Due to increased survival rates for children with a CNS tumor, the late effects of the tumor and its treatment are becoming more visible and more important [1]. Childhood brain tumor survivors (CBTS) often report a low quality of life and an important factor that may influence the degree of quality of life is their quality of sleep [2].
Sleep is a complex neurophysiologic process. The suprachiasmatic nuclei are key regulators of the circadian rhythm, controlling sleep and wakefulness [3, 4]. Melatonin, excreted by the pineal gland in the dark, greatly influences this circadian rhythm (Fig. 1a) [4]. In children with a (supra) sellar tumor the circadian rhythm may be disturbed due to a distorted melatonin excretion or a distorted response to melatonin [5,6,7]. In addition to the suprachiasmatic nuclei, the ventrolateral preoptic nucleus (VLPO) together with the lateral hypothalamus area (LHA) (sleep-promoting), and monoaminergic cell groups (MCG) (the arousal system) also regulate sleep [8]. These sleep-promoting pathways and arousal pathways can mutually influence each other by the “flip-flop” switch (Fig. 1b) [9]. This interaction rapidly promotes the transition between waking and sleeping. Damage to the VLPO results in insomnia and damage to the LHA results in both sleep disruption as well as daytime hypersomnolence [10,11,12,13].
It is well known that patients with a (supra) sellar tumor are prone to develop sleep problems or daytime sleepiness [14, 15]. While the physical damage caused by the tumor or its treatment is a probable causal mechanism, other risk factors, such as psychological, behavioral, and social environmental should also be considered. Parenting strategies that include regular bedtime routines and consistent limit setting are required to develop healthy sleep habits, but may be a challenge to parents of a child with a life-threatening or chronic disease [16, 17].
There are currently no guidelines for assessment of sleep disturbances in this group. Early referral to a specialized sleep clinic may reveal the etiology of the sleep disturbance and will give direction to the proper treatment. The following cases illustrate the importance of specialized diagnostics to distinguish the different etiologies of sleep disturbances in children with a suprasellar tumor enabling proper treatment.
Case 1
A 13 year-old girl, presented with frequent headaches during day and night, inability to fall asleep, difficulty maintaining sleep, and daytime sleepiness. She was diagnosed with craniopharyngioma at the age of six and underwent gross total resection. Magnetic Resonance Imaging (MRI) of the brain at follow-up showed absence of the pituitary stalk and damage of the anterior and posterior hypothalamic region with atrophic mammillary bodies, scored by the neuroradiologist as grade II, according to the Muller grading for hypothalamic damage [18]. After surgery, she developed panhypopituitarism and morbid obesity (Body Mass Index (BMI) Standard Deviation Score (SDS) of 5.1). Patient had been adequately hormonally supplemented for all pituitary deficiencies and used dextroamphetamine for her hypothalamic obesity. Her medical history further contained repeated surgery of her knees due to varus position. Due to her knee problems together with her morbid obesity, she was partially wheel chair bound.
Sleep history revealed long screen time before and during bed time, difficulty in sleep initiation and maintenance, and worrying during the night. There were no complaints of snoring, but a moaning sound was frequently heard by parents in the night.
Polysomnography (PSG) with capnography revealed a normal sleep latency with a recognizable cyclic sleep structure. Patient had a continuous tachypnea of 35- 40 times per minute, with frequently a typical breathing pattern in REM sleep, starting with a deep sigh following a long exhale in combination with a moaning sound, indicative of catathrenia. She had obstructive sleep apnea, with an apnea–hypopnea index of 19.4 (normal in children < 1/h), and an oxygenation-desaturation index (≥ 3%) of 33.8 (> 10 indicative for moderate to severe obstructive sleep apnea). Lowest oxygen level was 63%. Her carbon dioxide was normal during the day, but increased upon awakening (49.4 mmHg) (Table 1). The melatonin test showed no increase in melatonin concentration (Table 2). Patient was diagnosed with obstructive sleep apnea, sleep related hypoventilation and catathrenia according to the ICSD-3 criteria. Patient was referred for nocturnal home bi-level ventilation, with a inspiratory pressure support of 18 and external pressure support of 6, after which she experienced less symptoms of insomnia, less headaches and less daytime sleepiness.
Table 1 Sleep evaluation data of all four cases Table 2 Measured melatonin values of four cases Case 2
A 12 year-old girl with complaints of waking up earlier than desired and daytime sleepiness was referred for sleep evaluation. She had been diagnosed with craniopharyngioma at age five. Patient underwent subtotal resection, complicated by a subdural hematoma and meningitis. After surgery, patient received cranial irradiation. MRI of the brain at follow-up, after surgery and irradiation, showed severe anterior and posterior hypothalamic damage behind the mammillary bodies, grade II according to the Muller grading of hypothalamic damage. She experienced rapid weight gain (BMI SDS 4.3) with obsessive compulsive mood disorder. Medical history showed no other relevant comorbidities. Patient received adequate hormonal supplementation for all pituitary deficiencies.
