Rapid Correction Of Chronic Hyponatremia Research Articles

Central and Extrapontine Myelinolysis in the Setting of Hyperglycemia.

Osmotic demyelination syndrome (ODS) was first described by Adams et al. in 1959 as a combination of quadriparesis, pseudobulbar paralysis, and the distinctive myelin loss in the pons, attributable to alcoholism or malnutrition.[1] ODS has since been commonly attributed to rapid correction of chronic hyponatremia. Other reported etiologies include alcohol withdrawal, liver transplantation, hypokalemia, hypernatremia as well as severe hyperglycemia. [2-6] (e1-20) Here, we describe a case of ODS associated with diabetic ketoacidosis (DKA) and review the existing literature on hyperglycemia-related ODS.

Osmotic Demyelination Syndrome following Correction of Hyponatremia by ≤10 mEq/L per Day.

Overly rapid correction of chronic hyponatremia may lead to osmotic demyelination syndrome. European guidelines recommend a correction to ≤10 mEq/L in 24 hours to prevent this complication. However, osmotic demyelination syndrome may occur despite adherence to these guidelines. We searched the literature for reports of osmotic demyelination syndrome with rates of correction of hyponatremia ≤10 mEq/L in 24 hours. The reports were reviewed to identify specific risk factors for this complication. We identified 19 publications with a total of 21 patients that were included in our analysis. The mean age was 52 years, of which 67% were male. All of the patients had community-acquired chronic hyponatremia. Twelve patients had an initial serum sodium <115 mEq/L, of which seven had an initial serum sodium ≤105 mEq/L. Other risk factors identified included alcohol use disorder (n=11), hypokalemia (n=5), liver disease (n=6), and malnutrition (n=11). The maximum rate of correction in patients with serum sodium <115 mEq/L was at least 8 mEq/L in all but one patient. In contrast, correction was <8 mEq/L in all but two patients with serum sodium ≥115 mEq/L. Among the latter group, osmotic demyelination syndrome developed before hospital admission or was unrelated to hyponatremia overcorrection. Four patients died (19%), five had full recovery (24%), and nine (42%) had varying degrees of residual neurologic deficits. Osmotic demyelination syndrome can occur in patients with chronic hyponatremia with a serum sodium <115 mEq/L, despite rates of serum sodium correction ≤10 mEq/L in 24 hours. In patients with severe hyponatremia and high-risk features, especially those with serum sodium <115 mEq/L, we recommend limiting serum sodium correction to <8 mEq/L. Thiamine supplementation is advisable for any patient with hyponatremia whose dietary intake has been poor.

A case report of pregnant lady with hyperemesis gravidarum that led to osmotic demyelinolysis

Background: The fall of serum sodium concentration may happen in hyperemesis gravidarum and subsequently can result into hypotonic hyponatremia. This would cause water to move into the brain and develop cerebral edema manifested with neurologic symptoms. However, adaptive mechanism by brain would lower the cerebral volume to a normal range. On the other hand, rapid correction of chronic hyponatremia would damage the brain cells. The symptoms depicted because of rapid over correction of sodium is known as osmotic demyelination syndrome. Case Presentation: The pregnant lady with hyperemesis gravidarum went to severe hyponatremia. And further, she underwent dilatation and evacuation because of the intrauterine fetal death. The normal saline administered to correct the state of hyponatremia caused the patient to be in depression with catatonia and aphasia. The symptoms were correlated with osmotic demyelinolysis and the event was confirmed with magnetic resonance imaging of brain. Conclusion: The administration of sodium should be performed with utmost cautions and under the supervision of welltrained healthcare providers. Any sign or symptom of neurological abnormalities observed because of overcorrection should be considered seriously.

Osmotic demyelination syndrome: are patients with end-stage liver disease a special risk group?

