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Nicaise C, Marneffe C, Bouchat J, Gilloteaux J. Osmotic Demyelination: From an Oligodendrocyte to an Astrocyte Perspective. Int J Mol Sci 2019; 20:E1124. [PMID: 30841618 PMCID: PMC6429405 DOI: 10.3390/ijms20051124] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 02/26/2019] [Accepted: 02/27/2019] [Indexed: 12/15/2022] Open
Abstract
Osmotic demyelination syndrome (ODS) is a disorder of the central myelin that is often associated with a precipitous rise of serum sodium. Remarkably, while the myelin and oligodendrocytes of specific brain areas degenerate during the disease, neighboring neurons and axons appear unspoiled, and neuroinflammation appears only once demyelination is well established. In addition to blood‒brain barrier breakdown and microglia activation, astrocyte death is among one of the earliest events during ODS pathology. This review will focus on various aspects of biochemical, molecular and cellular aspects of oligodendrocyte and astrocyte changes in ODS-susceptible brain regions, with an emphasis on the crosstalk between those two glial cells. Emerging evidence pointing to the initiating role of astrocytes in region-specific degeneration are discussed.
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Affiliation(s)
| | - Catherine Marneffe
- Laboratory of Glia Biology (VIB-KU Leuven Center for Brain & Disease Research), Department of Neuroscience, KU Leuven, 3000 Leuven, Belgium.
| | - Joanna Bouchat
- URPhyM-NARILIS, Université de Namur, 5000 Namur, Belgium.
| | - Jacques Gilloteaux
- URPhyM-NARILIS, Université de Namur, 5000 Namur, Belgium.
- Department of Anatomical Sciences, St George's University School of Medicine, Newcastle upon Tyne NE1 8ST, UK.
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Abstract
The osmotic demyelination syndrome (ODS) has been a recognized complication of the rapid correction of hyponatremia for decades. However, in recent years, a variety of other medical conditions have been associated with the development of ODS, independent of changes in serum sodium. This finding suggests that the pathogenesis of ODS may be more complex and involve the inability of brain cells to respond to rapid changes in osmolality of the interstitial (extracellular) compartment of the brain, leading to dehydration of energy-depleted cells with subsequent axonal damage that occurs in characteristic areas. Features of the syndrome include quadriparesis and neurocognitive changes in the presence of characteristic lesions found on magnetic resonance imaging of the brain. Although slow correction of hyponatremia seems to be the best way to prevent development of the syndrome, there are new data that suggest reintroduction of hyponatremia in those patients who have undergone inadvertent rapid correction of the serum sodium and corticosteroids may play a role in prevention of ODS.
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Norenberg MD. Central pontine myelinolysis: historical and mechanistic considerations. Metab Brain Dis 2010; 25:97-106. [PMID: 20182780 DOI: 10.1007/s11011-010-9175-0] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2009] [Accepted: 01/28/2010] [Indexed: 02/06/2023]
Abstract
Central pontine myelinolysis (CPM) is a demyelinating condition affecting not only the pontine base, but also involving other brain areas. It usually occurs on a background of chronic systemic illness, and is commonly observed in individuals with alcoholism, malnutrition and liver disease. Studies carried out 25-30 years ago established that the principal etiological factor was the rapid correction of hyponatremia resulting in osmotic stress. This article reviews progress achieved since that time on its pathogenesis, focusing on the role of organic osmolytes, the blood-brain, barrier, endothelial cells, myelinotoxic factors triggered by osmotic stress, and the role of various factors that predispose to the development of CPM. These advances show great promise in providing novel therapeutic options for the management of patients afflicted with CPM.
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Affiliation(s)
- Michael D Norenberg
- Departments of Pathology, University of Miami School of Medicine, PO Box 016960, Miami, FL 33101, USA.
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Re-induction of hyponatremia after rapid overcorrection of hyponatremia reduces mortality in rats. Kidney Int 2009; 76:614-21. [DOI: 10.1038/ki.2009.254] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Kleinschmidt-Demasters BK, Rojiani AM, Filley CM. Central and Extrapontine Myelinolysis: Then…and Now. J Neuropathol Exp Neurol 2006; 65:1-11. [PMID: 16410743 DOI: 10.1097/01.jnen.0000196131.72302.68] [Citation(s) in RCA: 106] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
In this review, we emphasize neuropathologic and neurobehavioral aspects of central pontine and extrapontine myelinolysis (CPM/EPM), also known as the osmotic demyelination syndrome. The literature is reviewed from the time of the initial report in 1959 and from key developments that have occurred more recently. Particular consideration is given to pathogenic mechanisms as revealed by recent animal studies. The role of white matter pathology in neurobehavioral dysfunction is also considered. The "then" and "now" of CPM and EPM tell 2 different stories. Yet, in many respects, this expansion of information over the past nearly 50 years simply represents a continuum, as well as recognition, of the vast gaps that still persist in our understanding of this disorder.
