A 16-year-old male with acute myeloid leukemia (AML), who had experienced a relapse after the first bone marrow transplant, developed intermittent fever on day 30 after his second unmatched familial peripheral blood stem cell transplantation (SCT).

Five days later, he presented disorientation and impairment of short term memory. On posttransplant day (PTD) 37, his urine output dramatically increased to 6,690 mL/day (4,430 mL/m²/day), with approximately 2 L of negative fluid balance. The serum sodium level was decreased at 119 mEq/L, followed by generalized tonic-clonic seizure. Considering the possibility of SIADH, fluid restriction was instituted. But severe hyponatremia and significant polyuria persisted and next day and he was consulted to pediatric endocrinologists.

On the past history, vital signs and physical examination at admission was unremarkable. The pretransplantation conditioning regimen comprised busulfan (130 mg/m²), fludarabine (65 mg/m²), and antithymocyte immunoglobulin (ATG, 2.5 mg/kg). Short course methotrexate and cyclosporine were used for the GVHD prophylaxis. Acute GVHD of skin developed at PTD 12 and methylprednisolone (2 mg/kg) was started. Leukocyte engraftment was obtained on PTD 14. Two weeks later, he developed fever. Routine fever studies were performed and urine culture was positive for Klebsiella pneumoniae. Intermittent fever was persisted despite of antibiotics treatment with teicoplanin (10 mg/kg) and meropenem (60 mg/kg). On PTD 35, he developed neurologic symptoms such as disorientation, amnesia and headache. His serum sodium (Na) at this time was 135 mEq/L and the results of lumbar puncture and brain magnetic resonance imaging (MRI) were unremarkable. Two days later, acyclovir (30 mg/kg) was added for continued fever and neurological symptoms.

At the time of consultation (PTD 38), his body weight had decreased by 14% since admission, from 56 kg (25th-50th percentile) to 48.5 kg (5th-10th percentile). Physical examination revealed signs of volume depletion such as weight loss, dry tongue and reduced skin turgor. Central neurologic symptoms with intermittent confusion, disorientation, and short-term memory loss were observed. His serum Na was 114 mEq/L, potassium (K) 3.2 mEq/L, blood urea nitrogen (BUN) 4.6 mg/dL, and osmolality (Osm) 240 mOsm/kg, urine Na 217 mEq/L, and urine Osm 513 mOsm/kg. Thyroid hormone, cortisol, and antidiuretic hormone (ADH) were within normal ranges, while pro-brain natriuretic peptide (pro-BNP) was increased to 534 pg/mL (reference range, <84 pg/mL) and plasma renin activity was suppressed to 0.01 ng/mL/hr (reference range, 0.3-2.9 ng/mL/hr).

The patient was diagnosed as CSW syndrome on the basis of hyponatremia, natriuresis, polyuria with volume depletion, increased pro-BNP level, and absence of response to fluid restriction. Aggressive water and salt replacement was initiated with isotonic and hypertonic saline based on urine output and sodium. Despite adequate fluid replacement, excessive urine output consistently above up to 12,000-14,000 mL (8,000-9,600 mL/m²) with significant urine salt loss of over 200 mEq/L. At this point, pro-BNP levels were significantly elevated to 3,337 pg/mL. To maintain fluid and electrolyte balance, continuous treatment with over 10 L of large volume isotonic fluid and hypertonic saline was required for six day. We then stated fludrocortisone (FC) 0.1 mg per day on PTD 44, but increased urine output was persisted for next 3 days. FC dose was then increased to 0.2 mg per day. Before increased FC, his urine output was 13,320 mL (8,821 mL/m²), serum Na was 130 mEq/L. But 3 days after increasing FC dose, urine output decreased to 5,890 mL (3,875 mL/m²) and serum Na was normalized with this therapy and then hypertonic saline was weaned. On PTD 78, his urine output and serum Na was kept stabilized, FC was weaned. On PTD 83, pro-BNP levels were decreased to 177.2 mL and oral salt tablets were started and 2 weeks later, isotonic fluid was discontinued. On PTD 102, the patient was discharged without neurologic sequelae related with the treatment.

A 16-year-old female who was diagnosed with Philadelphia chromosome-positive acute lymphoblastic leukemia presented intermittent fever immediately after transplantation. Fungal pneumonia was developed on PTD 7 and cytomegalovirus (CMV) viremia was diagnosed on PTD 18. The following day, she developed intermittent short-term memory loss, drowsiness and tremor in both hands. Serum Na level was 130 mEq/L and brain MRI was unremarkable. Mild hyponatremia of approximately 130 mEq/L was persisted for next 4 days, urine output dramatically increased to 5,528 mL (4,035 mL/m²), with 1 L of negative fluid balance on PTD 22. Serum Na decreased to 124 mEq/L and she developed seizures. Following conservative fluid treatment using 3% and 0.9% saline for 24 hours, serum Na was normalized. However, the serum Na decreased again to 129 mEq/L on PTD 45, but did not respond to conservative treatment including fluid restriction. Therefore, pediatric hemato-oncologist was consulted on PTD 53.

