An 8-year-and-1-month old Caucasian female presented to her pediatrician with complaints of nocturnal enuresis and hyperactivity. Child was adopted at 2 years of age along with her younger sibling due to history of parental neglect by biological parents. Adoptive parents reported hyperactivity as a major concern. Physical examination revealed her weight to be 24.8 Kg (25th percentile for age) and height to be 128.7 cm (35th percentile for age). Vitals were stable and blood pressure at presentation was 113/75 mmHg. A comprehensive neurologic exam by her pediatrician revealed fine tremors in the upper extremity. Laboratory workup was initiated and a comprehensive metabolic panel revealed sodium (Na) of 124 mEq/L. She was referred to our medical center for comprehensive evaluation. Initial exam revealed an otherwise healthy child who was alert and oriented in time, space, and person. Vitals including blood pressure were normal for age. Admission chemistry and other laboratory values are shown in Table 1.
While the causes of hyponatremia can be extensive, her presentation was consistent with euvolemic hyponatremia suggestive of Syndrome of Inappropriate Antidiuretic Hormone (SIADH). Evaluation by us confirmed our impression of SIADH with serum Na of 123 mEq/L, serum osmolality of 264 mOsm/Kg (ref range 280-300), and urine osmolality of 614 mOsm/Kg (300-900). Adrenal function as assessed by early morning cortisol of 8.6 mcg/dL and thyroid function tests were normal. Magnetic resonance imaging of the brain demonstrated asymmetric T2/FLAIR hyperintense, nonenhancing enlargement of the right hypothalamus, concerning for a hypothalamic glioma (Figure 1). Other workups including ultrasound of abdomen, pelvis, chest X-ray, and a PPD (purified protein derivative) skin test to rule out tuberculosis were essentially negative.
Initial management consisted of fluid restriction, furosemide (at a dose of 2 mg/Kg/day divided into three doses), and salt and potassium chloride supplementation. Though this resulted in her Na levels gradually improving to a maximum value of 130 mEq/L, the fluid restriction regimen was very difficult to follow and family expressed ongoing frustration. Given limitations for treatment options in treating children with SIADH and with Na levels trending down (range: 121-124 mEq/L), we initiated Arginine Vasopressin (AVP) V2 receptor antagonist therapy with oral tolvaptan. Current literature is lacking data on use of these agents in children. So tolvaptan therapy was started at a dose of 7.5 mg under close supervision in the inpatient setting. The dose initiated was half of the lowest approved dose in adults which is 15 mg. Initial response to therapy was dramatic in terms of correction of hyponatremia, with Na improving to low 130 mEq/L range.
With initiation of tolvaptan therapy, her Na levels improved allowing us to loosen our recommendation on water intake to a maximum of 2.5 L/day. Liberalization of fluid intake with this regimen seemed to help the family initially. Gradually though, Na levels trended down because her water intake was much more than her urine output with the therapy (Table 2). Child psychology and later child psychiatry were involved to help family and child be compliant with the fluid restriction. Dose of tolvaptan had to be increased gradually to a maximum of 30 mg daily. In an effort to keep the Na levels up, water restriction to 2.5 L/day was encouraged. But even this degree of fluid restriction proved to be difficult as she developed compulsive drinking behaviors. She would sneak water from bottles in trash cans, bathtub, faucet, and even toilets.
With ongoing management issues due to behavior problems and recent black box warning issued by the Food and Drug Administration (FDA) for liver failure in patients on long-term therapy, decision was made to wean tolvaptan. She was weaned off V2 antagonist therapy over a period of 6 months. While her persistent hyponatremia was concerning, the limited benefits we were observing with treatment and the potential side effects led us to make this decision. Following this, patient was briefly on oral furosemide, which was eventually discontinued as long-term furosemide is known to exacerbate chronic hyponatremia.
She was also noted to develop hypertension with blood pressures ranging around 140/106 mmHg requiring input from pediatric nephrology during the course of her treatment. She was initially started on amlodipine 2.5 mg twice a day but needed the addition of enalapril maleate in 4 months due to poor control of her blood pressure. She is currently on amlodipine 2.5 mg twice a day and enalapril 10 mg twice a day. Secondary causes of hypertension were ruled out by pediatric nephrology team. While hypertension was noticed after initiation of therapy, this is not a reported side effect of V2 receptor antagonist therapy. Her hypertension continued after she was weaned of tolvaptan therapy. It is unlikely that the hypertension was caused by volume overload as her weight continued to be stable. Etiology of hypertension is unclear as preliminary workups including renal ultrasound and renal Doppler were all within normal limits.
A complete neuropsychological assessment revealed IQ to be low normal. Patient had reading, attention, and auditory processing problems making school more challenging for her. She had no difficulties in doing grade level mathematics and spelling. These contributed to ongoing difficulties at school. Due to the well-known determinant effect of hyponatremia on bone health, DXA scan was done which revealed Z-score of -1.8 at AP spine and -1.1 at total body less head region. Since she never suffered from any pathological fracture, education was provided to optimize calcium and vitamin D intake. 25-Hydroxyvitamin D levels checked periodically were always in the sufficient range (>30 ng/mL).
Currently, she is off all pharmacological therapy for her hyponatremia and her sodium levels range within 113-118 mEq/L. Fluid restriction is encouraged but not very strictly enforced due to fear of her developing unhealthy drinking habits. She is performing at age appropriate level in school. Regular monitoring for endocrinopathies by stimulation testing has so far been normal.