The osmotic demyelination syndrome (ODS) is a serious neurological complication associated with the rapid correction of chronic hyponatremia and is associated with high morbidity and mortality. The incidence of ODS after liver transplantation (LT) is 0.8% to 1.4% and is higher than in the general population. Patients with end stage liver disease (ESLD) are very susceptible to ODS primarily because chronic hyponatremia is the most common electrolyte disorder in these patients. Impaired liver function also leads to disruption of astrocyte metabolism resulting in abnormalities of blood-brain barrier function and a decreased ability to generate new intracellular osmotically active compounds (osmolytes) in response to osmotic changes. LT is the only definitive treatment for hyponatremia in ESLD. Massive fluid shifts that occur intraoperatively can change serum sodium concentration (sNa) significantly. The severity of preoperative chronic hyponatremia is an important risk factor for ODS after LT. ODS after LT is most likely due to unintentional sodium administration intraoperatively. Measures to prevent ODS should cover the entire perioperative period. Chronic symptomatic hyponatremia should be carefully treated if LT is imminent. An intraoperative management strategy to minimize increases in sNa is vital and includes limiting fresh frozen plasma and cryoprecipitate administration by using concentrated clotting factors, administering hypotonic intravenous fluids and sodium-free buffering solutions, as well as using low-sodium continuous renal replacement therapy. sNa levels and urine output should be monitored frequently intraoperatively as well as postoperatively. Neurological symptoms are common after LT, and a high index of suspicion must be maintained to diagnose ODS.

Adverse Consequences of Overly-Rapid Correction of Hyponatremia.

A time-dependent loss of cell solute protects against lethal cerebral edema in hyponatremia. This adaptation, which makes survival possible when the serum sodium concentration is extremely low, also makes the brain vulnerable to injury if chronic (>48 hours) hyponatremia is corrected more rapidly than lost brain solutes can be recovered. Rapid correction of chronic hyponatremia results in programmed cell death of astrocytes and oligodendrocytes and presents clinically with a delayed onset of neurological findings, known as the osmotic demyelination syndrome. This iatrogenic complication can be avoided by limiting correction of hyponatremia to <8 mEq/L per day.

A Multidisciplinary Approach for the Management of Severe Hyponatremia in Patients Requiring Continuous Renal Replacement Therapy

IntroductionHyponatremia is a common electrolyte disorder in critically ill patients. Rapid correction of chronic hyponatremia may lead to osmotic demyelination syndrome. Management of severe hyponatremia in patients with acute or chronic kidney disease who require continuous renal replacement therapy (CRRT) is limited by the lack of commercially available hypotonic dialysate or replacement fluid solutions.MethodsThis was a single-center quality improvement project that consisted of the development and implementation of a multidisciplinary protocol for gradual correction of severe hyponatremia in patients who were admitted to the intensive care unit (ICU) and required CRRT. The protocol utilized a simplified method based on single-pool urea kinetic modeling and a hybrid technique of volume exchange, and addition of sterile water for sodium dilution of commercially available dialysate and replacement fluid solutions.ResultsWe report data of the first 3 ICU patients who required CRRT for acute kidney injury management, had severe hyponatremia (serum sodium <120 mEq/l), and were treated under the protocol. Targeted and gradual hyponatremia correction was achieved in all 3 patients. The observed versus the predicted serum sodium correction in each patient was concordant. No complications related to the protocol were reported. We detailed facilitators of and hindrances to the development and successful implementation of our multidisciplinary protocol.ConclusionWe demonstrated gradual and individualized rates of severe hyponatremia correction utilizing customized (sodium dilution) dialysate/replacement fluid solutions in ICU patients who required CRRT. It is not known whether the use of customized solutions to prevent hyponatremia overcorrection has a significant impact on patient outcomes. Further research in this susceptible population is needed.

Osmotic Stress-Induced Defective Glial Proteostasis Contributes to Brain Demyelination after Hyponatremia Treatment.