On the past medical history, The pretransplantation conditioning regimen comprised cyclophosphamide (260 mg/kg), ATG (2.5 mg/kg), methylprednisolone (1 mg/kg), and total body irradiation (total dose, 1,320 cGy/8 fx). Short course methotrexate and cyclosporine were used for the GVHD prophylaxis. Emperical antibiotics with teicoplanin (10 mg/kg) and meropenem (60 mg/kg) were given to her due to fever. On PTD 7, voriconazole (loading dose of 6 mg/kg/dose every 12 hours for 2 doses on day 1, followed by maintenance dose at 4 mg/kg/dose every 12 hours) was initiated due to fungal pneumonia. Leukocyte engraftment was obtained on PTD 12. Six days later, CMV real-time quantitative polymerase chain reaction was positive with 21,000 copies/mL (reference range, <500 copies/mL) and ganciclovir (10 mg/kg) was initiated.

At the time of consultation (PTD 53), her body weight was 36 kg (<3rd percentile), a 15% reduction since admission. Urine output was 2,424 mL (1,924 mL/m²) with approximately 1.6 L of negative fluid balance. She developed NCs such as disorientation and short-term memory loss. Her serum Na was 126 mEq/L, BUN 21 mg/dL, and Osm 266 mOsm/kg, urine Na 121 mEq/L, and urine Osm 311 mOsm/kg. Thyroid hormones, cortisol and ADH levels were within normal ranges, while BNP was increased to 154 pg/mL (reference range, <100 pg/mL). The clinical pictures and laboratory profiles was highly suggestive of CSW. Her urine volume was replaced by an intravenous fluid with isotonic saline. Two days later, serum Na levels became normal and her vital findings stabilized. Despite stabilized vital signs, appropriate water balance with normal electrolyte levels, her abnormal neurological symptoms such as amnesia, disorientation and tremor persisted until PTD 64. Brain MRI was reperformed and the result showed chemotherapy-related leukoencephalopathy (Fig. 1A). On PTD 100, the patient was discharged without neurologic sequelae or electrolyte imbalance.

A 15-year-old male, who was diagnosed with acute myelocytic leukemia developed fever on PTD 18. The next day, he developed mild headache and tremor in both hands. Three days later, headache was exacerbated and neurologic symptoms include personality changes, decreased activity, drowsiness was developed. Brain MRI revealed prominent pachy-meningeal enhancement and then meningitis was highly suspected (Fig. 1B). That afternoon, serum Na was rapidly decreased to 128 mEq/L and fluid restriction was instituted. But severe hyponatremia was persisted and pediatric hemato-oncologist was consulted on PTD 22.

The conditioning regimens were comprised of busulfan (130 mg/m²), fludarabine (40 mg/m²), and ATG (2.5 mg/kg). Short course methotrexate and cyclosporine were used for the GVHD prophylaxis. Leukocyte engraftment was obtained on PTD 12. Acute GVHD of skin developed at PTD 13 and methylprednisolone (2 mg/kg) was started. Five days later, he developed fever and emperical antibiotics with teicoplanin (10 mg/kg) and meropenem (60 mg/kg) were initiated.

At the time of consultation (PTD 22), his body weight was 66 kg (75th-90th percentile), a 8% reduction since hospitalization. He had a NCs such as change in personality, slurred and inappropriate speech, truncal ataxia and tremor in both hands. Clinical evaluation revealed signs of volume depletion such as weight loss, decreased skin turgor. His urine output was 4,770 mL (2,650 mL/m²), with approximately 1 L of negative fluid balance. His serum Na was 127 mEq/L, serum Osm 265 mOsm/kg, urine Na 114 mEq/L, and urine Osm 578 mOsm/kg. While thyroid hormones and ADH levels were within normal ranges, pro-BNP was elevated at 401 pg/mL (reference range, <84 pg/mL). The clinical pictures and laboratory profiles was highly suggestive of CSW. Fluid and salt replacement was instituted with isotonic saline based on urine output and serum Na levels. His serum Na levels began to rise next day. The following day, his serum electrolytes were stabilized and then, clinical condition was improved. Lumbar puncture was performed. The analysis of CSF revealed the following values: red blood cell, 0 cells/mm³; white blood cell count, 13 cells/mm³ (4% segmented neutrophil, 40% lymphocytes); protein levels, 82.5 mg/dL; and glucose levels, 59 mg/dL. The findings of an examination of the CSF for tuberculosis and parasites were normal. No pathogens were seen on direct CSF smears, and findings from bacterial and viral cultures remained negative. The diagnosis of CSWS associated with aseptic meningitis was made. We kept continue to use the empirical antibiotics and isotonic fluid treatment. Appropriate positive fluid balance was made by fluid therapy and his serum Na level remained normal levels despite of excessive urine output. His urine output was slowly decreased. The patient was discharged from the hospital with normal electrolyte levels and urine output at day 55 posttransplant (Table 1).