Neurologic Complications of Electrolyte Disturbances

Keywords

electrolytes, hypernatremia, hyponatremia, cerebral salt wasting, central pontine myelinolysis, hyperkalemia, hypokalemia, hypercalcemia, hypocalcemia, hypomagnesemia, hypermagnesemia

Electrolyte disturbances occur frequently in clinical practice and are associated with a variety of characteristic central or peripheral (including muscle) neurologic manifestations. Since electrolyte disturbances are usually secondary processes, effective management requires prompt identification and treatment of the underlying primary disorder in addition to correction of the electrolyte abnormality. Moreover, the neurologic consequences of electrolyte disorders are usually functional rather than structural. Consequently, the neurologic manifestations of electrolyte disturbances are often reversible, particularly if corrected and effectively managed at an early stage. The neurologic manifestations of abnormalities of serum sodium, potassium, calcium, and magnesium are reviewed.

Sodium

Extracellular fluid volume is directly dependent on total body sodium, the principal osmotic component of that fluid compartment. Consequently, most patients with hyponatremia are also hypo-osmolar, and those with hypernatremia are hyperosmolar. The symptomatic neurologic manifestations of serum sodium abnormalities typically involve the central, rather than the peripheral, nervous system and generally are the consequence of hypo-osmolarity in hyponatremia and hyperosmolarity in hypernatremia. Because of the brain’s ability to adapt effectively to changes in serum osmolarity, the propensity of hyponatremia or hypernatremia to produce neurologic symptoms generally depends on the rapidity with which the sodium disturbance develops.

Hyponatremia

Hyponatremia with normal osmolarity (pseudohyponatremia) is relatively infrequent and usually occurs in the setting of hyperlipidemia or hyperproteinemia. Hyponatremia with hyperosmolarity usually occurs in the setting of hyperglycemia. Hyponatremia is most often associated with hypo-osmolarity and is classified into three categories that are dependent on whether the extracellular fluid volume is decreased, normal, or increased. Hypo-osmolar hyponatremia with hypovolemia results from excessive renal sodium loss (e.g., from diuretic usage, mineralocorticoid deficiency, salt-losing nephropathy, or osmotic diuresis) or extrarenal sodium loss (e.g., from vomiting, diarrhea, or third-space losses). Hypo-osmolar hyponatremia with normovolemia (no edema) results from conditions such as the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), glucocorticoid deficiency, hypothyroidism, and stress, or in response to various drugs, including carbamazepine and many psychotropic agents. Hypo-osmolar hyponatremia with excess extracellular fluid (edema) occurs in conditions such as cirrhosis, cardiac failure, nephrotic syndrome, and acute or chronic renal failure. The separation of hypo-osmolar hyponatremia into these three categories based on the extracellular fluid volume status has therapeutic implications. In normovolemic and hypervolemic hypo-osmolar hyponatremia, the fundamental principle of therapy is water restriction, whereas in hypovolemic hypo-osmolar hyponatremia the basis of therapy is replacement of water and sodium (generally with isotonic saline or lactated Ringer solution).

Among hospitalized patients, hyponatremia is the most common electrolyte abnormality encountered and is associated with a significant increased risk of death, although this increased mortality likely reflects the seriousness of underlying disorders rather than the hyponatremia itself.

Neurologic symptoms related to hyponatremia are seen much more frequently in patients with acute, rather than chronic, hyponatremia. For example, a serum sodium concentration of 130 mEq/L might produce neurologic symptoms if it developed rapidly, whereas a serum sodium concentration of 115 mEq/L might be asymptomatic if it developed very slowly. An alteration in mental status is the most common neurologic manifestation of hyponatremia and ranges from mild confusion to coma; patients with underlying neurodegenerative disorders and those of advanced age are particularly susceptible to delirium from even small changes in serum sodium. This hyponatremic encephalopathy may be associated with nonspecific generalized slowing on the electroencephalogram. As the level of serum sodium decreases, the risk of seizures increases. The occurrence of convulsions in the setting of acute hyponatremia (typically with a serum sodium concentration less than 120 mEq/L) can be ominous and portend a mortality rate exceeding 50 percent. The occurrence of seizures in patients with acute hyponatremia represents a medical emergency and necessitates rapid, but only partial, correction of the serum sodium concentration. Control of hyponatremic seizures can obtained by the judicious use of 3 percent saline (4 to 6 ml/kg) in an attempt to raise the serum sodium concentration by small 3 to 5 mEq/L increments; careful monitoring with frequent sodium measurements is required to avoid rapid correction. Occasionally, focal neurologic signs and symptoms are seen in the setting of hyponatremia and include hemiparesis, monoparesis, ataxia, nystagmus, tremor, rigidity, aphasia, and unilateral corticospinal tract signs. These focal abnormalities can represent aggravation of an underlying structural lesion and often remit with resolution of the hyponatremia. Such focal deficits therefore require neuroimaging even if they fully resolve with sodium correction. Although occasional muscle twitches and fasciculations may be seen in acute hyponatremia, muscle symptoms other than cramps are not common. The central nervous system (CNS) manifestations of acute hyponatremia are related to cerebral edema, but understanding is incomplete regarding the factors that mitigate hyponatremic osmotic brain swelling and reduction in the brain’s intracellular organic osmolytes.