Adequate protein folding is necessary for normal cell function and a tightly regulated process that requires proper intracellular ionic strength. In many cell types, imbalance between protein synthesis and degradation can induce endoplasmic reticulum (ER) stress, which if sustained, can in turn lead to cell death. In nematodes, osmotic stress induces massive protein aggregation coupled with unfolded protein response and ER stress. In clinical practice, patients sustaining rapid correction of chronic hyponatremia are at risk of osmotic demyelination syndrome. The intense osmotic stress sustained by brain cells is believed to be the major risk factor for demyelination resulting from astrocyte death, which leads to microglial activation, blood-brain barrier opening, and later, myelin damage. Here, using a rat model of osmotic demyelination, we showed that rapid correction of chronic hyponatremia induces severe alterations in proteostasis characterized by diffuse protein aggregation and ubiquitination. Abrupt correction of hyponatremia resulted in vigorous activation of both the unfolded protein response and ER stress accompanied by increased autophagic activity and apoptosis. Immunofluorescence revealed that most of these processes occurred in astrocytes within regions previously shown to be demyelinated in later stages of this syndrome. These results identify osmotic stress as a potent protein aggregation stimuli in mammalian brain and further suggest that osmotic demyelination might be a consequence of proteostasis failure on severe osmotic stress.

Urea minimizes brain complications following rapid correction of chronic hyponatremia compared with vasopressin antagonist or hypertonic saline

Hyponatremia is a common electrolyte disorder that carries significant morbidity and mortality. However, severe chronic hyponatremia should not be corrected rapidly to avoid brain demyelination. Vasopressin receptor antagonists (vaptans) are now being widely used for the treatment of hyponatremia along with other alternatives like hypertonic saline. Previous reports have suggested that, in some cases, urea can also be used to correct hyponatremia. Correction of severe hyponatremia with urea has never been compared to treatment with a vaptan or hypertonic saline with regard to the risk of brain complications in the event of a too rapid rise in serum sodium. Here, we compared the neurological outcome of hyponatremic rats corrected rapidly with urea, lixivaptan, and hypertonic saline. Despite similar increase in serum sodium obtained by the three drugs, treatment with lixivaptan or hypertonic saline resulted in a higher mortality than treatment with urea. Histological analysis showed that treatment with urea resulted in less pathological change of experimental osmotic demyelination than was induced by hypertonic saline or lixivaptan. This included breakdown of the blood-brain barrier, microglial activation, astrocyte demise, and demyelination. Thus, overcorrection of hyponatremia with urea resulted in significantly lower mortality and neurological impairment than the overcorrection caused by lixivaptan or hypertonic saline.

Minocycline prevents osmotic demyelination associated with aquaresis.

Overly rapid correction of chronic hyponatremia can cause osmotic demyelination syndrome (ODS). Minocycline protects ODS associated with overly rapid correction of chronic hyponatremia with hypertonic saline infusion in rats. In clinical practice, inadvertent rapid correction frequently occurs due to water diuresis, when vasopressin action suddenly ceases. In addition, vasopressin receptor antagonists have been applied to treat hyponatremia. Here the susceptibility to and pathology of ODS were evaluated using rat models developed to represent rapid correction of chronic hyponatremia in the clinical setting. The protective effect of minocycline against ODS was assessed. Chronic hyponatremia was rapidly corrected by 1 (T1) or 10 mg/kg (T10) of tolvaptan, removal of desmopressin infusion pumps (RP), or administration of hypertonic saline. The severity of neurological impairment in the T1 group was significantly milder than in other groups and brain hemorrhage was found only in the T10 and desmopressin infusion removal groups. Minocycline inhibited demyelination in the T1 group. Further, immunohistochemistry showed loss of aquaporin-4 (AQP4) in astrocytes before demyelination developed. Interestingly, serum AQP4 levels were associated with neurological impairments. Thus, minocycline can prevent ODS caused by overly rapid correction of hyponatremia due to water diuresis associated with vasopressin action suppression. Increased serum AQP4 levels may be a predictive marker for ODS.