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Sugimura Y, Murase T, Takefuji S, Hayasaka S, Takagishi Y, Oiso Y, Murata Y. Protective effect of dexamethasone on osmotic-induced demyelination in rats. Exp Neurol 2005; 192:178-83. [PMID: 15698632 DOI: 10.1016/j.expneurol.2004.10.018] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2004] [Revised: 10/08/2004] [Accepted: 10/20/2004] [Indexed: 12/17/2022]
Abstract
Central pontine myelinolysis (CPM) is a serious demyelination disease commonly associated with the rapid correction of hyponatremia. Although its pathogenesis remains unclear, the disruption of the blood-brain barrier (BBB) as a consequence of a rapid increase in serum sodium concentration is considered to play a critical role. Since glucocorticoids are known to influence BBB permeability and prevent its disruption as a result of hypertension or hyperosmolarity, we investigated whether dexamethasone (DEX) could protect against osmotic demyelination in an animal model of CPM. Hyponatremia was induced in rats by liquid diet feeding and dDAVP infusion. Seven days later, the animals' hyponatremia was rapidly corrected by injecting a bolus of hypertonic saline intraperitoneally. Rats subjected to this treatment displayed serious neurological impairment and 77% died within 5 days of rapid correction of their hyponatremia; demyelinative lesions were observed in various brain regions in these animals. On the other hand, rats that were treated with DEX (2 mg/kg, 0 and 6 h after hypertonic saline injection) exhibited minimal neurological impairment and all were alive after 5 days. Demyelinative lesions were rarely seen in the brains of DEX-treated rats. A marked extravasation of endogenous IgG was observed in the demyelinative lesions in the brains of rats that did not receive DEX, indicating disruption of the BBB, but was not observed in DEX-treated rats. Furthermore, Evans blue injection revealed a significant reduction in staining in the brains of DEX-treated rats (P < 0.05). These results indicate that early DEX treatment can prevent the BBB disruption that is caused by the rapid correction of hyponatremia and its associative demyelinative changes, and suggest that DEX might be effective in preventing CPM.
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Affiliation(s)
- Yoshihisa Sugimura
- Department of Teratology and Genetics, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
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Yu J, Zheng SS, Liang TB, Shen Y, Wang WL, Ke QH. Possible causes of central pontine myelinolysis after liver transplantation. World J Gastroenterol 2004; 10:2540-3. [PMID: 15300900 PMCID: PMC4572157 DOI: 10.3748/wjg.v10.i17.2540] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To sum up the clinical characteristics of patients with central pontine myelinolysis (CPM) after orthotopic liver transplantation (OLT) and to document the possible causes of CPM.
METHODS: Data of 142 patients undergoing OLT between January 1999 to May 2003 were analyzed retrospectively. Following risk factors during perioperation were analyzed in patients with and without CPM: primary liver disease, preoperative serum sodium level, magnesium level and plasma osmolality, fluctuation degree of serum sodium concentration, and immunosuppressive drug level, etc.
RESULTS: A total of 13 (9.2%) neurologic symptoms appeared in 142 patients post-operation including 5 cases (3.5%) with CPM and 8 cases (5.6%) with cerebral hemorrhage or infarct. Two patients developing CPM after OLT had a hyponatremia history before operation (serum sodium < 130 mmol/L), their mean serum sodium level was 130.6 ± 5.54 mmol/L. The serum sodium level was significantly lower in CPM patients than in patients without neurologic complications or with cerebral hemorrhage/infarct (P < 0.05).The increase in serum sodiumduring perioperative 48 h after OLT in patients with CPM was significantly greater than that in patients with cerebral hemorrhage/infarct but without neurologic complications (19.5 ± 6.54 mmol/L, 10.1 ± 6.43 mmol/L, 4.5 ± 4.34 mmol/L, respectively, P < 0.05). Plasma osmolality was greatly increased postoperation in patients with CPM. Hypomagnesemia was noted in all patients perioperation, but there were no significant differences between groups. The duration of operation on patients with CPM was longer than that on others (492 ± 190.05 min, P < 0.05). Cyclosporin A (CsA) levels were normal in all patients, but there were significant differences between patients with or without neurologic complications (P < 0.05).
