Neural Networks

Resetting craniopharyngioma patient sleep cycles 

Craniopharyngioma, a common childhood tumor that occurs along the mid-line of the brain near the hypothalamus or pineal gland, is highly curable with surgery and/or radiation. Unfortunately, treatment often causes unwanted side effects, including hypopituitarism, vision problems, obesity, sleep abnormalities and daytime hypersomnolence (DH).  

“Generally, patients gain about 50 pounds, need several pituitary hormone replacements including growth hormone, and experience sleep abnormalities within six weeks of beginning treatment,” says Sanjeev V. Kothare, MD, a pediatric neurologist and associate director (neurology), Center for Pediatric Sleep Disorders at Children’s Hospital Boston. “Some of these issues can be treated with supplemental hormones or by making lifestyle changes, but patients who experience erratic sleep patterns have not traditionally been helped by hormone replacement or treatment of the commonly associated obstructive sleep apnea.”

Finding the cause of daytime hypersomnia

Sleep is regulated by two factors: the circadian rhythm, regulated by the body’s melatonin levels, and sleep homeostasis, the body’s attempt to balance the sleep/awake schedule. The circadian rhythm is controlled by a tiny region of the brain called the suprachiasmatic nucleus (SCN). When light hits the retina, it sends impulses to the SCN, which sends triggers to the pineal gland to produce melatonin. Located in close proximity to most craniopharyngiomas, the SCN is at high risk of damage from surgical treatment.

Plasma melatonin profiles measured in craniopharyngioma subjects (colored circles) and controls (open circles). Clock hour indicated on x-axis. CT = circadian time in hours from onset of inpatient monitoring.

In 2001, Scott Pomeroy, MD, PhD, Children’s neurologist-in-chief, began recording data on DH in craniopharyngioma patients, hoping to discover why patients could not keep a normal sleep schedule. He knew daily variations in levels of melatonin indicated a functioning circadian rhythm, and also that low salivary melatonin had been documented in obese craniopharyngioma survivors. But no detailed analysis of circadian rhythms in children with craniopharyngioma existed.

A pivotal study

In 2008, Pomeroy, Kothare and Jonathan Lipton, MD, PhD, also a pediatric neurologist at Children’s, launched a two-part trial to determine if craniopharyngioma patients had a functioning hypothalamic circadian pacemaker in the SCN. Three craniopharyngioma patients treated at Dana-Farber Cancer Institute and Children’s who self-reported DH requiring daytime stimulant medication were enrolled. All were between the ages of 15 and 22, had surgery and radiation therapy, and were morbidly obese.

Patients wore a wrist actigraph, which measures body movement, for 14 to 21 days before admission to the General Clinical Research Center sleep laboratory. They kept their usual routine for most of the time, only adhering to strict, consistent sleep/awake times in the final week. In the sleep lab, patients stayed in dimly lit conditions for 72 hours. Doctors collected blood samples every 20 minutes, allowing for continuous monitoring of their plasma melatonin levels.

The results were significant. The actigraphs showed that patients experienced irregular bedtimes, frequent nighttime activity, and inappropriate daytime episodes of rest, even when trying to keep a normal sleep cycle. Laboratory results showed no melatonin level surges; patients had completely flat plasma melatonin levels for the entire three days. “The data supported our hypothesis that there is a dysfunction in the circadian mechanisms in these patients, presumably as a result of surgery and radiation treatment,” says Lipton. “This is an extremely detailed study to assess the output of the circadian oscillator.”  

Applying the findings

The researchers believe patients may benefit from prescribed melatonin during nighttime hours to stimulate their sleep cycle. “It’s very exciting,” says Kothare, “because now we can work on a treatment plan.”  

In the spring of 2010, Children’s will open a pilot study on 10 randomized patients with craniopharyngioma after their surgery and radiation, to evaluate the efficacy of melatonin hormone supplements in addressing their sleep wake cycles. But Kothare is looking even further ahead. “Sleep is emerging as a major regulator of all aspects of health,” he says. “Poor sleep is linked with higher stress and blood pressure levels, weight gain and in extreme cases of obesity, with obstructive sleep apnea.”

By helping patients sleep better, Kothare believes they will improve not only in their related health problems, but also decrease their risk factors for developing other serious conditions like the metabolic syndrome (high blood pressure, heart attacks, hyperlipidemia, diabetes mellitus, and strokes).