Osmotic Demyelination Disorders

The most well-known of these disorders, central pontine myelinolysis, was first described by Adams, Victor and Mancall in 1959. They reported 4 cases of symmetric demyelination of the central pons, without evidence of axonal loss, inflammation, or vascular injury. The patients were alcoholic and/or chronically malnourished. Two cases were felt to be asymptomatic, and the other 2 presented with pseudobulbar palsy and quadriplegia evolving over several days. In the years following this initial report, it was recognized that demyelination could occur in other regions; this was termed extrapontine myelinolysis (Wright et al., 1979). In a study of 58 cases of osmotic demyelination syndromes (Gocht and Colmant, 1987), 47% had exclusively central pontine involvement, 22% had exclusively extrapontine involvement, and 31% had both central pontine and extrapontine myelinolysis. Extrapontine demyelination involves white matter tracts closely abutting or interpenetrating grey matter structures, including deep cortical layers, layers adjacent to crowns of cerebral gyri, external and extreme capsules, cerebellum, basal ganglia, and thalamus (Gocht and Colmant 1987; Okeda et al., 1986).


While central pontine myelinolysis was initially linked with alcoholism, it was subsequently recognized to be associated with electrolyte derangements, particularly fluctuations in serum sodium sufficient to cause rapid changes in serum osmolality. Causes of hyponatremia are numerous, and may reflect derangements in water or sodium intake (e.g., psychogenic polydipsia), changes in the balance of intra- and extra- cellular fluids (e.g., “third spacing” during or after surgery), alterations of other osmotically active electrolytes (e.g. hyperglycemia), alterations in renal function (as may occur in renal failure or through use of diuretics), or abnormalities of antidiuretic hormone (e.g., Syndrome of Inappropriate secretion of AntiDiuretic Hormone, or SIADH) (Adrogue and Madias, 2000). Hyponatremia may occur in association with inappropriate ADH secretion after tumor lysis from antineoplastic agents such as cyclophosphamide, or in some instances from direct effects of these agents themselves on ADH secretion. There are reports of cases of patients with pontine and extrapontine myelinolysis from hyponatremia induced by primary diabetes insipidus, use of angiotensin converting enzyme (ACE) inhibitors, or use of thiazide diuretics (Tinker et al., 1990; Chen et al., 1996; Tomita et al., 1997; Nagamitsu et al., 1999; Koussa and Nasnas, 2003). In this patient’s case, the use of DDAVP (desmopressin), vomiting, and the postoperative state were recognized as predisposing factors for rapid osmotic alterations.


When serum sodium levels fall, the resulting hypotonic state can lead to brain edema. Clinical symptoms typically are seen as serum sodium acutely falls below 125 mmol/L, and include muscle aches, headache, nausea, vomiting, lethargy, confusion, seizures, coma, respiratory arrest, brainstem herniation, and death (Adrogue and Madias, 2000). Following acute drops in serum sodium concentrations, the body rapidly adapts over a period of hours with efflux of sodium, potassium, and chloride ions from the intracellular compartment to adapt and restore normal cellular volume (Adrogue and Madias, 2000). Rapid correction of sodium levels may then cause cellular shrinkage. However, the mechanism by which demyelination results remains unclear. Due to the preferential involvement of white matter tracts closely adjacent to gray matter in both central pontine and extrapontine syndromes, the production of a “myelinotoxic” substance by gray matter has been proposed (Norenberg, 1983; Okeda et al., 1986). However, a compelling explanation for the preferential involvement of these brain regions remains to be demonstrated.
The nature and degree of insult required to trigger osmotic injury remains unclear. A 1986 study by Sterns et al. recognized that correction of hyponatremia at a rate greater than 12 mmol/L/day was associated with development of osmotic demyelination; no patient in their study who was corrected at slower rates suffered permanent neurologic deficit as a result of hyponatremia alone. Based on these observations, Sterns et al. (1986) termed central pontine myelinolysis an “iatrogenic disease” caused by parenteral sodium repletion. Others have argued that it may not be solely the rate of change but also the degree of total change that places patients at risk (Ayus et al., 1987). The role of hyponatremia-induced seizures in predisposing to later osmotic demyelination is also not well understood. To date, experimental models using vasopressin-induced hyponatremia in rats, dogs, and rabbits demonstrate brain demyelination only when sodium is rapidly corrected, and not with slow correction or no correction (Kleinschmidt-DeMasters and Norenberg, 1981; Laureno, 1983; Laureno and Karp, 1997). These models do not, however, take into account the effects of underlying disorders which may be present in human patients. It should be noted that although correction of hypernatremia has been associated with osmotic myelinolysis, patients with normal sodium levels have also been reported to develop changes characteristic of osmotic demyelination syndromes. These patients may include alcoholics and malnourished individuals. Patients with liver disease or liver transplants, sepsis, acute pancreatitis, renal failure, diabetic ketoacidosis, adrenal insufficiency, and amyotrophic lateral sclerosis have also been reported to be at increased risk for development of osmotic demyelination (Brown, 2000). Patients with extensive and severe burn injuries may be especially susceptible to development of osmotic demyelination syndromes.