Single-, low-dose cyclophosphamide-associated severe hyponatremia with seizures in a patient with breast cancer

Cyclophosphamide, an agent used to treat various malignant and autoimmune disorders, can cause severe hyponatremia with seizures in rare cases. The exact mechanism of cyclophosphamide-induced hyponatremia is poorly understood, but is thought to occur from a drug- associated antidiuretic hormone (ADH) release leading to free water retention.¹ This unusual phenomenon of cyclophosphamide-associated syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been described only in case reports, most of which reported the development of severe hyponatremia within a week after administration of cyclophosphamide.^2-5 We report a unique case of a patient who developed severe, symptomatic hyponatremia with seizures, with her serum sodium decreasing from 137 mEq to 112 mEq within 30 hours after her first dose of low-dose cyclophosphamide (600 mg/m²).

Case presentation and summary

A 68-year-old white woman with a history of bilateral invasive ductal carcinoma of the breast (status-post bilateral mastectomy) presented to the emergency department (ED) at our facility with new onset seizure. The patient had been diagnosed 8 months earlier with stage I (T1c, N0, M0) poorly differentiated infiltrating ductal carcinoma (triple negative) of the left breast for which she underwent left segmental mastectomy about 1 month after diagnosis. She was subsequently found to have progressive disease with stage IIIC (T2, N3, and M0) infiltrating ductal carcinoma with lobular features (ER/PR+, Her2) of the right breast. She underwent a right modified radical mastectomy 5 months after her stage IIIC breast cancer diagnosis. She received her first cycle of adjuvant chemotherapy with intravenous doxorubicin (60 mg/m²) and cyclophosphamide (600 mg/m²), which included pre-hydration, a day before presenting to our facility.

According to the patient’s family who provided the initial history, the patient reported tightness in her left arm while sitting at the dinner table. She was confused and subsequently had jerking movement of her right upper extremity with left facial twitching which lasted about 40 seconds. There was no loss of consciousness, or bowel or bladder control. She became unresponsive after the episode. Review of systems was negative except for a report of nausea a few hours before the onset of seizures, which resolved with ondansetron. Her past medical history was significant for breast cancer as already mentioned, seasonal allergic rhinitis, and hypertension. Home medications included hydrochlorothiazide 12.5 mg oral daily, aspirin 81 mg oral daily, and fexofenadine and loratadine oral daily as needed for allergies. There were no other significant surgical history other than already stated. The patient lived at home with her family and was independent with her instrumental activities of daily living. She is a former smoker of tobacco and quit smoking 30 years ago.

On arrival at our facility, the patient had normal vital signs. Significant findings on physical examination were an elderly female who seemed somnolent; not able to follow commands with a documented Glasgow Coma Scale of 10 with eyes opening spontaneously, incomprehensible sounds, and flexion withdrawal from pain as her best responses. She had an increased tone in her left upper extremity and had a brisk, deep tendon reflexes without clonus or 3+ (range, 0-5+, with 2+ being normal). The remainder of her physical exam was unremarkable. Laboratory testing revealed a glucose level of 120 mg/dL (normal, 65-110 mg/dL), sodium of 112 mEq/L (normal, 135-145 mmol/L), and chloride of 78 mEq/L (normal, 95-105 mmol/L). Serum osmolality and urine osmolality were 242 mOsm/kg (normal, 282-295 mOsm/kg) and 449 mOsm/kg (normal, 500-800 mOsm/kg) respectively, indicative of suboptimally dilute urine despite relatively low serum osmolality or SIADH. Urine electrolytes were not obtained.

Imaging studies including computed-tomography scans of the head and chest x-ray performed in the ED were unremarkable. After a phenytoin load, an electroencephalogram was obtained which showed diffuse encephalopathy without active seizure foci. A non-contrast magnetic-resonance imaging (MRI) of the brain was performed but it failed to show acute infarct, mass, mass effect, or brain herniation. There was nonspecific white matter abnormality with compromise of the bilateral cerebral hemispheres, calloseptal junction, left posterior pillar, and bilateral anterior pillars of the fornix, possibly representative of chronic white matter microvascular ischemic changes or less likely vasculitis or demyelination. Correction of her hyponatremia with normal saline was started in the ED with a change in serum sodium from 112 mEq/L to 115 mEq/L within 2 hours. She was admitted to the intensive care unit (ICU) where her sodium correction with normal saline and free water restriction was continued with a goal correction rate of 8-12 mEq/L in 24 hours. The patient’s serum sodium as well as level of consciousness improved gradually over the course of her ICU stay. After 64 hours in the hospital, her sodium had corrected to 137 mEq/L (normal, 135-145 mmol/L; Figure). She was then alert and oriented to person, place, and time. All motor findings noted on presentation had resolved. Her saline infusion was discontinued and serum sodium remained within normal range. She was discharged to a rehabilitation facility. Her hydrochlorothiazide was also discontinued.