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.

Clinical practice guideline on diagnosis and treatment of hyponatraemia.

Hyponatraemia, defined as a serum sodium concentration <135 mmol/l, is the most common disorder of body fluid and electrolyte balance encountered in clinical practice. It can lead to a wide spectrum of clinical symptoms, from subtle to severe or even life threatening, and is associated with increased mortality, morbidity and length of hospital stay in patients presenting with a range of conditions. Despite this, the management of patients remains problematic. The prevalence of hyponatraemia in widely different conditions and the fact that hyponatraemia is managed by clinicians with a broad variety of backgrounds have fostered diverse institution- and speciality-based approaches to diagnosis and treatment. To obtain a common and holistic view, the European Society of Intensive Care Medicine (ESICM), the European Society of Endocrinology (ESE) and the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA), represented by European Renal Best Practice (ERBP), have developed the Clinical Practice Guideline on the diagnostic approach and treatment of hyponatraemia as a joint venture of three societies representing specialists with a natural interest in hyponatraemia. In addition to a rigorous approach to methodology and evaluation, we were keen to ensure that the document focused on patient-important outcomes and included utility for clinicians involved in everyday practice.

Intestinal Pseudo-Obstruction with Life-Threatening Hypokalaemia in a Patient with Adult-Onset Still's Disease.

Adult-onset Still's disease (AOSD) is a rare autoinflammatory disorder that can lead to a cytokine storm, causing a range of symptoms. Acute intestinal pseudo-obstruction is another rare condition that results in intestinal obstruction without anatomical cause. Although the two conditions are rarely reported together, we present the case of a 62-year-old male who developed acute intestinal pseudo-obstruction in the context of an AOSD flare. This led to severe hypokalaemia and a critical condition. Other symptoms included a high-spiking fever lasting for weeks, polyarthralgias and a typical salmon-coloured rash. After ruling out other potential causes, the patient was diagnosed with AOSD. Our findings suggest that the cytokine storm associated with this disease triggered the acute intestinal pseudo-obstruction and life-threatening hypokalaemia, establishing a causal relationship. Only four other cases of AOSD complicated by intestinal pseudo-obstruction have been reported, and this is the first to present with life-threatening hypokalaemia. This case serves as a crucial reminder that, despite being a diagnosis of exclusion, Still's disease should be considered as a potential cause of intestinal pseudo-obstruction, as prompt recognition and treatment of the underlying cause is crucial in managing this potentially life-threatening condition. LEARNING POINTS: Acute intestinal pseudo-obstruction is one of the systemic complications that can occur in autoinflammatory diseases such as AOSD, although it has rarely been described.If AOSD presents with abdominal presentation, such as acute intestinal pseudo-obstruction, then amyloidosis should always be carefully considered.

Spontaneous Periodic Hypothermia with Confirmed Epilepsy: A Report of Two Cases.

Spontaneous periodic hypothermia (SPH) is an exceptionally rare condition characterised by paroxysmal episodes of spontaneous hypothermia. While commonly associated with Shapiro syndrome, which includes SPH, hyperhidrosis and agenesis of the corpus callosum, there are also cases of SPH that do not exhibit these defining characteristics, known as 'Shapiro syndrome variant'. These variants may present with diverse brain imaging findings but no agenesis of the corpus callosum, suggesting different potential aetiologies. Notably, the association of SPH with epilepsy has only been reported in a few cases, and confirming epileptic activity in the context of SPH remains a challenge. In line with this, our report presents two exceptional cases of SPH without significant brain malformation, where we successfully confirmed the presence of epilepsy. The confirmation of epilepsy in these cases is particularly noteworthy, as it adds to the limited documentation of SPH cases with confirmed epilepsy. These findings contribute valuable insights into the association between SPH and epilepsy, enhancing our understanding of this rare condition. Our report also addresses the broader clinical presentations and the physiopathological mechanisms of SPH. By providing comprehensive insights into these aspects, we aim to advance the existing literature and improve our understanding of SPH and its association with epilepsy. LEARNING POINTS: SPH is a rare condition, characterised by paroxysmal episodes of spontaneous hypothermia.A dysregulation of the hypothalamic thermostat is thought to be involved in the pathogenesis.Epilepsy may contribute to the pathogenesis of SPH, potentially by involving the hypothalamus.