During the night, the mother occasionally heard snoring and apneas. The girl experienced early awakenings (4.00 a.m.) with a strong urge to search for food. This food seeking behavior was present both day and night. She was aware of her behavior, but could not control this strong urge. Sleepiness was present in the morning and evening, which resulted in falling asleep in public places, with extreme difficulty to be woken up.
Both the PSG with capnography and melatonin test (Tables 1 and 2) showed normal results, with no indication for a obstructive sleep apnea syndrome or a circadian rhythm disorder. Based on her sleep wake calendar and history taking, she met the criteria of the ICSD-3 for a chronic insomnia disorder, in which her obsessive compulsive disorder and strong urge for food in combination with poor sleep hygiene were the most important perpetuating factors. For the prominent obsessive compulsive behavior, she was referred for psychiatric consultation. Dextroamphetamine was started to reduce her obsessive compulsive complaints, also aiming to positively affect her hypothalamic obesity.
Case 3
A 16 year-old girl with complaints of difficulty initiating sleep and daytime sleepiness was referred for sleep evaluation. She was treated at age 8 years for suprasellar germinoma with chemotherapy, neurosurgery, and radiotherapy. MRI of the brain at follow-up showed no hypothalamic damage, only damage in the sellar region, grade 0 according to the Muller grading of hypothalamic damage. She had been diagnosed with panhypopituitarism and obesity. Patient had been adequately hormonally supplemented for all pituitary deficiencies. Medical history showed no other relevant comorbidities.
Her sleep history showed relatively long screen time before sleeping and irregular and long time in bed (between 11 and 14 h), but with a normal sleep duration of over 8 h (Table 1). She had no complaints of waking up during the night, snoring, dry mouth, or nycturia. She frequently had headaches during the day.
A dim light melatonin onset test was performed and showed a normal but late increase of melatonin (Table 2). She met the ISCD-3 criteria for a delayed sleep phase syndrome diagnosis together with an inadequate sleep hygiene. She received education for improving her sleep hygiene, with special attention to a regular sleep wake rhythm, less time in bed, and avoidance of screen time before going to bed. With this advice, the sleep wake rhythm normalized and daytime complaints disappeared.
Case 4
A 16 year old boy presented with complaints of difficulty initiating sleep and maintaining sleep, waking up earlier than desired, and daytime sleepiness. He had been diagnosed with pilocytic astrocytoma in the suprasellar region and neurofibromatosis type I at age 7. Therapy consisted of subsequent episodes of neurosurgery, chemotherapy, and irradiation. MRI of the brain at follow-up, after neurosurgery, chemotherapy, and irradiation, showed abnormalities due to Moya-Moya syndrome and neurofibromatosis, plus anterior and posterior hypothalamic damage behind the mammillary bodies (grade II Muller et al.) with residual cystic mass in the suprasellar region. He developed panhypopituitarism in combination with the syndrome of inappropriate antidiuretic hormone (SIADH) and weight gain. Due to Moyamoya syndrome, patient also developed transient ischemic attacks. Patient had been adequately hormonally supplemented for all pituitary deficiencies. Medical history showed no other relevant comorbidities.
Sleep history showed insomnia during the night consisting of sleep onset problems, prolonged night time awaking of several hours, and early morning awakening. He frequently left bed during the night, to secretly eat and drink. This food seeking behavior was present both day and night. Patient was aware of this behavior, but could not control this strong urge. He also tended to secretly watch TV when awake in the night. Parents had already received guidance by behavioral therapists to alter this behavior, but still had difficulties in addressing this behavior, because they were often not aware of his night time awakenings. During the day, he suffered from severe hypersomnolence with falling asleep at school, when watching TV or even during meals, resulting a very high Epworth sleepiness scale score of 23 out of 24 (normal < 11).
Actigraphy confirmed insomnia with prolonged sleep onset, early morning awakening, and frequent naps during the day. PSG showed a normal cyclic sleep structure, with normal sleep duration of more than 9 h. The multiple sleep latency test showed a short sleep latency of 2.7 min (normal > 8 min) and one sleep-onset REM period (SOREMP) (Table 1). A mildly delayed increase of melatonin concentration in the evening was seen (Table 2). These mixed results made it difficult to make a formal ICSD-3 diagnosis. Narcolepsy was ruled out based on the MSLT results in combination with absence of other narcolepsy symptoms, but secondary organic hypersomnia was suspected based on the severe daytime sleepiness. Treatment was based on a multidisciplinary symptom-based approach. Behavioral therapy was started to address the behavior of going out of bed in the night and improving sleep hygiene. Additionally, pharmacological treatment with modafinil was started. These measures improved both his daytime functioning as well stabilized his sleep rhythm with less night time awakening.