Scholar 

  24. Spasovski G, Vanholder R, Allolio B, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol. 2014;170(3):G1–47. Spasovski et al. compiled the most recent and comprehensive guidelines on hyponatremia diagnosis and treatment. These guidelines were developed by a joint venture of the European Society of Intensive Care Medicine (ESICM), the European Society of Endocrinology (ESE) and European Renal Best Practice (ERBP).

    Article  CAS  PubMed  Google Scholar 

  25. Sajadieh A, Binici Z, Mouridsen MR, et al. Mild hyponatremia carries a poor prognosis in community subjects. Am J Med. 2009;122(7):679–86.

    Article  PubMed  Google Scholar 

  26. Hoorn EJ, Zietse R. Hyponatremia and mortality: moving beyond associations. Am J Kidney Dis. 2013;62(1):139–49.

    Article  CAS  PubMed  Google Scholar 

  27. Gunathilake R, Oldmeadow C, McEvoy M, et al. Mild hyponatremia is associated with impaired cognition and falls in community-dwelling older persons. J Am Geriatr Soc. 2013;61(10):1838–9.

    PubMed  Google Scholar 

  28. Renneboog B, Musch W, Vandemergel X, et al. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med. 2006;119(1):71.e1–8.

  29. Wright WL. Sodium and fluid management in acute brain injury. Curr Neurol Neurosci Rep. 2012;12(4):466–73.

    Article  CAS  PubMed  Google Scholar 

  30. Ayus JC, Arieff AI. Brain damage and postoperative hyponatremia: the role of gender. Neurology. 1996;46(2):323–8.

    Article  CAS  PubMed  Google Scholar 

  31. Chawla A, Sterns RH, Nigwekar SU, et al. Mortality and serum sodium: do patients die from or with hyponatremia? Clin J Am Soc Nephrol. 2011;6(5):960–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Adams RD, Victor M, Mancall EL. Central pontine myelinolysis: a hitherto undescribed disease occurring in alcoholic and malnourished patients. AMA Arch Neurol Psychiatry. 1959;81(2):154–72.

    Article  CAS  PubMed  Google Scholar 

  33. Gankam Kengne F, Nicaise C, Soupart A, et al. Astrocytes are an early target in osmotic demyelination syndrome. J Am Soc Nephrol. 2011;22(10):1834–45. Kengne et al. explored the role of astrocytes damage in the development of ODS. They established a reliable model for the pathophysiology of ODS based on the crucial involvement of astrocytes apoptosis leading to an impairment of the trophic network between astrocytes and oligodendrocytes, subsequent inflammation, microglial reaction, and demyelination.

    Article  PubMed Central  PubMed  Google Scholar 

  34. Popescu BF, Bunyan RF, Guo Y, et al. Evidence of aquaporin involvement in human central pontine myelinolysis. Acta Neuropathol Commun. 2013;1(1):40.

    Article  PubMed Central  PubMed  Google Scholar 

  35. Norenberg MD. Central pontine myelinolysis: historical and mechanistic considerations. Metab Brain Dis. 2010;25(1):97–106.

    Article  PubMed  Google Scholar 

  36. Kleinschmidt-Demasters BK, Rojiani AM, Filley CM. Central and extrapontine myelinolysis: then…and now. J Neuropathol Exp Neurol. 2006;65(1):1–11.

    Article  CAS  PubMed  Google Scholar 

  37. Burg MB, Ferraris JD. Intracellular organic osmolytes: function and regulation. J Biol Chem. 2008;283(12):7309–13.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Orthmann-Murphy JL, Freidin M, Fischer E, et al. Two distinct heterotypic channels mediate gap junction coupling between astrocyte and oligodendrocyte connexins. J Neurosci. 2007;27(51):13949–57.

    Article  CAS  PubMed  Google Scholar 

  39. Rouach N, Koulakoff A, Abudara V, et al. Astroglial metabolic networks sustain hippocampal synaptic transmission. Science. 2008;322(5907):1551–5.