Treatment Guidelines for Hyponatremia: Stay the Course.

International guidelines designed to minimize the risk of complications that can occur when correcting severe hyponatremia have been widely accepted for a decade. On the basis of the results of a recent large retrospective study of patients hospitalized with hyponatremia, it has been suggested that hyponatremia guidelines have gone too far in limiting the rate of rise of the serum sodium concentration; the need for therapeutic caution and frequent monitoring of the serum sodium concentration has been questioned. These assertions are reminiscent of a controversy that began many years ago. After reviewing the history of that controversy, the evidence supporting the guidelines, and the validity of data challenging them, we conclude that current safeguards should not be abandoned. To do so would be akin to discarding your umbrella because you remained dry in a rainstorm. The authors of this review, who represent 20 medical centers in nine countries, have all contributed significantly to the literature on the subject. We urge clinicians to continue to treat severe hyponatremia cautiously and to wait for better evidence before adopting less stringent therapeutic limits.

Astrocytes are an early target in osmotic demyelination syndrome.

Abrupt osmotic changes during rapid correction of chronic hyponatremia result in demyelinative brain lesions, but the sequence of events linking rapid osmotic changes to myelin loss is not yet understood. Here, in a rat model of osmotic demyelination syndrome, we found that massive astrocyte death occurred after rapid correction of hyponatremia, delineating the regions of future myelin loss. Astrocyte death caused a disruption of the astrocyte-oligodendrocyte network, rapidly upregulated inflammatory cytokines genes, and increased serum S100B, which predicted clinical manifestations and outcome of osmotic demyelination. These results support a model for the pathophysiology of osmotic brain injury in which rapid correction of hyponatremia triggers apoptosis in astrocytes followed by a loss of trophic communication between astrocytes and oligodendrocytes, secondary inflammation, microglial activation, and finally demyelination.

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.

Treatment of euvolemic hyponatremia in the intensive care unit by urea.

INTRODUCTION: Hyponatremia in the intensive care unit (ICU) is most commonly related to inappropriate secretion of antidiuretic hormone (SIADH). Fluid restriction is difficult to apply in these patients. We wanted to report the treatment of hyponatremia with urea in these patients. METHODS: Two groups of patients are reported. The first one is represented by a retrospective study of 50 consecutive patients with mild hyponatremia treated with urea. The second group is presented by a series of 35 consecutive patients with severe hyponatremia acquired outside the hospital (≤ 115 mEq/L) who where treated by isotonic saline and urea (0.5 to 1 g/kg/day), administered usually by gastric tube. RESULTS: In the first group with mild hyponatremia (128 ± 4 mEq/L) the serum sodium (SNa) increased to a mean value of 135 ± 4 mEq/L (P < 0.001) after two days of urea therapy (46 ± 25 g/day), despite a large fluid intake (> 2 L/day). The mean duration of urea therapy was six days (from 2 to 42 days). Six patients developed hyponatremia again once the urea was stopped, which necessitated its reintroduction. Six patients developed hypernatremia (maximum value 155 mEq/L). In the second group, SNa increased from 111 ± 3 mEq/L to 122 ± 4 mEq/L in one day (P < 0.001). All the patients with neurological symptoms made a rapid recovery. No side effects were observed. CONCLUSIONS: These data show that urea is a simple and inexpensive therapy to treat euvolemic hyponatremia in the ICU.

Re-induction of hyponatremia after rapid overcorrection of hyponatremia reduces mortality in rats.

