BRAIN COMPOSITION IN ACUTE VERSUS CHRONIC HYPONATREMIA
In animals that have hyponatremia for <24 hours, cerebral edema is severe and rapid correction of hyponatremia returns brain water content to normal with no adverse consequences.8 After 3 days of hyponatremia, brain swelling is minimal and brain histology remains normal, even when the serum sodium concentration is maintained at very low levels for several weeks.14 However, if more sustained hyponatremia is rapidly corrected, the animals deteriorate neurologically and myelinolysis develops.8, 15, 16, 17 Similarly, in humans with acutely developing hyponatremia (e.g., subjects with self-induced water intoxication due to psychosis or marathon running and whose hyponatremia developed in <1 day), rapid correction of hyponatremia improves symptoms, alleviates brain edema, and does not usually cause myelinolysis.18 In contrast, in patients with chronic hyponatremia whose serum sodium levels are ≤105 mEq/L (by definition, patients who become hyponatremic at home drinking conventional amounts of water), correction by ≥18 mEq/L over 48 hours leads to transient or permanent neurologic sequelae in approximately 50% of individuals.8
In rats with uncorrected chronic hyponatremia, brain sodium content is low. If the disturbance is corrected rapidly, brain sodium content rapidly increases and an overshoot of brain sodium to supernormal levels occurs.8, 19, 20 Regardless of whether hyponatremia is corrected rapidly or slowly, it takes several days for organic osmolytes to return to the brain.10, 20, 21 The reuptake of organic osmolytes after correction of hyponatremia is slower than is the loss of organic osmolytes during the adaptation to hyponatremia. Similar slow recovery of myoinositol has been shown by magnetic resonance spectroscopy in a human subject with a serum sodium level of 101 mEq/L. Before correction, brain myoinositol was almost undetectable. By 10 days after correction of hyponatremia, brain myoinositol levels were still very low; repeat spectroscopy 2 months later showed a return of brain myoinositol to normal levels.22
The recovery of organic osmolytes by the brain after the correction of hyponatremia occurs at different rates in different brain regions. Of note, there is an inverse correlation between the regional efficiency of recovering organic osmolytes and the severity of myelinolysis that occurs in that region.21
The precise cause of brain injury after rapid correction of hyponatremia is not fully known. However, as experimentally induced myelinolysis is associated with disruption of the blood-brain barrier, shrinkage of endothelial cells may play an important role.23, 24 Disruption of the blood-brain barrier allows complement components, which are toxic to oligodendrocytes, and other potentially neurotoxic components to enter the brain after rapid correction of hyponatremia.23 The localization of complement components corresponds to areas of myelinolysis. Other observations suggest that the osmotic insult created by a rapidly increasing serum sodium concentration triggers apoptosis in myelin-producing cells.25