The use or restriction of fluids can have profound effects on the eventual outcome of patients with hyponatremia and neurologic symptoms and therefore any specific treatment approach should be implemented carefully.

Subarachnoid Hemorrhage and Other Intracranial Diseases

Hyponatremia frequently develops in patients with subarachnoid hemorrhage and has often been attributed to SIADH. Clinicians typically manage all forms of SIADH by instituting some degree of fluid restriction. In an insightful retrospective study of 134 consecutive patients from the Netherlands, 44 patients developed hyponatremia between the second and tenth days following subarachnoid hemorrhage. Hyponatremia was defined as a serum sodium level below 135 mEq/L on at least two consecutive days. Of the 44 hyponatremic patients, 25 fulfilled the laboratory criteria for SIADH. Cerebral infarction, defined as a focal neurologic deficit with or without computed tomography (CT) confirmation or deterioration in the level of consciousness with CT confirmation of ischemic changes, occurred in 46 of the 134 patients. Of the cerebral infarcts, 27 occurred in the 44 hyponatremic patients (61.4%), but only 19 occurred in the 90 normonatremic patients (21.1%). Of the 44 hyponatremic patients, 26 were fluid-restricted; of these, 21 developed infarcts (80.8%). Of the 18 hyponatremic patients who were not fluid-restricted, only 6 developed infarcts (33.3%). Of the 25 patients who fulfilled the laboratory criteria for SIADH, 17 were fluid-restricted; of these, 15 developed infarcts (88.2%). Thus, fluid restriction in hyponatremia following subarachnoid hemorrhage, particularly in those thought to have SIADH, appears to markedly increase the risk of cerebral infarction.

Understanding has been gained of the basis for this risk in fluid restriction in patients with subarachnoid hemorrhage and other intracranial disorders. Care should be taken to carefully distinguish between SIADH and cerebral salt wasting. Because absence of hypovolemia is considered one of the criteria for making the diagnosis of SIADH, the finding of decreased blood volume in patients with hyponatremia and intracranial disease suggests that these patients do not have SIADH. In a prospective study of 21 patients with aneurysmal subarachnoid hemorrhage, plasma volume decreased by more than 10 percent in 11 of the patients. Serum sodium decreased in 9 of the 21 patients. Plasma volume decreased by more than 10 percent in 6 of 9 patients with hyponatremia, and a similar decrease occurred in 5 of 12 patients with normal serum sodium. Eight of the 9 patients with hyponatremia had a negative sodium balance, whereas only 4 of the 12 patients with normal serum sodium had a negative sodium balance. Finally, 10 of the 12 patients with a negative sodium balance had a decrease in plasma volume exceeding 10 percent. Hyponatremia following aneurysmal subarachnoid hemorrhage appears frequently to be related to cerebral salt-wasting and not SIADH. Fluid restriction instituted to correct hyponatremia attributed to presumed SIADH in patients with subarachnoid hemorrhage may exacerbate an already volume-depleted state and subject patients to a greater risk of ischemic cerebral damage from vasospasm. Therefore, patients with subarachnoid hemorrhage and hyponatremia are typically treated instead with oral or intravenous sodium repletion in an attempt to restore or maintain normovolemia.

Central Pontine Myelinolysis (Osmotic Myelinolysis)

The history of the recognition and pathogenesis of central pontine myelinolysis has been summarized elsewhere. Central pontine myelinolysis was recognized as a distinct clinical entity in 1959 in four cases, occurring on a background of alcoholism and malnutrition. Its pathologic features involve a symmetric noninflammatory demyelination in the base of the pons with relative sparing of neurons and axons. The classic clinical presentation includes pseudobulbar palsy and spastic quadriparesis. Following the original description, many additional cases were reported in rapid succession, suggesting that central pontine myelinolysis is not a rare disorder. Many cases were not associated with alcoholism or malnutrition. It may, for example, occur in subjects with extensive burns. By 1964, the relatively high frequency of subclinical lesions ( Fig. 17-1 ) was noted, and this was validated by many subsequent reports.

In 1963, Aleu and Terry suggested that central pontine myelinolysis is related to some recently introduced factors. Also in 1963, the initial suggestion that an electrolyte imbalance was a contributing factor in the pathogenesis of central pontine myelinolysis was first made. It was subsequently observed that acute cases of central pontine myelinolysis (i.e., acute quadriparesis) developed only in hospitalized patients who were being hydrated. From an analysis of 12 acute cases in 1980, Leslie and associates noted that there had been a recent rapid rise of serum sodium in each patient, suggesting that central pontine myelinolysis was an iatrogenic disorder that in most cases was caused by too rapid correction of serum sodium. The factors that led to the appearance of this disorder during the 1950s were the introduction of diuretics, the liberal use of intravenous fluids, and the ability to rapidly measure serum electrolytes. Prospective magnetic resonance imaging (MRI) studies have demonstrated the development of characteristic pontine lesions in patients treated for hyponatremia in whom the rate of correction of the hyponatremia was rapid. In one retrospective study of published reports of patients with central pontine myelinolysis in whom initial values of sodium and potassium were given, all patients who developed the disorder were also hypokalemic initially; this observation is of unclear significance. Patients who develop hyponatremia following liver transplantation may be particularly vulnerable to central pontine myelinolysis if their hyponatremia is corrected rapidly.

