Hyponatremia as the presenting manifestation of empty sella syndrome is rare. There is little clinical experience in the management of this problem and its possible therapeutic complications. We herein report on a 44-year-old woman with a past history of massive postpartum hemorrhage who was admitted because of hyponatremia and disturbed consciousness. Initial biochemical data suggested the effects of antidiuretic hormone, but fluid restriction alone offered limited benefit. Later, hormonal levels indicated hypopituitarism. Magnetic resonance imaging and cisternography led to a diagnosis of empty sella. Although glucocorticoid substitution was initiated and the clinical condition initially improved, possible myelinolysis subsequently became a complication. With early recognition and immediate replacement of hypotonic fluid, the patient completely recovered. We report this case to illustrate the fact that glucocorticoid substitution and concurrent fluid restriction can probably lead to myelinolysis in empty sella syndrome patients. We suggest that the serum sodium level should be frequently monitored and that much more attention should be paid to the neurologic signs when substituting glucocorticoids in these patients, even though the increment in the serum sodium level is acceptable. Once possible myelinolysis develops, early recognition is critical, and the immediate replacement of hypotonic fluid is suggested.
(Chang Gung Med J 2002;25:838-43)
Keywords：
glucocorticoid substitution, hyponatremia, empty sella, myelinolysis.

Hyponatremia as the presenting manifestation of empty sella syndrome was first reported in 1987.(1) Its clinical presentation resembles that of the syndrome of inappropriate antidiuretic hormone (ADH) secretion, but fluid restriction alone is unable to correct this problem. Sheehan's syndrome (postpartum anterior pituitary necrosis) is often accompanied by empty sella.(2,3) As such, glucocorticoid substitution is the mainstay treatment in this setting. However, there are no practical guidelines for glucocorticoid substitution in these hyponatremic patients. Excessive glucocorticoids given in too short of a period of time may increase the risk of rapid correction of the hyponatremia and resultant neurologic deficits. In addition to the well-known risk factors for myelinolysis, such as alcoholism, liver disease, malnutrition, thiazide therapy, and extreme hyponatremia (< 105 mmol/l),(4) adrenocortical insufficiency may also be a potential risk factor. Herein, we report on an empty sella syndrome patient who received glucocorticoid substitution and concurrent fluid restriction to correct hyponatremia, subsequently developed possible myelinolysis, and ultimately survived with no neurologic sequelae. Causes of the rapid correction of the hyponatremia in this setting are further discussed.
CASE REPORT