Osmotic demyelination syndrome is a devastating neurologic disorder often seen after the rapid correction of chronic hyponatremia. The permeability of the blood-brain barrier is increased in experimental osmotic demyelination, and some have suggested that corticosteroids protect against this disorder by keeping the permeability of the blood-brain barrier low. We previously reported that re-lowering of the serum sodium after rapid correction of chronic hyponatremia was beneficial if performed early in the course (12 to 24 h). Here we compared mortality, blood-brain barrier permeability, and microglial activation in rats after the rapid correction of chronic hyponatremia. We studied three groups of rats after correction of chronic hyponatremia: and treated them with sodium chloride, with or without dexamethasone; or with sodium chloride followed by re-induction of hyponatremia. We found that treatment with dexamethasone or re-induction of hyponatremia effectively prevented the opening of the blood-brain barrier, reduced neurological manifestations, and decreased microglial activation; however, only re-induction of hyponatremia resulted in a significant decrease in mortality 5 days after the correction of chronic hyponatremia. Restoring the permeability of the blood-brain barrier to normal levels did not decrease mortality. Our results suggest that after inadvertent rapid correction of hyponatremia, treatment options should favor re-lowering serum sodium. The increased permeability of blood-brain barrier seen in osmotic demyelination syndrome may not be a primary pathophysiologic insult of this syndrome.

Non-peptide arginine-vasopressin antagonists: the vaptans.

Arginine-vasopressin is a hormone that plays an important part in circulatory and water homoeostasis. The three arginine-vasopressin-receptor subtypes--V1a, V1b, and V2--all belong to the large rhodopsin-like G-protein-coupled receptor family. The vaptans are orally and intravenously active non-peptide vasopressin receptor antagonists that are in development. Relcovaptan is a selective V1a-receptor antagonist, which has shown initial positive results in the treatment of Raynaud's disease, dysmenorrhoea, and tocolysis. SSR-149415 is a selective V1b-receptor antagonist, which could have beneficial effects in the treatment of psychiatric disorders. V2-receptor antagonists--mozavaptan, lixivaptan, satavaptan, and tolvaptan--induce a highly hypotonic diuresis without substantially affecting the excretion of electrolytes (by contrast with the effects of diuretics). These drugs are all effective in the treatment of euvolaemic and hypervolaemic hyponatraemia. Conivaptan is a V1a/V2 non-selective vasopressin-receptor antagonist that has been approved by the US Food and Drug Administration as an intravenous infusion for the inhospital treatment of euvolaemic or hypervolaemic hyponatraemia.

Hyponatraemia diagnosis and treatment clinical practice guidelines. / Guía de práctica clínica sobre el diagnóstico y tratamiento de la hiponatremia.

Hyponatremia, defined as a serum sodium concentration <135mmol/l, is the most common water-electrolyte imbalance encountered in clinical practice. It can lead to a wide spectrum of clinical symptoms, from mild to severe or even life threatening, and is associated with increased mortality, morbidity and length of hospital stay. Despite this, the management of hyponatremia patients remains problematic. The prevalence of hyponatremia in a wide variety of conditions and the fact that hyponatremia is managed by clinicians with a broad variety of backgrounds have fostered diverse institution- and specialty-based approaches to diagnosis and treatment. To obtain a common and holistic view, the European Society of Intensive Care Medicine (ESICM), the European Society of Endocrinology (ESE) and the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA), represented by European Renal Best Practice (ERBP), have developed clinical practice guidelines on the diagnostic approach and treatment of hyponatremia as a joint venture of 3societies representing specialists with a natural interest in hyponatremia. In addition to a rigorous approach to the methodology and evaluation of the evidence, the document focuses on patient-positive outcomes and on providing a useful tool for clinicians involved in everyday practice. In this article, we present an abridged version of the recommendations and suggestions for the diagnosis and treatment of hyponatremia extracted from the full guide.

Treatment of symptomatic hyponatremia.

Inadequate treatment of severe hyponatremia (<120 mEq/L) can be associated with severe neurological damage. In acute (<48 hours) hyponatremia, usually observed in the postoperative period, prompt treatment with hypertonic saline (3%) can prevent seizures and respiratory arrest. For patients with chronic (>48-72 hours) symptomatic hyponatremia, correction must be rapid during the first few hours (to decrease brain edema) followed by a slow correction limited to 10 mmol/L over 24 hours to avoid the development of osmotic demyelinating syndrome. In patients with asymptomatic hyponatremia, slow correction is the appropriate approach. When patients are overtreated, neurologic damage can be prevented by relowering the serum sodium (SNa) so that the daily increase in SNa remains below 10 mmol/L/24 hours. Frequent measurements of SNa during the correction phase of SNa are mandatory to avoid overcorrection. The use of urea to treat hyponatremia represents an advantageous alternative to hypertonic saline.