Primary cerebral and cerebellar astrocytes display differential sensitivity to extracellular sodium with significant effects on apoptosis

Central pontine myelinolysis is one of the idiopathic or iatrogenic brain dysfunction, and the most common cause is excessively rapid correction of chronic hyponatraemia. While myelin disruption is the main pathology, as the diagnostic name indicates, a previous study has reported that astrocyte death precedes the destruction of the myelin sheath after the rapid correction of chronic low Na(+) levels, and interestingly, certain brain regions (cerebral cortex, hippocampus, etc.) are specifically damaged but not cerebellum. Here, using primary astrocyte cultures derived from rat cerebral cortex and cerebellum, we examined how extracellular Na(+) alterations affect astrocyte death and whether the response is different between the two populations of astrocytes. Twice the amount of extracellular [Na(+) ] and voltage-gated Na(+) channel opening induced substantial apoptosis in both populations of astrocytes, while, in contrast, one half [Na(+) ] prevented apoptosis in cerebellar astrocytes, in which the Na(+) -Ca(2+) exchanger, NCX2, was highly expressed but not in cerebral astrocytes. Strikingly, the rapid correction of chronic one half [Na(+) ] exposure significantly increased apoptosis in cerebellar astrocytes but not in cerebral astrocytes. These results indicate that extracellular [Na(+) ] affects astrocyte apoptosis, and the response to alterations in [Na(+) ] is dependent on the brain region from which the astrocyte is derived.

Central Pontine and Extrapontine Myelinolysis: The Great Masquerader—An Autopsy Case Report

Central pontine myelinolysis is a demyelinating disorder characterized by the loss of myelin in the center of the basis pontis usually caused by rapid correction of chronic hyponatremia. The clinical features vary depending on the extent of involvement. Demyelination can occur outside the pons as well and diagnosis can be challenging if both pontine and extrapontine areas are involved. We herein report a case of myelinolysis involving pons, lateral geniculate bodies, subependymal region, and spinal cord. To the best of our knowledge, this case represents the second case of spinal cord involvement in osmotic demyelination syndrome and the first case of involvement of thoracic region of spinal cord.

A New Murine Model Of Osmotic Demyelination Syndrome

Event Abstract Back to Event A New Murine Model Of Osmotic Demyelination Syndrome Joanna Bouchat1*, Bruno Couturier2, 3, Fabrice Gankam-Kengné2, 3, Guy Decaux2 and Charles Nicaise1 1 Université de Namur, Laboratory Neurodegeneration and Regeneration, URPhym - NARILIS, Belgium 2 Erasme Hospital, Université Libre de Bruxelles, Research Unit for the Study of Hydromineral Metabolism, Department of General Internal Medicine, Belgium 3 Université Libre de Bruxelles, Laboratory of Histology, Histopathology and Neuroanatomy, Belgium Osmotic demyelination syndrome (ODS) is a severe neurological complication occuring after inadvertant rapid correction of chronic hyponatremia. This pathology primarily affects the CNS and is characterized by large areas of demyelination in centropontine or extrapontine regions, often correlated with clinical symptoms : from lethargia to coma or even death. Historically, the most used ODS animal model is Rattus norvegicus, that mimicked myelin and oligodendrocyte loss and allowed important insights in the management and in the understanding of ODS pathology. According to an adapted protocol from the rat model, we developed a murine model of ODS that will help at unravelling the molecular and cellular pathophysiological mechanisms. Chronic hyponatremia was induced in mice using continuous desmopressin infusion and a low-sodium liquid diet. After 4 days, blood sodium dropped to 113±11 mEq/L in the hyponatremic group (compared to normonatremic group 148±1 mEq/L, p<0.001) and animals showed clinical signs of mild lethargia. Hyponatremia was next corrected by a single injection of hypertonic saline solution targeting a normal range of blood sodium. 24 hours after correction, blood natremia was measured to determine the final 24-hours sodium correction gradient (33±3 mEq/L, p<0.001 between hyponatremia and correction of hyponatremia). Interestingly, mice displayed transient increased overall locomotor activity during the first 12 hours post-correction before a drastic worsening of neurological symptoms, most likely due to occurrence of demyelination. Histopathologically, ODS mice showed large areas of demyelination in subcortical, midbrain regions and in the pons, attested by loss of myelin in Eriochrome R staining and anti-myelin binding protein immunohistochemistry. In conclusion, we successfully translated the rat model of ODS to a mouse model and reproduced the neurological as well as the histological outcomes observed in human cases of ODS. Keywords: Osmotic Demyelination Syndrome, chronic hyponatremia, demyelination, mouse model, histopathological analysis Conference: Belgian Brain Council 2014 MODULATING THE BRAIN: FACTS, FICTION, FUTURE, Ghent, Belgium, 4 Oct - 4 Oct, 2014. Presentation Type: Poster Presentation Topic: Basic Neuroscience Citation: Bouchat J, Couturier B, Gankam-Kengné F, Decaux G and Nicaise C (2014). A New Murine Model Of Osmotic Demyelination Syndrome. Conference Abstract: Belgian Brain Council 2014 MODULATING THE BRAIN: FACTS, FICTION, FUTURE. doi: 10.3389/conf.fnhum.2014.214.00017 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 27 Jun 2014; Published Online: 27 Jun 2014. * Correspondence: Miss. Joanna Bouchat, Université de Namur, Laboratory Neurodegeneration and Regeneration, URPhym - NARILIS, Namur, Belgium, joanna.bouchat@unamur.be Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Joanna Bouchat Bruno Couturier Fabrice Gankam-Kengné Guy Decaux Charles Nicaise Google Joanna Bouchat Bruno Couturier Fabrice Gankam-Kengné Guy Decaux Charles Nicaise Google Scholar Joanna Bouchat Bruno Couturier Fabrice Gankam-Kengné Guy Decaux Charles Nicaise PubMed Joanna Bouchat Bruno Couturier Fabrice Gankam-Kengné Guy Decaux Charles Nicaise Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Central pontine myelinolysis in a patient with persistent mild hypernatremia following cadaver donor liver transplantation