CONCLUSION: CPM may be more prevalent following liver transplantation. Although the diagnosis of CPM after OLT can be made by overall neurologic evaluations including magnetic resonance imaging (MRI) of the head, the mortality is still very high. The occurance of CPM may be associated with such factors as hyponatremia, rapid rise of serum sodium concentration, plasma osmolality increase postoperation, the duration of operation, and high CsA levels.
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Affiliation(s)
- Jun Yu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital, Medical School of Zhejiang University,Hangzhou 310003, Zhejiang Province, China
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Lin SH, Chau T, Wu CC, Yang SS. Osmotic demyelination syndrome after correction of chronic hyponatremia with normal saline. Am J Med Sci 2002; 323:259-262. [PMID: 12018668 DOI: 10.1097/00000441-200205000-00005] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Rapid correction of severe chronic hyponatremia with hypertonic saline has been known to cause osmotic demyelination syndrome (ODS). Less recognized are the dangers of rapid correction with normal saline. A 60-year-old woman on thiazide diuretics for hypertension presented with profound hyponatremia (94 mmol/L) and hypokalemia (1.9 mmol/L) associated with volume depletion. Normal saline (2 L/day) and (KCl 40 mmol/day) were given for 5 days. Serum Na+ concentration rose to 106 mmol/L within 18 hours. With improvement of her hyponatremia, she became more alert although the hypokalemia persisted. However, she developed progressive obtundation, quadriplegia, and respiratory failure 6 days later. Magnetic resonance imaging of the brain clearly showed typical features of pontine and extrapontine myelinolysis. We suggest that the aggressive KCl supplement would have been the first-line therapy for this patient presenting with chronic hyponatremia and hypokalemia associated with volume depletion.
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Affiliation(s)
- Shih-Hua Lin
- Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China.
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Affiliation(s)
- P Gross
- Universitätsklinikum Carl Gustav Carus, Dresden, Federal Republic of Germany.
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Tabarki B, Durand P, Husson B, Loiseau-Corvez MN, Tardieu M. [Central pontine myelinolysis: apropos of 2 case in children]. Arch Pediatr 1997; 4:645-9. [PMID: 9295902 DOI: 10.1016/s0929-693x(97)83364-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Central pontine myelinolysis has been rarely reported in children. This report concerns two children, aged 4 1/2 years. CASE REPORTS The main clinical features were altered level of consciousness, tetraplegia and signs of brain stem dysfunctions. In both cases, magnetic resonance imaging (MRI) revealed hypersignal of protuberance in association with cerebellar lesion in one case and occipital lesion in the other, compatible with central and extrapontine myelinolysis. No underlying disease or electrolytic disorders was identified. Clinical outcome was good. Mental status was normal after 9 months for patient one and 4 months for patient two. The MRI abnormality was reduced at 9-month follow-up in patient two and unchanged at 4 months in patient one. CONCLUSION The incidence of central pontine myelinolysis is probably underestimated in children. MRI allows a greater sensitivity in identifying areas of focal demyelination where diagnosis was previously only established by post mortem studies.
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Affiliation(s)
- B Tabarki
- Service de neurologie, hôpital de Bicêtre, Le Kremlin-Bicêtre, France
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Mattson LR, Lindor NM, Goldman DH, Goodwin JT, Groover RV, Vockley J. Central pontine myelinolysis as a complication of partial ornithine carbamoyl transferase deficiency. AMERICAN JOURNAL OF MEDICAL GENETICS 1995; 60:210-3. [PMID: 7573173 DOI: 10.1002/ajmg.1320600308] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Central pontine myelinolysis (CPM) is a demyelinating condition of the central pons with or without associated foci of demyelination in extrapontine areas. We present a case of partial ornithine carbamoyl transferase deficiency in a 5-year-old girl which was complicated by CPM. The patient was a previously undiagnosed girl who presented with mild hyperammonemic encephalopathy with a maximum plasma ammonia level of 376 microM on admission. Laboratory testing established the diagnosis of OCT deficiency, and therapy with hydration and protein restriction was successful in returning the plasma ammonia levels to normal. Five days after correction of her hyperammonemia, the patient developed intractable seizures and coma. Serial MRI scans of the brain revealed the evolution of the characteristic findings of CPM. Plasma ammonia and electrolyte concentrations were well controlled throughout this time. This represents the first description of CPM in a patient with a urea cycle defect.
