Hyponatremia and the Brain
Brain capillaries, unlike systemic capillaries, are impermeable to sodium, owing to endothelial tight junctions, and astrocyte foot processes that surround brain capillary walls. Hypotonic hyponatremia creates an osmotic force across the blood–brain barrier that results in water movement into the brain through aquaporin 4 water channels, expressed on astrocyte membranes. Astrocytes play a central role in water handling during hyponatremia.[2–4] In contrast to neurons, which retain their normal volume, astrocytes swell when confronted with hyponatremia. Brain swelling from acute hyponatremia increases intracranial pressure, impairing cerebral blood flow, leading rarely to fatal herniation. Within 48 h (which defines 'chronic'), astrocytes adapt to hyponatremia with an adaptive loss of cell solute, most notably organic osmolytes (e.g., glutamate, myoinositol, and taurine), permitting intracellular osmolality to equal plasma osmolality without increasing cell volume.[1–4] Organic osmolytes are intracellular solutes found throughout nature; their concentrations can vary without perturbing cell functions. Hyponatremia results in the release of organic osmolytes through volume-sensitive leak pathways, and down regulates osmolyte-accumulating transporters. Although this adaptation permits survival, it also may contribute to symptoms; for example, the adaptive loss of glutamate, an excitatory neurotransmitter, may increase the susceptibility to seizures in acute hyponatremia, and depletion of intracellular glutamate, may contribute to some of the neurological findings of chronic hyponatremia. In addition, osmolyte depletion makes astrocytes susceptible to injury if chronic hyponatremia is corrected too rapidly. Recovery of lost brain osmolytes may take a week or longer; therefore, rapid correction of hyponatremia is an osmotic stress to astrocytes, resulting in apoptosis and a delayed onset of demyelination that presents clinically as the osmotic demyelination syndrome (ODS).[2–4]
Patients with ODS have a biphasic course: an initial improvement in hyponatremic symptoms is followed by new findings, which can include seizures, behavioral changes, swallowing and speech dysfunction, paralysis, and movement disorders.[4,6] Although ODS can cause permanent disability or death, it is potentially reversible, even in patients who require ventilator support. Experiments in animals indicate that ODS can be prevented by relowering the serum sodium concentration after rapid correction, or by the administration of exogenous myoinositol.[4,7] The treatment of hyponatremia with urea rather than with hypertonic saline or vasopressin antagonists reduces the incidence and severity of ODS in animals. However, the initial rate of correction was likely to have been slower after urea, making it difficult to interpret these findings.[8,9] High levels of urea may prevent brain dehydration after rapid correction of hyponatremia, but uremia does not provide full protection against dialysis-related ODS. Several techniques have been described to prevent a large increase in serum sodium when dialyzing high-risk patients.[10,11]
Chronic hyponatremia is common in hepatic cirrhosis; untreated hyponatremia is associated with impaired cognition and poor outcomes, and neurological complications related to rapid correction of hyponatremia often complicate liver transplantation.[12–14] In an uncontrolled open label study, increasing serum sodium from 126 ± 2 to 132 ± 3 mmol/l with tolvaptan significantly decreased white mater but not gray matter volume, as determined by MRI, and significantly improved cognitive test performance in 14 cirrhotic patients; a 30% reduction in blood ammonia levels, possibly from decreased ammonia reabsorption caused by increased urine flow, could explain both decreased brain swelling and improved cognitive performance.
Curr Opin Nephrol Hypertens. 2016;25(2):114-119. © 2016 Lippincott Williams & Wilkins