    Article  CAS  PubMed  Google Scholar 

  40. Murase T, Sugimura Y, Takefuji S, et al. Mechanisms and therapy of osmotic demyelination. Am J Med. 2006;119(7 Suppl 1):S69–73.

    Article  CAS  PubMed  Google Scholar 

  41. Baker EA, Tian Y, Adler S, et al. Blood–brain barrier disruption and complement activation in the brain following rapid correction of chronic hyponatremia. Exp Neurol. 2000;165(2):221–30.

    Article  CAS  PubMed  Google Scholar 

  42. Iwama S, Sugimura Y, Suzuki H, et al. Time-dependent changes in proinflammatory and neurotrophic responses of microglia and astrocytes in a rat model of osmotic demyelination syndrome. Glia. 2011;59(3):452–62. Iwama et. al investigated the role of microglia and astrocytes activation in an ODS animal model. They fully characterized the involvement of proinflammatory cytokines and neurotrophic factors secreted by microglia in the development of the brain damage in a time dependent manner. Their results suggested that the modulation of inflammatory glial reaction during the early phase of ODS might be effective in ODS treatment.

    Article  PubMed  Google Scholar 

  43. Gankam-Kengne F, Soupart A, Pochet R, et al. Minocycline protects against neurologic complications of rapid correction of hyponatremia. J Am Soc Nephrol. 2010;21(12):2099–108.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Martin RJ. Central pontine and extrapontine myelinolysis: the osmotic demyelination syndromes. J Neurol Neurosurg Psychiatry. 2004;75(Suppl 3):iii22–8.

    PubMed Central  PubMed  Google Scholar 

  45. Price BH, Mesulam MM. Behavioral manifestations of central pontine myelinolysis. Arch Neurol. 1987;44(6):671–3.

    Article  CAS  PubMed  Google Scholar 

  46. Tosaka M, Kohga H. Extrapontine myelinolysis and behavioral change after transsphenoidal pituitary surgery: case report. Neurosurgery. 1998;43(4):933–6.

    Article  CAS  PubMed  Google Scholar 

  47. Lee TM, Cheung CC, Lau EY, et al. Cognitive and emotional dysfunction after central pontine myelinolysis. Behav Neurol. 2003;14(3–4):103–7.

    Article  CAS  PubMed  Google Scholar 

  48. Chalela J, Kattah J. Catatonia due to central pontine and extrapontine myelinolysis: case report. J Neurol Neurosurg Psychiatry. 1999;67(5):692–3.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. van Zandvoort M, de Haan E, van Gijn J, et al. Cognitive functioning in patients with a small infarct in the brainstem. J Int Neuropsychol Soc. 2003;9(3):490–4.

    PubMed  Google Scholar 

  50. Vermetten E, Rutten SJ, Boon PJ, et al. Neuropsychiatric and neuropsychological manifestations of central pontine myelinolysis. Gen Hosp Psychiatry. 1999;21(4):296–302.

    Article  CAS  PubMed  Google Scholar 

  51. Menger H, Jorg J. Outcome of central pontine and extrapontine myelinolysis (n = 44). J Neurol. 1999;246(8):700–5.

    Article  CAS  PubMed  Google Scholar 

  52. Miller GM, Baker Jr HL, Okazaki H, et al. Central pontine myelinolysis and its imitators: MR findings. Radiology. 1988;168(3):795–802.

    Article  CAS  PubMed  Google Scholar 

  53. Nagler EV, Vanmassenhove J, van der Veer SN, et al. Diagnosis and treatment of hyponatraemia: a systematic review of clinical practice guidelines. Nephrol Dial Transplant. 2013;28:i385–91.

    Article  Google Scholar 

  54. Hsu YJ, Chiu JS, Lu KC, et al. Biochemical and etiological characteristics of acute hyponatremia in the emergency department. J Emerg Med. 2005;29(4):369–74.