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Affiliation(s)
- L R Mattson
- Department of Medical Genetics, Mayo Clinic, Rochester, MN 55905, USA
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Videen JS, Michaelis T, Pinto P, Ross BD. Human cerebral osmolytes during chronic hyponatremia. A proton magnetic resonance spectroscopy study. J Clin Invest 1995; 95:788-93. [PMID: 7860762 PMCID: PMC295555 DOI: 10.1172/jci117728] [Citation(s) in RCA: 149] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
The pathogenesis of morbidity associated with hyponatremia is postulated to be determined by the state of intracellular cerebral osmolytes. Previously inaccessible, these metabolites can now be quantitated by proton magnetic resonance spectroscopy. An in vivo quantitative assay of osmolytes was performed in 12 chronic hyponatremic patients (mean serum sodium 120 meq/liter) and 10 normal controls. Short echo time proton magnetic resonance spectroscopy of occipital gray and parietal white matter locations revealed dramatic reduction in the concentrations of several metabolites. In gray matter, myo-inositol was most profoundly reduced at 49% of control value. Choline containing compounds were reduced 36%, creatine/phosphocreatine 19%, and N-acetylaspartate 11% from controls. Similar changes were found in white matter. Recovery of osmolyte concentrations was demonstrated in four patients studied 8-14 wk later. These results are consistent with a reversible osmolyte reduction under hypoosmolar stress in the intact human brain and offer novel suggestions for treatment and monitoring of this common clinical event.
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Affiliation(s)
- J S Videen
- Magnetic Resonance Spectroscopy Unit, Huntington Medical Research Institutes, Pasadena, California 91105
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Abstract
Hyponatremia is a relatively common medical disorder frequently of endocrinologic origin. Although the neurologic signs and symptoms associated with hyponatremia are well known, recent clinical and experimental studies have shown that rapid correction of hyponatremia can in some cases cause a brain-demyelinating disease that can lead to consequences just as severe as those of hyponatremia itself. Understanding the physiologic mechanisms by which the brain adapts to hypoosmolar conditions has led to a better appreciation of the pathogenesis of neurologic dysfunction during both hyponatremia and its therapy, and this in turn has allowed the establishment of rational guidelines for safe therapy of hyponatremic patients. In cases such as this, however, in which a spontaneous rapid water diuresis occurs following a change in hormonal therapy, the rate and magnitude of the increase in serum [Na+J may exceed these guidelines unless active intervention is undertaken to interrupt the induced diuresis.
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Affiliation(s)
- J G Verbalis
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
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Trachtman H. Cell volume regulation: a review of cerebral adaptive mechanisms and implications for clinical treatment of osmolal disturbances: II. Pediatr Nephrol 1992; 6:104-12. [PMID: 1536729 DOI: 10.1007/bf00856852] [Citation(s) in RCA: 56] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Cerebral cell volume regulatory mechanisms are activated by sustained disturbances in plasma osmolality. Acute hypernatremia causes a predictable shrinkage of brain cells due to the sudden imposition of a plasma-to-cell osmolal gradient. However, during chronic hypernatremia cerebral cell volume is maintained close to the normal range as a result of the accumulation of electrolytes and organic osmolytes including myo-inositol, taurine, glutamine, glycerophosphorylcholine, and betaine. The increased cytosolic level of these molecules is generally accomplished via increased activity of sodium (Na+)-dependent cotransport systems. The slow dissipation of these additional osmotically active solutes from the cell during treatment of hypernatremia necessitates gradual correction of this electrolyte abnormality. Acute hyponatremia leads to cerebral cell swelling and severe neurological dysfunction. However, prolonged hyponatremia is associated with significant reductions in brain cell electrolyte and organic osmolyte content so that cerebral cell volume is restored to normal. While acute hyponatremia can be treated with the administration of moderate doses of hypertonic saline in order to control seizure activity, chronic hyponatremia should be corrected slowly in order to prevent subsequent neurological deterioration. If the rate of correction exceeds 0.5 mmol/l per hour, or if the total increment in serum [Na+] exceeds 25 mmol/l in the first 48 h of therapy, then there is an increased risk of the development of cerebral demyelinating lesions. Chronic hyperglycemia activates the brain cell volume regulatory adaptations in the same manner as hypernatremia. Therefore, during the treatment of diabetic ketoacidosis, it is imperative to restore normoglycemia gradually in order to prevent the occurrence of cerebral edema.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- H Trachtman
- Department of Pediatrics, Schneider Children's Hospital, Albert Einstein College of Medicine, New Hyde Park, NY 11042
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