We experienced a case of central pontine myelinolysis (CPM) development in the setting of mild hypernatremia. A 46-year-old female was diagnosed with cryptogenic liver cirrhosis due to autoimmune disease. She was scheduled for emergency cadaver donor liver transplantation. A pre-operative examination revealed the following parameters: total bilirubin (36.22 mg/dl), aspartate aminotransferase (52 IU/L), alanine transaminase (49 IU/L), glutamate-pyruvate transaminase (101 IU/L), serum creatinine (1.2 mg/dl), serum sodium (147 mmol/L), serum magnesium (0.87 mmol/L), plasma osmotic pressure (289 mOsm/kg H2O), Child-Pugh score C, MELD score (36). During the operation, the sodium concentration was maintained between 145 and 150 mmol/L. The total operation time was 15 hr. Electrolytes were immediately re-evaluated after the operation in the intensive care unit: serum sodium was 149 mmol/L and plasma osmotic pressure was 291 mOsm/kg H2O. At 19 hours following surgery, the patient was extubated. The patient was on hemofiltration due to degraded renal function and persisting hypernatremia. The patient was treated with tacrolimus 1 mg, mycophenolic acid 250 mg (oral, twice daily), and prednisolone 5 mg (iv). During the first week, the patient was nearly alert and could provide correct answers to simple questions. Tendon reflexes were symmetric and active, with pathological sign (-). On day 7 after the surgery, the patient became lethargic, only opened eyes when powerfully stimulated, could not pronounce or perform autonomic limb activities, and thus underwent tracheostomy. She was mechanically ventilated due to a pulmonary infection. Since then, the patient's mental status continued to decline. A review of the patient's laboratory data showed that her hypernatremia continued to be between 150 and 157 mmol/L and plasma osmotic pressure was persisted between 280 and 300 mOsm/kg H2O. After all our efforts for correcting serum sodium level and osmolarity using half saline and hemofiltration, hypernatremia persisted. On day 18 after the surgery, the patient developed a moderate coma, with good recovery of liver function. On day 21, brain magnetic resonance imaging revealed CPM (Fig. 1). Subsequently, the patient developed severe sepsis and multiple organ failure, and expired. Fig. 1 Magnetic resonance imaging displayed high-signal intensity on T2-weighted images of the central pons 21d after surgery. Our patient differs from the classic cases of CPM as hyponatremia was not present. The unique feature of our case is that CPM developed in the setting of relatively mild hypernatremia. One may intuitively say that the authors should correct the hypernatremia on recognition. However, once developed, it is known that overly rapid correction of hypernatremia is potentially very dangerous, and can lead to cerebral edema, potentially resulting in seizures, permanent brain damage, or death [1]. In addition, Go et al. [2] reported a case of CPM and EPM after rapid correction of hypernatremia. The patient's initial serum sodium value of 186 mEq/L was corrected to 139 mEq/L in 5 days. Although rapid correction of hypernatremia has been reported in association with CPM, to our knowledge, where the serum sodium went from upper normal to hypernatremic, appears to be unique. In addition, the post-operative increase of sodium concentration never exceeded 1-2 mmol/L per day, yet the patient developed CPM. Several reports have shown that underlying hypokalemia may predispose patients to more pronounced myelin damage. In this patient, although the hypokalemia was mild, we cannot deny the possibility that it may have had a pathological effect with regard to the unusual accompaniment of CPM. Also, the post-operative lab results showed that the level of phosphates was normal. The authors need to point out the recent conflicting animal experiments that have shown an alternative approach to prevent osmotic demyelination to re-lower serum sodium following overly rapid correction. Kengne et al. [3] reported that the relowering of the serum sodium after rapid correction of chronic hyponatremia was beneficial if performed early in the course (12 to 24 h). The results suggest that after inadvertent rapid correction of hyponatremia, treatment options should favor re-lowering serum sodium. The increased permeability of the blood-brain barrier seen in osmotic demyelination may not be a primary pathophysiologic insult of CPM. There was a limitation for our case in that we used Taclolimus for the postoperative immunosuppressive regimen. Fukazawa et al. [4] provided evidence of Tacrolimus-associated CPM after transplantation, which presented with a classic lock-in syndrome with radiographic confirmation. In conclusion, our case illustrated the development of severe CPM in a patient with mild hypernatremia despite the absence regarding the rapid elevation of serum sodium and significant metabolic derangement. Slow correction of chronic hyponatremia or, in the case of our patient, avoidance of postoperative hypernatremia in the setting of an orthotopic liver transplant, is crucial for the prevention of central pontine myelinolysis. Our case may broaden the clinical spectrum of CPM and suggests that this clinical entity should be considered in various clinical settings.

