osmoticdemyelinationsyndrome (ODS) is a severe neurological disorder that manifests mainly as centralpontinemyelinolysis (CPM) and extrapontinemyelinolysis (EPM). In 1976, Tomlinson first suggested that rapid correction of sodium levels in the treatment of chronic severe hyponatremia could be a serious complication of ODS.1 Since then, there has been evidence that chronic alcohol abuse, malnutrition, chronic diuretic use, liver failure, burns, etc. liver failure, and burns may also be risk factors for ODS. In this paper, we will introduce ODS associated with hyponatremia due to neurological disorders, and review the pathogenesis and relevant advances in clinical management. 1. Neurological diseases and hyponatremia Hyponatremia is more common among the problems of water and salt metabolism disorders caused by neurological diseases. Central hyponatremia is mainly associated with neurological primary diseases (including craniocerebral injury, intracranial inflammation, intracranial hemorrhage, intracranial tumor, etc.), neurosurgery, and taking neurophilic drugs. CSWS is mainly due to cerebral malfunction resulting in altered renal function and sodium loss from urine, while SIADH is mainly due to overproduction of antidiuretic hormone. Hyponatremia is closely related to the occurrence of ODS when various factors cause hypothalamic-pituitary system dysfunction. Tsutsumi3 and Srimanee et al4 have reported hyponatremic ODS associated with craniopharyngioma and pituitary gonadotrophic adenoma in the pterygoid area, respectively, pointing out that changes in pituitary hormones lead to uncontrollable blood sodium levels during hyponatremia correction and make it more likely to develop ODS. 2. Clinical manifestations and diagnosis of hyponatremia-associated ODS Hyponatremia-associated ODS occurs The first phase of hyponatremia is the manifestation of encephalopathy, followed by a rapid correction of the sodium level to normal, but after a period of time, the neurological symptoms will further deteriorate, and this is the second phase, which indicates the beginning of ODS. CPM manifestations include dysphonia and dysphagia (secondary to damage to the cortical medullary tract); if the lesion involves the dorsal part of the pons, pupillary and oculomotor abnormalities will be present. In addition, the patient may have impaired consciousness, which in severe cases may manifest as an “atresia syndrome”. The MRI of CPM is characterized by low signal in the T1 phase and high signal in the T2 phase, and Moreno et al. performed an MRI study of 13 patients with a clinical diagnosis of ODS: although the clinical presentation varied in severity and the underlying disease differed widely, all patients showed typical ODS imaging in the T2 and FLAIR phases of the brainstem. Diffusionweightedimaging (DWI) can detect lesions that are undetectable in the T2 phase, and a case report has shown that DWI imaging changed within 24 h of onset in a paralyzed patient, whereas no significant changes were detected by conventional MRI during this time. It is important to note that there is a time delay from onset to the appearance of imaging changes on MRI. Generally, MRI may show more meaningful changes after 10-14 days of onset than before. However, because the MRI presentation of CPM is so specific that many people are accustomed to conclude the diagnosis on the basis of MRI, it is easy to miss such patients at an early stage, and the current diagnostic criteria reported in the literature do not yet refer to pathological evidence. Nevertheless, MRI does not provide prognostic information, nor does it predict disease outcome by the extent and duration of the lesion. Moreover, many clinical cases have shown that the extent of lesions on MRI imaging is not necessarily related to the degree of clinical neurological impairment or the course of the disease itself. 3. Pathophysiological mechanisms The exact mechanism of the occurrence of ODS due to hyponatremia with excessive sodium entrapment is widely discussed, among which the apoptosis hypothesis is more representative. This hypothesis believes that apoptosis of glial cells caused by metabolic stress is the most fundamental reason for the occurrence of ODS. As a sensitive cell for ODS, glial cells play a significant role in regulating extracellular osmotic pressure and electrolyte balance. When the brain interstitium is in a hypotonic state during hyponatremia, glial cells translocate water into the cells through water channels, leading to cell swelling. To avoid further cellular swelling, cells will transfer osmotically active substances out of the cell to lower the cytoplasmic osmolarity, thus limiting water accumulation. Once serum sodium is elevated and normal extracellular osmolarity is restored, water will be translocated out of the interstitium from ion deficient as well as hypotonic cells, which will result in relative cellular dehydration. In order to reduce their own crumpling, the cells must again initiate a pathway to maintain intracellular osmotic pressure. At this point, glial cells must activate the Na+-K+-ATP pump (NKAT) to transport ions in order to adjust intracellular electrolyte levels, thus bringing about metabolic stress, and the metabolic characteristics and structure of glial cells determine that they are very sensitive to energy depletion and eventually activate apoptosis through the glutamate toxic metabolic pathway. 