This 44-year-old woman, a housewife, was admitted because of hyponatremia and disturbed consciousness. She had no liver disease and never drank alcohol. She also denied any history of using diuretics. She had a history of postpartum hemorrhage which had occurred 13 years previous. Amenorrhea and failure to lactate developed thereafter. Fatigue and cold intolerance were also found. She neglected these problems and received no treatment. She lived an uneventful life until 1 day prior to this admission when she suffered from vomiting and diarrhea. Drowsiness developed the next day. She was then sent to our hospital for further management.
Physical examination revealed a chronically ill-looking, moderately nourished female. She weighed 48 kg and was 156 cm tall. Her blood pressure was 120/67 mmHg. Her pulse rate was 60 beats/min, her respiratory rate was 19/min, and her temperature was 36.5oC. She was drowsy, her fluid status was clinically euvolemic, and her conjunctiva appeared anemic. There was scanty axillary and pubic hair. The thyroid gland was not palpable, and no remarkable findings were present in the chest or abdomen. Laboratory data were as follows: hemoglobin 95 g/l, white blood count 8.1×109/l, platelets 177×109/l, glucose 5.8 mmol/l, blood urea nitrogen 1.1 mmol/l, serum creatinine 62 mmol/l, sodium 116 mmol/l, potassium 2.6 mmol/l, chloride 85 mmol/l, calcium 2.1 mmol/l, albumin 35 g/l, serum osmolality 231 mmol/kg, urine osmolality 257 mmol/kg, urinary sodium 155 mmol/l, urinary potassium 20 mmol/l, and urinary chloride 140 mmol/l. Urinalysis revealed unremarkable findings. Hypopituitarism was confirmed by a determination of the hormonal levels (Table 1). Severe adrenocortical insufficiency with a low cortisol level was found. Initial brain computed tomography (CT) revealed no evidence of cerebral edema, infarction, hemorrhage, or mass. Magnetic resonance imaging (MRI) showed an equal intensity of both the sella turcica and the cerebrospinal fluid (Fig. 1). Cisternography demonstrated an intrasellar filling of contrast in the pituitary fossa. Thus, a diagnosis of empty sella was made.
She received a normal saline infusion and potassium supplements in the emergency room. The hypokalemia was thus corrected, but the serum sodium level continued to drop. Intravenous fluid supplementation was discontinued on admission. After 4 days of water restriction, the sodium concentration rose to 121 mmol/l, and her consciousness became clearer. Unfortunately, her blood pressure dropped to 90/60 mmHg the next day. Hydrocortisone (100 mg) was given intravenously at 8-h intervals because an adrenal crisis was suspected. Three days later, although her blood pressure had returned to normal values, mutism and spastic quadriparesis developed and progressed to a "locked-in" state. The brain CT at that time revealed no evidence of infarction, hemorrhage, or mass. The sodium concentration was elevated to 142 mmol/l. Because myelinolysis was suspected, hypotonic fluid was given immediately. The glucocorticoid was also tapered-down to 20 mg/day prednisolone. Three days later, the neurologic deficit had gradually improved. Although the MRI, which was performed 6 days after the onset of the neurologic deficit, revealed no evidence of myelinolysis, complete recovery was reached after 5 days of hypotonic fluid supplementation. The serum sodium concentration remained at 136 mmol/l (Fig. 2).
After hormonal substitution of 50 mg cortisone acetate in 2 divided doses and 0.1 mg/day L-thyroxin, the hyponatremia no longer recurred.