Hyponatraemia: more than just a marker of disease severity?

Hyponatraemia--the most common serum electrolyte disorder--has also emerged as an important marker of the severity and prognosis of important diseases such as heart failure and cirrhosis. Acute hyponatraemia can cause severe encephalopathy, but the rapid correction of chronic hyponatraemia can also profoundly impair brain function and even cause death. With the expanding elderly population and the increased prevalence of hyponatraemia in this segment of society, prospective studies are needed to examine whether correcting hyponatraemia in the elderly will diminish cognitive impairment, improve balance and reduce the incidence of falls and fractures. Given that polypharmacy is also common in the elderly population, the various medications that may stimulate arginine vasopressin release and/or enhance the hormone's action to increase water absorption must also be taken into consideration. Whether hyponatraemia in a patient with cancer is merely a marker of poor prognosis or whether its presence may alter the patient's quality of life remains to be examined. In any case, hyponatraemia can no longer be considered as just a biochemical bystander in the ill patient. A systematic diagnostic approach is necessary to determine the specific aetiology of a patient's hyponatraemia. Therapy must then be dictated not only by recognized reversible causes such as advanced hypothyroidism, adrenal insufficiency, diuretics or other medicines, but also by whether the hyponatraemia occurred acutely or chronically. Information is emerging that the vast majority of cases of hyponatraemia are caused by the nonosmotic release of arginine vasopressin. Now that vasopressin V2-receptor blockers are available, a new era of clinical investigation is necessary to examine whether hyponatraemia is just a marker of severe disease or whether correction of hyponatraemia could improve a patient's quality of life. Such an approach must involve prospective randomized studies in different groups of patients with hyponatraemia, including those with advanced heart failure, those with cirrhosis, patients with cancer, and the elderly.