Actual Therapeutic Indication of an Old Drug: Urea for Treatment of Severely Symptomatic and Mild Chronic Hyponatremia Related to SIADH.

Oral urea has been used in the past to treat various diseases like gastric ulcers, liver metastases, sickle cell disease, heart failure, brain oedema, glaucoma, Meniere disease, etc. We have demonstrated for years, the efficacy of urea to treat euvolemic (SIADH) or hypervolemic hyponatremia. We briefly describe the indications of urea use in symptomatic and paucisymptomatic hyponatremic patients. Urea is a non-toxic, cheap product, and protects against osmotic demyelinating syndrome (ODS) in experimental studies. Prospective studies showing the benefit to treat mild chronic hyponatremia due to SIADH and comparing water restriction, urea, high ceiling diuretics, and antivasopressin antagonist antagonist should be done.

Clinical practice guideline on diagnosis and treatment of hyponatraemia.

Hyponatraemia, defined as a serum sodium concentration <135 mmol/l, is the most common disorder of body fluid and electrolyte balance encountered in clinical practice. It can lead to a wide spectrum of clinical symptoms, from subtle to severe or even life threatening, and is associated with increased mortality, morbidity and length of hospital stay in patients presenting with a range of conditions. Despite this, the management of patients remains problematic. The prevalence of hyponatraemia in widely different conditions and the fact that hyponatraemia is managed by clinicians with a broad variety of backgrounds have fostered diverse institution- and speciality-based approaches to diagnosis and treatment. To obtain a common and holistic view, the European Society of Intensive Care Medicine (ESICM), the European Society of Endocrinology (ESE) and the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA), represented by European Renal Best Practice (ERBP), have developed the Clinical Practice Guideline on the diagnostic approach and treatment of hyponatraemia as a joint venture of three societies representing specialists with a natural interest in hyponatraemia. In addition to a rigorous approach to methodology and evaluation, we were keen to ensure that the document focused on patient-important outcomes and included utility for clinicians involved in everyday practice.

Clinical practice guideline on diagnosis and treatment of hyponatraemia.

Hyponatraemia, defined as a serum sodium concentration <135 mmol/L, is the most common disorder of body fluid and electrolyte balance encountered in clinical practice. Hyponatraemia is present in 15-20% of emergency admissions to hospital and occurs in up to 20% of critically ill patients. Symptomatology may vary from subtle to severe or even life threatening. Despite this, the management of patients remains problematic. Against this background, the European Society of Intensive Care Medicine, the European Society of Endocrinology and the European Renal Association-European Dialysis and Transplant Association, represented by European Renal Best Practice have developed a Clinical Practice Guideline on the diagnostic approach and treatment of hyponatraemia as a joint venture of three societies representing specialists with a natural interest in hyponatraemia.

Efficacy and tolerance of urea compared with vaptans for long-term treatment of patients with SIADH.

BACKGROUND AND OBJECTIVES: Vaptans (vasopressin V(2)-receptor antagonists) are a new approach for the treatment of hyponatremia. However, their indications remain to be determined, and their benefit compared with that of the usual treatments for the syndrome of inappropriate antidiuretic hormone secretion (SIADH) have not been evaluated. This prospective, long-term study compared the efficacy, tolerability, and safety of two oral vaptans with those of oral urea in patients with SIADH. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients with chronic SIADH of various origins were treated first with vaptans for 1 year. After an 8-day holiday period, they received oral urea for an additional 1-year follow-up. Serum sodium was measured every 2 months, and drug doses were adjusted accordingly. RESULTS: Thirteen participants were initially included in the study (serum sodium, 125±3 mEq/L); 12 completed the 2-year treatment period. Treatment with vaptans (satavaptan, 5-50 mg/d, n=10; tolvaptan, 30-60 mg/day, n=2) increased natremia (serum sodium, 135±3 mEq/L) during the 1-year vaptan period without escape. Hyponatremia recurred in the 12 participants when vaptans were stopped (holiday period). Urea improved the natremia with the same efficacy (serum sodium, 135±2 mEq/L) as vaptans during the 1-year urea treatment period. One participant treated with tolvaptan withdrew from the study early because of excessive thirst. Another patient receiving urea developed hypernatremia without complications. CONCLUSIONS: Urea has efficacy similar to that of vaptans for treatment of chronic SIADH. Tolerance is generally good for both agents.