4. Treatment of hyponatremia due to neurological diseases occurring in ODS and prevention of treatment There are some key principles to deal with ODS, to identify risk factors in time, such as excessive alcohol intake, nutritional deficiency resulting in significant weight loss, etc. Of course, more attention should be paid to correct the blood sodium rate should not be too fast. Recent experiments have shown that treatment with antidiuretic hormone can improve the condition when CPM begins to show symptoms related to myelinolysis. In cases of overcorrection of hyponatremia, the use of desmopressin (AVP) has been shown to be effective in inhibiting the progression of the disease. In patients who have reached or exceeded the limit of sodium replacement, desmopressin can be given intravenously to prevent or reverse excessive increases in sodium levels if hypotonic urine is still being excreted. The reported treatments for CPM with thyrotropin-releasing hormone, methylprednisolone, and immunoglobulin lack evidence-based medical evidence and the specific mechanism of action is unclear, so they have limited persuasive power. Minocycline has recently been found to be effective in reducing the demyelinating effects of brain and clinical symptoms, and in reducing the risk of death after rapid correction of hyponatremia. The theoretical basis may be related to minocycline reducing blood-brain barrier permeability, inhibiting glial cell activation, reducing IL-1α expression and protein nitrosylation, etc. 5. Prevention of hyponatremia management The key to the prevention of hyponatremia-related ODS is the rational management of hyponatremia. Obviously, the cause of hyponatremia must be clarified (abnormal antidiuretic hormone secretion syndrome, hyperalgesia, salt-losing nephropathy, etc.), and the management of the cause must be given extra attention. Management of asymptomatic hyponatremia The general principle for patients with hyponatremia without obvious symptoms is that there is no urgent need for intervention. Some patients may not have any significant symptoms even if the blood sodium level has dropped to 115-120 mmol/L due to chronic adaptation. However, some patients may have mild impairment such as fatigue, drowsiness, nausea, abnormal gait, and abnormal concentration. Such patients should be recognized clinically in time to avoid the persistence of some reversible excessive volume factors. Management of symptomatic hyponatremia The treatment of hyponatremia, whether etiologic or specific measures to correct sodium, is not directly related to the development of ODS, whereas the rate of sodium correction is critical. The treatment of any patient with hyponatremia must consider the issue of the rate of sodium correction. Many people realize that the dilemma in the management of hyponatremia is that “it seems wrong to do or not to do”, referring to the consequences of rapid and slow sodium correction, which cannot be fully balanced between the development of ODS due to rapid sodium replacement and cerebral edema due to too slow sodium replacement in hyponatremia. Treatment of acute hyponatremia (hyponatremia occurring in less than 48h) Retrospective studies have shown that rapid sodium correction in acute hyponatremia has a good prognosis. Even with a rapid and relatively large rise in serum sodium, patients rarely develop neurological complications. Some cases have also reported that rapid sodium correction in acute hyponatremia can lead to myelinolysis, but evidence suggests that a rate of sodium correction below 3-4 mmol/L may increase the risk of death in patients with acute or postoperative hyponatremia. Considering that the risk of death from cerebral edema is much higher than the risk of individual ODS due to rapid sodium correction, rapid correction of sodium levels is still used for acute hyponatremia. However, there are no objective and uniform clinical criteria in determining acute and chronic. Therefore, it is not possible to simply correct sodium quickly whenever chronicity is suspected. Treatment of chronic hyponatremia (hyponatremia for more than 48h or if the duration of hyponatremia cannot be determined) Complications often arise from the “self-correction” of hyponatremia by the patient’s body, which is difficult to recognize during the treatment of hyponatremia. In the absence of secretory release of ADH, patients may excrete large amounts of dilute urine, which can lead to a rise in blood sodium levels of more than 2 mmol/L per hour, with the potential for life-threatening sodium overload within 12 hours. Because of these dangers, the rate of exogenous sodium correction is generally adjusted to approximately 8 mmol/L per day, and frequent monitoring of blood sodium levels and urination is required. In the case of severe hyponatremia, on the other hand, considering that the severe damage of hyponatremia itself has exceeded myelinolysis, rapid and restrictive sodium replacement may be used, such as in patients with chronic hyponatremia combined with epilepsy, which requires prompt management. In general, it is feasible if the total rise in serum sodium does not exceed 10 mmol/L in 24 hours or 18 mmol/L in 48 hours. 6. Prognosis Twenty-five patients with ODS were reported, all with blood sodium levels below 120 mEq/l, with clinical neurological symptoms, and all received intravenous infusion of 3% NaCl. The results showed that 11 patients had a “good” outcome and 13 patients had a “poor” outcome. Of the 11 with good outcomes, 7 recovered completely and the remaining patients achieved functional independence with only minor cognitive impairment or extrapyramidal sequelae, while of the 13 with poor outcomes, 12 died and 1 was in a persistent vegetative state. In the univariate analysis, three factors were strongly associated with adverse outcome: hyponatremic blood sodium level ≤115 mEq/l; combined hypokalemia; and GCS score ≤10 at admission, whereas clinical features, primary illness, ODS type, EEG and MRI features were not available as prognostic evaluation indicators. In the multifactorial analysis, only the effect of blood sodium level was the most significant. The cases of ODS that occurred in patients with non-severe hyponatremia and strict slow sodium supplementation suggest that there are more in-depth pathogenetic mechanisms to be investigated, which may be related to certain cytokines in the regulatory apoptosis system, especially those related to energy metabolism at the same time. In future experimental studies the presence of abnormal energy metabolism should be explored along with the establishment of animal models of osmotic stress; meaningful structural mutations should be found in animal models of abnormal glucose metabolic pathways to explain the susceptibility factors of ODS. As for the treatment of hyponatremia, AVP receptor antagonists need to be validated in further clinical trials.