Improvement in Central Pontine Myelinosis with IV immunoglobulin

Improvement in Central Pontine Myelinosis with IV immunoglobulin Vesper Fe Marie Llaneza Ramos,1 J Americo Fernandes Filho,1 Arun Raj Antony,1 Jason T. Helvey,2 John Bertoni1 1Department of Neurological Sciences, University of Nebraska Medical Center; 2Department of Radiology, University of Nebraska Medical Center Introduction: Central pontine myelinolysis (CPM) is a rare, serious demyelinating disease, associated with rapid correction of chronic hyponatremia, usually in the setting of alcoholism and electrolyte disturbance.1 2 Magnetic resonance imaging (MRI) is a decisive diagnostic tool for CPM.3 The pathogenesis is unknown and there is no established treatment. There have been case reports on the efficacy of intravenous immunoglobulin (IVIG).4 5 Postulated mech-anisms include reduction of myelinotoxic agents, development of antimyelin antibodies, and promotion of remyelination.4 We report a case of CPM associated with chronic alcoholism and hyponatremia, with significant clinical improvement and resolution of MRI changes after treatment with IVIG.

Pontine hemorrhage at a microbleed site in a patient with central pontine myelinolysis

Central pontine myelinolysis (CPM) is an uncommon disorder, characterized by non-inflammatory demyelination, which may be caused by an abrupt change of serum osmolarity, especially of sodium concentration [1]. Although rapid correction of chronic hyponatremia leads to the disruption of the blood–brain-barrier (BBB) [2], CPM associated with intracerebral hemorrhage (ICH) has rarely been reported [3, 4]. Cerebral microbleed (CMB) is a 2–5-mm sized small hypointense lesion that is generally detected by gradient echo (GRE) magnetic resonance imaging (MRI), which is thought to be associated with advanced microangiopathy, focal breakdown of the BBB and risk of bleeding [5]. In view of the possible effects of CPM and CMB on the BBB, we can postulate that the affected region is in a hemorrhagic-prone state. We describe a patient who suffered CPM and subsequent ICH at the site of pontine microbleeds. An 89-year-old female attended the emergency room (ER) with stuporous mentality. In the past, she had suffered from hypertension and chronic kidney disease with antihypertensives and diuretics without dialysis. Seven days before visiting the ER, her general condition had worsened after fall down and oral intake was poor. It had not been possible to wake her for the last 5 h before she appeared in the ER. Neurological examination revealed stupor mentality with decreased corneal, vestibulo-ocular and gag reflexes. Her withdrawal response to painful stimuli on all extremities was reduced especially on her left side. Laboratory findings revealed mild anemia (hemoglobin 9.3 g/dL) and elevated renal function values (blood urea nitrogen 42 mg/dL, creatinine 3.2 mg/dL) and normal range electrolyte values. Total protein (4.9 g/dL) and albumin (2.6 g/dL) levels were low, suggesting malnutrition. Brain fluid attenuated inversion recovery (FLAIR) MRI revealed diffuse high signal areas in the basis pontis (Fig. 1a). In addition, multiple microbleed signals were detected in the whole brain area as well as the lower pons within FLAIR high signal area on GRE imaging (Fig. 1b). Her diagnosis was CPM without any hyponatremia correction and we initiated general and nutritional care. Three days after admission, she became alert and motor power was partially recovered. However, on the 8th day, her mental functioning deteriorated abruptly to stupor. Neurological examination showed pin-pointed pupils with impaired light reflex. Brainstem reflexes were also completely absent. Brain MRI revealed pontine hemorrhage in two different foci that coincided with microbleed sites on the previous MRI (Fig. 1c, d). The patient died from respiratory and renal failure 3 weeks after admission. CPM is an osmotic demyelination syndrome (ODS) which is a well-known disease caused by rapid correction of hyponatremia, alcoholism, liver transplantation and malnutrition [1]. Although the exact mechanism of ODS is not clear, it has been suggested that any rapid change in serum osmolality with resulting changes in brain cell volume may lead to stereotyped injury to myelin sheaths [2]. Therefore, ICH, which is due to rupture of intracerebral arteries, is an unusual complication and has been rarely reported [3, 4]. However, these previous reports differ from Y. S. Kim and J. Lee equally contributed to this work.