DISCUSSION

An empty sella turcica is defined as a sella, which is completely or partly filled with cerebrospinal fluid.(5) When seen after surgery, irradiation, or medical treatment of the pituitary gland, it is considered secondary, but otherwise it is primary. Sheehan's syndrome is often accompanied with an empty sella. Fleckman et al.(2) and Bakiri et al.(3) reported that an empty sella was shown by CT in 12 of 13 patients and 39 of 54 patients with Sheehan's syndrome, respectively. Sheehan's syndrome in this case was responsible for the secondary empty sella syndrome. Both primary and secondary empty sella syndrome can cause hyponatremia, which results from hypopituitarism.
Hyponatremia can be the presenting manifestation of Sheehan's syndrome. It can be chronic or appear in the early post-partum period.(6) ADH is known to play a role in the pathogenic mechanism.(7) However, the cause of ADH secretion in hyponatremia associated with hypopituitarism is related to adrenocortical insufficiency.(8) The glucocorticoid deficit is not an osmotic but a physiological stimulus for ADH secretion.(7,9) Glucocorticoids have been shown to reverse the impaired water diuresis of this disorder by increasing the renal excretion of solute-free water. Ahmed et al. suggested that glucocorticoids promote normal water diuresis by inhibiting the secretion of ADH from the neurohypophysis.(10) Thus, glucocorticoid substitution has been the mainstay treatment of hyponatremia associated with hypopituitarism. In reviewing the literature, we found that the dosage of this hormone substitution has varied (Table 2),(1,6,7,11) ranging from 25 mg/day cortisone to 640 mg/30 hours hydrocortisone. In our case, however, 100 mg hydrocortisone was given intravenously at 8-h intervals due to fear of an adrenal crisis. Unfortunately, neurologic deficits ensued, and myelinolysis was highly suspected.
Myelinolysis was first described as a pathologic entity. However, a reliable diagnosis before death is now possible on the basis of the clinical syndrome and setting. Typical features are disorders of the upper motor neurons, spastic quadriparesis and pseudobulbar palsy, and mental disorders ranging from mild confusion to coma.(12) Brain imaging is the most useful diagnostic test, and an MRI is more sensitive. Nevertheless, myelinolytic lesions may not be apparent on scans during the first 2 weeks of illness. Thus, a diagnosis of myelinolysis should not be ruled out simply because brain imaging during the first 2 weeks of the illness shows no lesions.(12,13) Because therapeutic complications developed and the brain CT showed no evidence of infarction, hemorrhage, or mass in our patient, myelinolysis was first considered.
Myelinolysis is associated with a rapid rate of hyponatremia correction, rather than with the absolute sodium concentration. Chronically hyponatremic patients do not necessarily develop myelinolysis, which can even occur with hypernatremia.(12) Two possible factors in our case may have contributed to the rapid rate of correction. First, fluid restriction resulted in a negative water balance. Second, a large dose of glucocorticoid substitution as a life-saving measure for the adrenal crisis may have greatly promoted normal water diuresis. In addition, the half-life of ADH is only 15-20 min. Hence, the effect of ADH suppression by glucocorticoids may appear in a short period of time, and result in rapid correction of the hyponatremia. Lower doses of hydrocortisone are usually effective in the correction of hyponatremia resulting from hypopituitarism.(1,6,7) However, when a patient presents with an adrenal crisis and hyponatremia, high-dose hydrocortisone is life-saving. Furthermore, as shown in Table 2, case 7 received an even larger dose of glucocorticoid in a short period of time, and developed no neurologic deficit. Cases 1 and 8 both received glucocorticoid substitution and concurrent fluid restriction and suffered no neurologic deficit, either. Since there are so few reported cases, we cannot infer from Table 2 that cortisol level, initial serum sodium level, or the dosage of glucocorticoids can predict the occurrence of this therapeutic complication. Further study is needed to reveal the factors which affect the rapidity of the correction of hyponatremia with glucocorticoid substitution.
Myelinolysis can occur even if the increment change in the serum sodium level is deemed acceptable.(12,14,15) Thus, even though data from clinical and animal studies indicate a low incidence of myelinolysis if the increase in serum sodium is 12 mmol/l or less in 24 hours, it may be impossible to define a level of correction that is always completely free of risk.(12) Furthermore, considering the short half-life of ADH, clinicians should frequently monitor the serum sodium level, especially during the first few hours of glucocorticoid substitution in hypopituitarism-associated hyponatremic patients.
The outcome of patients with myelinolysis varies, ranging from complete recovery to death.(12) There is also no specific treatment for myelinolysis. Preliminary data from animal studies suggest that re-lowering the serum sodium in the initial hours and days after rapid correction may be beneficial.(16) In our case, we immediately used hypotonic fluid, and the patient gradually achieved complete recovery. More data are needed before re-lowering plasma sodium can be recommended. It should be considered only in patients for which the condition has been corrected too rapidly, and who have developed early neurologic symptoms compatible with possible myelinolysis.
In conclusion, glucocorticoid substitution is the mainstay treatment of hyponatremia associated with hypopituitarism, but the treatment may possibly precipitate myelinolysis. In addition to the well-known risk factors for myelinolysis, such as alcoholism, liver disease, malnutrition, thiazide therapy, and extreme hyponatremia,(2) adrenocortical insufficiency may also be a potential risk. As practical guidelines for glucocorticoid substitution in cases such as this cannot yet be proposed, clinicians should frequently monitor the serum sodium level and neurologic signs when correcting hyponatremia with glucocorticoids, even though the incremental change in the serum sodium level is acceptable. Once possible myelinolysis develops, early recognition is critical, and immediate replacement with hypotonic fluid is suggested.

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From the Division of Nephrology, Department of Internal Medicine, Chang-Gung Memorial Hospital, Kaohsiung.
Received: Jan. 11, 2002; Accepted: Apr. 4, 2002
Address for reprints: Dr. Wen-Chin Lee, Division of Nephrology, Department of Internal Medicine, Chang Gung Memorial Hospital, 123, Ta Pei Road, Niaosung 833, Kaohsiung, Taiwan, R.O.C. Tel.: 886-7-7317123 ext. 8306; Fax: 886-7-7322402; E-mail: pooh@anet.net.tw