Sterns and colleagues, in a review of their experience, noted neurologic complications in eight patients whose serum sodium had been corrected by more than 12 mEq/L per day. Conversely, patients with hyponatremia that was corrected more slowly made uncomplicated recoveries. In a review of the literature, those authors found 80 patients with severe hyponatremia (less than 106 mEq/L). Of these 80 patients, enough detail was reported in 51 to determine a maximal rate of correction of serum sodium. In 39 of 51 patients who were corrected rapidly (greater than 12 mEq/L per day), 22 (58%) had some type of neurologic complication. Of these 22 patients, 14 (64%) were suspected of having central pontine myelinolysis. Of the 13 patients who were corrected slowly (less than 12 mEq/L per day), none experienced a neurologic complication.

Because chronic hyponatremia is less likely to produce neurologic symptoms, and rapid correction of chronic hyponatremia is more likely to produce neurologic injury in experimental models, a judicious approach to the correction of chronic hyponatremia is urged, especially in cases where the sodium has been chronically depressed. There is no justification for using hypertonic saline to treat asymptomatic hyponatremia, or to rapidly correct hyponatremia to levels above 120 to 125 mEq/L in significantly symptomatic hyponatremia.

Animal models of central pontine myelinolysis have been developed in the dog and the rat. In both animals, demyelination follows rapid correction of sustained, vasopressin-induced hyponatremia with hypertonic saline. The label osmotic myelinolysis has been suggested in preference to central pontine myelinolysis because of the well-recognized occurrence of extrapontine myelinolysis. This myelinolysis occurs in areas of the brain characterized by an extensive admixture and apposition of gray and white matter. Although the pathogenesis of osmotic myelinolysis remains undefined, the topography of oligodendrocytes may play a role. Oligodendrocytes in these vulnerable areas are predominantly located within adjacent gray matter rather than within the white matter bundles ( Fig. 17-2 ). Because gray matter is much more vascular than white matter, oligodendrocytes in this location may be more vulnerable to serum osmotic shifts.

The rapid re-induction of hyponatremia has been associated with a reduction in neurologic signs and symptoms suggestive of osmotic myelinolysis in rats and in a single human case in which a rapid increase in serum sodium occurred during the treatment of chronic hyponatremia; it is unclear if this strategy should be employed routinely. Corticosteroids, myo -inositol, immunoglobulin, and thyrotrophin-releasing hormone have all been suggested as possible treatments of or preventive measures for the osmotic demyelination syndrome with little evidence to recommend such therapies. The lack of proven treatment for this disorder further emphasizes the need to avoid its occurrence by slow correction of hyponatremia.

Hypernatremia

Symptoms due to hypernatremia are usually referable to the CNS and most often are seen with serum sodium concentrations above 160 mEq/L. Hypernatremia is most frequently encountered in the very young or very old. In infants, fluid loss due to gastroenteritis is a common cause. In the elderly, dehydration resulting from an inability to obtain water because of debilitation is the most frequent cause. Diabetes insipidus rarely presents with severe hypernatremia unless the patient is also denied access to water. Structural lesions (e.g., gliomas and metastatic tumors) in the hypothalamic thirst center are an uncommon cause of hypernatremia in patients with neurologic disease.

Alteration of mental status is a frequent manifestation of hypernatremia and ranges from lethargy to coma. Pathologic studies suggest that osmotic forces present during the development of hypernatremia, particularly when acute, may produce shrinkage of brain parenchyma. This may result in parenchymal hemorrhages or tearing of bridging veins, producing subdural hematomas or subarachnoid hemorrhage. An initial mortality rate of 20 percent and an incidence of permanent brain damage of more than 33 percent have been noted in children with severe hypernatremia. Seizures may occur in the setting of hypernatremia and paradoxically may be more frequent during rehydration. These hypernatremic seizures may be related to either focal hemorrhages that occur during the development of hypernatremia or cerebral edema that may develop during rehydration. Rigidity, tremor, myoclonus, asterixis, and chorea have also been associated with hypernatremia. Transient thalamic signal changes on MRI have been seen with severe hypernatremia. Neuromuscular manifestations of hypernatremia are much less frequent. Rhabdomyolysis and episodic muscle weakness have been reported. Treatment of symptomatic hypernatremia typically involves administration of hypotonic fluids to correct the free water deficit, using caution to avoid rapid correction.

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