Managing Overly Rapid Correction of Chronic Hyponatremia

Rapid correction of chronic hyponatremia may lead to osmotic demyelination syndrome (ODS) and devastating neurologic sequelae.[1][1] The rate of rise in plasma sodium concentration (PNa) in patients with chronic hyponatremia should be <8 mmol/L per d[2][2] and even lower in patients at higher risk

Minocycline Protects against Neurologic Complications of Rapid Correction of Hyponatremia

Osmotic demyelination syndrome is a devastating neurologic condition that occurs after rapid correction of serum sodium in patients with hyponatremia. Pathologic features of this injury include a well-demarcated region of myelin loss, a breakdown of the blood-brain barrier, and infiltration of microglia. The semisynthetic tetracycline minocycline is protective in some animal models of central nervous system injury, including demyelination, suggesting that it may also protect against demyelination resulting from rapid correction of chronic hyponatremia. Using a rat model of osmotic demyelination syndrome, we found that treatment with minocycline significantly decreases brain demyelination, alleviates neurologic manifestations, and reduces mortality associated with rapid correction of hyponatremia. Mechanistically, minocycline decreased the permeability of the blood-brain barrier, inhibited microglial activation, decreased both the expression of IL1α and protein nitrosylation, and reduced the loss of GFAP immunoreactivity. In conclusion, minocycline modifies the course of osmotic demyelination in rats, suggesting its possible therapeutic use in the setting of inadvertent rapid correction of chronic hyponatremia in humans.

Minocycline Prevents Osmotic Demyelination Syndrome by Inhibiting the Activation of Microglia

Rapid correction of chronic hyponatremia can lead to osmotic demyelination syndrome (ODS), a severe demyelination disease. The microglia that accumulate in the demyelinative lesions may play a detrimental role in the pathogenesis of ODS by producing proinflammatory cytokines, suggesting that they may be a target for therapeutic intervention. Here, we investigated whether minocycline, a selective and potent inhibitor of microglial activation, could protect against ODS in rats. We induced hyponatremia by liquid diet feeding and dDAVP infusion. Rapid correction of the hyponatremia 7 days later resulted in neurologic impairment with severe demyelinative lesions. Activated microglia accumulated at the site of demyelination. Treatment with minocycline within 24 hours of rapid correction, however, was protective: rats exhibited minimal neurologic impairment, and survival improved. Histologic analysis showed that minocycline inhibited demyelination and suppressed the accumulation of microglia at the site of demyelination. Real-time RT-PCR and immunohistochemical analyses showed that minocycline inhibited the activity of microglia and the expression of inflammatory cytokines (e.g. IL-1β, inducible nitric-oxide synthase, and TNF-α), monocyte chemoattractant protein-1, and matrix metalloproteinase-12 in microglia. These results demonstrate that minocycline can protect against ODS by inhibiting the activation and accumulation of microglia at the site of demyelinative lesions, suggesting its possible use in clinical practice.

Management of hyponatremia: Providing treatment and avoiding harm

Hyponatremia, in its most severe form, requires urgent infusion of hypertonic saline to correct cerebral edema. However, overly rapid correction of chronic hyponatremia can cause osmotic demyelination syndrome. The authors review the treatment of hyponatremia in order to provide clinicians with a sound approach in a variety of settings in which severity, symptoms, and underlying disease states influence therapy. Also discussed is the current role of vasopressin antagonists in treatment.