    Article  PubMed  Google Scholar 

  55. Adrogue HJ, Madias NE. Hyponatremia. N Engl J Med. 2000;342(21):1581–9.

    Article  CAS  PubMed  Google Scholar 

  56. Ayus JC, Olivero JJ, Frommer JP. Rapid correction of severe hyponatremia with intravenous hypertonic saline solution. Am J Med. 1982;72(1):43–8.

    Article  CAS  PubMed  Google Scholar 

  57. Ellis SJ. Severe hyponatraemia: complications and treatment. QJM. 1995;88(12):905–9.

    CAS  PubMed  Google Scholar 

  58. Sterns RH, Nigwekar SU, Hix JK. The treatment of hyponatremia. Semin Nephrol. 2009;29(3):282–99.

    Article  CAS  PubMed  Google Scholar 

  59. Suzuki H, Sugimura Y, Iwama S, et al. Minocycline prevents osmotic demyelination syndrome by inhibiting the activation of microglia. J Am Soc Nephrol. 2010;21(12):2090–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Gankam Kengne F, Soupart A, Pochet R, et al. Re-induction of hyponatremia after rapid overcorrection of hyponatremia reduces mortality in rats. Kidney Int. 2009;76(6):614–21.

    Article  PubMed  Google Scholar 

  61. Takagi H, Sugimura Y, Suzuki H, et al. Minocycline prevents osmotic demyelination associated with aquaresis. Kidney Int. 2014;86(5):954–64. Takagi et al. demonstrated the protective effect of minocycline in a rat model of tolvaptan-induced hyponatremia rapid correction. Even though an overly rapid correction of sodium concentration through vasopressin blockage results in an increased risk of ODS, minocycline results effective in its prevention by inhibiting the activation of microglia. In addition, the authors found that AQP4 reflects the degree of CNS damage and may be a promising marker.

    Article  CAS  PubMed  Google Scholar 

  62. Sugimura Y, Murase T, Takefuji S, et al. Protective effect of dexamethasone on osmotic-induced demyelination in rats. Exp Neurol. 2005;192(1):178–83.

    Article  CAS  PubMed  Google Scholar 

  63. Bridgeford D, Arciniegas DB, Batkis M, et al. Methylphenidate treatment of neuropsychiatric symptoms of central and extrapontine myelinolysis. J Stud Alcohol. 2000;61(5):657–60.

    Article  CAS  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Manuel Alfredo Podestà, Irene Faravelli, David Cucchiari, Francesco Reggiani, Silvia Oldani, Carlo Fedeli, and Giorgio Graziani declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Nephrology and Dialysis Unit, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, Milano, Italy

    Manuel Alfredo Podestà, David Cucchiari, Francesco Reggiani & Giorgio Graziani

  2. Department of Pathophysiology and Transplantation (DEPT), Dino Ferrari Centre, Neuroscience Section, University of Milan, Neurology Unit, IRCCS Foundation Ca’Granda Ospedale Maggiore Policlinico, Milan, Italy

    Irene Faravelli

  3. Emergency Department, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, Milano, Italy

    Silvia Oldani & Carlo Fedeli

  4. Istituto Clinico Humanitas IRCCS, Via Manzoni 56, 20089, Rozzano, Milano, Italy

    Giorgio Graziani

Authors
  1. Manuel Alfredo Podestà
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Irene Faravelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David Cucchiari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Francesco Reggiani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Silvia Oldani
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carlo Fedeli
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Giorgio Graziani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Giorgio Graziani.

Additional information

Manuel Alfredo Podestà and Irene Faravelli contributed equally to this work.

This article is part of the Topical Collection on Neurology of Systemic Diseases

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Podestà, M.A., Faravelli, I., Cucchiari, D. et al. Neurological Counterparts of Hyponatremia: Pathological Mechanisms and Clinical Manifestations. Curr Neurol Neurosci Rep 15, 18 (2015). https://doi.org/10.1007/s11910-015-0536-2

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11910-015-0536-2

Keywords

Search

Navigation