Extrapontine myelinolysis following rapid correction of iatrogenic hyponatremia
The patient was transferred to the neurologic intensive care unit where he remained intubated and minimally responsive, ultimately requiring tracheostomy and placement of a gastrostomy tube for nutritional support. He was continued on prophylactic anticonvulsant medication, although no clinical seizure activity was observed following admission. A repeat electroencephalogram showed diffuse slowing, greatest in the frontal lobes, but no evidence of seizure activity. MRI of the brain showed increased T2-weighted signal hyperintensities involving the cerebral cortex and the basal ganglia, consistent with extrapontine myelinolysis. Over the following month the patient underwent slow improvement in neurologic function, with increased eye opening and tracking of movements, followed by spontaneous movements in the arms and legs. He required treatment with benzodiazepines and quetiapine for agitation. He also developed a resting tremor in both arms, and oral-facial dyskinesias attributed to damage in the basal ganglia. An extensive hematologic evaluation revealed no evidence of a bleeding disorder. At the time of discharge, the patient was able to follow three step commands, could communicate effectively through a Passy-Muir speaking valve with occasional word-finding difficulty, and could ambulate with support. He continued to experience confusion and exhibited poor short-term memory. MRI of the brain, repeated shortly prior to discharge, showed more pronounced frontal lobe cortical abnormalities, without other major changes from the prior study. The patient was discharged to a comprehensive rehabilitation facility, and was ultimately able to be released to the community. His extrapyramidal symptoms largely resolved, with the exception of mild dystonia in an upper extremity.
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.
For these reasons, patients at risk of developing significant hyponatremia should be closely monitored. Treatment of symptomatic acute hyponatremia must balance the risk of development of osmotic demyelination with the risk of complications from the hyponatremia itself. Recent recommendations suggest that hyponatremia be corrected at a rate of not more than 8 mmol/L/day, although initial rates of correction may be as much as 1-2 mmol/L/hour until life-threatening symptoms resolve (Adrogue and Madias, 2000). Monitoring of sodium levels every 2-3 hours may be necessary in order that adjustments in treatment can be made to avoid overly rapid changes or reduce the impact of overcorrection. Chronic hyponatremia without life-threatening symptoms should be corrected very slowly. It is difficult at times, however, to distinguish chronic from acute alterations in the emergency setting.
Diagnosis of osmotic demyelination syndromes begins with recognition of predisposing risk factors for hyponatremia, and a clinical course suggesting development of symptoms after a documented or suspected osmotic stress. Other disorders that could produce cortical, basal ganglia, or white matter injury, such as status epilepticus, hypoxic-ischemic events, hypertensive emergencies, and Wernicke encephalopathy, should be considered in the differential diagnosis.
The classic presentation of central pontine involvement is pseudobulbar palsy (dysphagia, dysarthria, ophthalmoplegia) and focal or generalized weakness progressing to quadriplegia. Extrapontine disease can present with ataxia, parkinsonism, athetosis, dystonia, confusion, behavioral or personality change, hallucinations, seizures, catatonia, and akinetic mutism depending on the areas involved (Brown, 2000; Chalela and Kattah, 1999). Symptoms may progress over several days, and in severe cases may lead to a locked-in state, coma, or death. Clinical symptoms of myelinolysis follow changes in sodium levels by an average of 6 days (Norenberg et al., 1982; Menger and Jorg, 1999), but the timing may vary considerably. Computed tomography may show hypodensities in affected areas, but generally is insensitive to detect osmotic injury (Sterns et al., 1986, Brown, 2000). Central pontine myelinolysis appears an area of hyperintensity on T2-weighted MRI sequences, and may show contrast enhancement early in the course of disease (Miller et al., 1988; Menger and Jorg, 1999). Extrapontine involvement has been described as hyperintense on T2-weighted images, with low to normal signal on T1-weighted images (Waragi and Satoh, 1998; Chen et al., 1996). MRI abnormalities may persist for years after the clinical syndrome has resolved (Thompson et al., 1989).
Initial descriptions of osmotic demyelination disorders were based on autopsy findings, and a very high mortality was thought to be the rule. As imaging techniques have improved diagnosis and supportive care has also advanced, many cases of survival with variable residual deficits have been reported. In a series of 34 patients with central and/or extrapontine myelinolysis, two died during the acute illness, 11 had no significant functional residual deficits, 11 had minor deficits but could live independently, and 10 had deficits leaving them dependent on assistance (Menger and Jorg, 1999). Outcome was not correlated with the degree or pattern of involvement seen on MRI imaging. In this same group, symptoms did not progress further beyond the acute phase of illness, with the exception of development of dystonia in one patient. Onset of delayed dystonia four months after acute disease has also been described in another patient (Sieser et al., 1998). The literature contains isolated case reports of patients improving after treatment with plasmapheresis, steroids, and/or thyroid releasing hormone, but no controlled trials have been performed (Brown et al., 2000). For patients with extrapyramidal symptoms resulting from extrapontine myelinolysis, symptomatic treatment with dopaminergic compounds does appear to provide benefit (Kim et al., 2003; Nagamitsu et al., 1999).
DDAVP (desmopressin acetate) is a synthetic compound structurally related to vasopressin (anti-diuretic hormone). Similarly to vasopressin, DDAVP is believed to increase water resorption in the kidney. However, DDAVP is more potent than vasopressin in regards to antidiuretic action, especially in its parenteral form (McEvoy, 2002). DDAVP also acts to increase the activity of plasma factor VIII and is indicated for perioperative use in patients with documented von Willebrand disease and Hemophilia A to control bleeding. It is recommended that patients receiving this medication be monitored for hyponatremia and water intoxication, especially in those persons who do not require the anti-diuretic effect of DDAVP.
We thank George Ringholz, M.D., Ph.D., of the Department of Neurology at Baylor College of Medicine, for his assistance with this patient's case. We also thank the patient, who gave permission for his case to be presented.
Comment: Many medical textbooks convey the impression that osmotic myelinolysis syndromes are rarely encountered. Based on our experience, we do not believe this impression to be correct. These syndromes are variable in their severity, clinical presentation and anatomic involvement, and their features are easily confused with the sequelae of comorbid illnesses. Osmotic demyelination is often diagnosed with hesitancy due to the difficulty of excluding competing diagnoses or due to potential medicolegal implications. For these reasons, we believe that the osmotic myelinolysis syndromes remain underdiagnosed, and deserve greater clinical awareness and research interest. Dr. Noe's case presentation and discussion aptly highlights a number of the issues involved.
-- Dennis R. Mosier, M.D., Ph.D.
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