Treatment of hyponatraemia by urea decreases risks of brain complications in rats. Brain osmolyte contents analysis.

BACKGROUND: Brain damage (myelinolysis) develops in hyponatraemia after a large increase in serum sodium regardless of the currently available methods of correction. However, a preliminary study suggests that treatment of hyponatraemia with urea limits the risks of brain lesions in rats. Benefits of sustained high blood levels of urea and mechanisms of protection remain hypothetical. METHODS: In the first part of the study, hyponatraemic rats received repeated (i.p.) doses of urea (2 g/kg b.w./6 h) leading to sustained blood levels (urea+/-230 mg/dl). Neurologic outcome was compared to correction of hyponatraemia by water diuresis. In the second part of the study, we analysed the adaptative response of the brain to correction of hyponatraemia with either urea or water diuresis, by measurement of cerebral osmolyte contents. RESULTS: Despite a large correction of the serum sodium (mean Delta SNa=32 mEq/l/24 h), mortality rate (13%) and neurological symptoms were low in the urea-treated group contrary to control groups treated by water diuresis (mortality: 87%). This shows with stronger evidence the protective effect of urea against brain myelinolysis. In the second part, analysis of brain composition shows that, in the urea groups, 24 h after correction, intracerebral hyperionization (NaCl) was avoided and brain water contents remained normal. No significant changes of the major brain organic osmolyte composition were observed after urea administration except reaccumulation of betaine. No difference in brain composition was noted regarding concomitant plasma urea levels (>or<150 mg/dl). In rats treated by water diuresis, the brain remained also significantly depleted in organic osmolytes 24 h after correction, but contrary to administration of urea, this treatment was associated with a high mortality rate. CONCLUSIONS: These comparative results suggest a specific brain-protective effect of urea itself against myelinolysis.

Successful long-term treatment of hyponatremia in syndrome of inappropriate antidiuretic hormone secretion with satavaptan (SR121463B), an orally active nonpeptide vasopressin V2-receptor antagonist.

The effects of satavaptan (SR121463B), a novel long-acting orally active vasopressin V(2)-receptor antagonist, were investigated in patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In the first part of this randomized, double-blind study, 34 patients first were treated with satavaptan (versus placebo) for up to 5 d and then during 23 d of open-label dosage-adjustment period. In the second part of the study, long-term efficacy and safety of satavaptan was assessed in an open-label trial during at least 12 mo. Mean (+/-SD) serum sodium (SNa) levels before treatment were 127 +/- 2 mmol/L (placebo, n = 8), 125 +/- 6 mmol/L (25 mg, n = 14), and 127 +/- 5 mmol/L (50 mg, n = 12). Responders (patients SNa levels normalized or increased by at least 5 mmol/L from baseline during the double-blind period) were 79% in the 25-mg group (SNa 136 +/- 3 mmol/L; P = 0.006), 83% in the 50-mg group (SNa 140 +/- 6 mmol/L; P = 0.005), and 13% in the placebo group (SNa 130 +/- 5 mmol/L). No drug-related serious adverse events were recorded. During the long-term treatment, 15 of 18 enrolled patients achieved 6 mo and 10 achieved 12 mo of treatment. The SNa response was maintained during this time with a good tolerance. The new oral vasopressin V(2)-receptor antagonist satavaptan adequately corrects mild or moderate hyponatremia in patients with SIADH and has a good safety profile.