Cancer has an immense impact on the physical and psychiatric health of patients. With improved survival rates of cancer patients, they may go on to experience multiple chronic illnesses. Chronic insomnia is a common complaint among patients undergoing treatment for various cancers and may persist even after the cancer is successfully treated.
Several studies document sleep complaints among childhood and adult cancer survivors, with higher degrees of emotional distress being associated with more sleep problems.1–3 In one report of cancer survivors referred to a pediatric sleep center, 24% presented with insomnia.4 The incidence rate of childhood (age 0–14 years) primary brain and other central nervous system tumors in the US is 5.65 per 100,000;5 as a result, there are limited data on sleep disturbance outcomes in these patients.
We present the case of a young woman with chronic insomnia in the setting of pediatric right temporal pilocytic astrocytoma, status postsurgical resection, chemotherapy, and stereotactic radiosurgery. Her psychiatric history included a diagnosis of obsessive-compulsive disorder (OCD), anxiety, depression, and nonepileptic spells. She presented for evaluation of chronic insomnia after treatment failure with multiple medications. Cognitive-behavioral therapy for insomnia combined with the use of sedative-hypnotic medications and major lifestyle modifications were effective in treating her insomnia.
A 23-year-old woman presented to our sleep center for evaluation and treatment of difficulty falling asleep and staying asleep for the last 10 years, and now requiring increased doses of sedative-hypnotic medications. She had significant history of a right temporal lobe pilocytic astrocytoma status post-craniotomy for partial resection at age 3 years, with resultant left-sided weakness of her upper and lower extremities. She underwent chemotherapy at age 8 years, followed by stereotactic radiosurgery at age 13 years for recurrent tumor. She had focal epilepsy secondary to her brain tumor, which was well controlled with oxcarbazepine twice daily. She had been seizure-free for more than 2 years at the time of the initial visit for insomnia. In adolescence she developed nonepileptic seizures, which prompted her initial evaluation by psychiatry. She was further diagnosed with OCD, generalized anxiety disorder, and major depression. She had two inpatient psychiatric hospitalizations for attempted suicide via medication (ibuprofen) overdose at age 18 and 20 years. At the time of her current presentation, she had been receiving psychotherapy on a monthly basis for the last 3 years for anxiety, depression, and OCD. She denied a history of either bipolar disorder or trauma.
Regarding her sleep disturbances, she reported difficulty falling asleep and staying asleep since age 13 years after undergoing stereotactic radiosurgery for a recurrent brain tumor. Her bedtime was between 8 pm and 10 pm, with a sleep latency of more than 120 minutes on most nights despite taking nighttime medications 2 hours prior to bedtime. She noted waking up 3 to 4 times nightly for unknown reasons, with a sleep latency of more than 60 minutes after each awakening. She used her phone for internet and social media browsing while in bed prior to falling asleep and after awakening in the morning. Her wake time was inconsistent and generally ranged between 7 am and 9 am. She estimated an average of 4 to 5 hours of fragmented sleep per night. She also reported taking two or three daytime naps on at least 5 days of the week, with each nap lasting 15 to 30 minutes. She did not feel rested in the morning and stated she would need at least 8 to 9 hours of sleep to feel rested. These sleep disturbances significantly affected her mood, appetite, and daytime activities. She occasionally canceled her social and medical appointments due to unrefreshing sleep. She also complained of discomfort in her legs that was worse in the evenings and relieved by activity. She described an urge to move or kick her legs to improve the unpleasant sensation. These leg symptoms occurred most nights and affected her ability to fall asleep and stay asleep.
The patient expressed compliance with her medications, which included 3 mg of eszopiclone and 37.5 mg of mirtazapine at bedtime, clonazepam at dose of 1 mg 3 times a day, and oxcarbazepine at a dose of 600 mg twice daily. She was previously taking quetiapine, but it was discontinued due to worsening of leg movement symptoms. For insomnia, she had tried zolpidem, melatonin, trazodone, doxepin, and amitriptyline in the past without significant improvement. For restless legs symptoms, she had tried baclofen, cyclobenzaprine, methocarbamol, and gabapentin with no significant relief.
She lived with her parents and younger sibling and she would occasionally spend a couple of weeks at a time at her boyfriend's apartment. She completed high school but did not attend college. She had never been employed and spent most of her time at home. Weakness of the left upper and left lower extremities deterred her from engaging in much physical activity. She admitted to smoking marijuana at irregular intervals throughout adolescence and claimed to have not used cannabis in at least the past 6 months. She denied alcohol or tobacco use.
Her physical examination was most notable for spastic left hemiplegia. She had no cranial nerve abnormalities. Her oral examination demonstrated a Mallampati class II oropharynx with 1+ tonsils and a high arched palate. She had a normal body mass index at 21 kg/m2. She was alert and oriented with an appropriate affect, normal speech, and normal vocabulary. She used a cane and left leg brace to assist in ambulation. The rest of her physical examination was unremarkable.
Her Epworth Sleepiness Scale score was 0 (on a scale from 0–24).
For management of clinically diagnosed chronic insomnia in this medically complex patient, a combination of pharmacotherapy and behavioral therapy was advised. We identified inadequate sleep hygiene and restless leg syndrome (RLS) as perpetuating factors of her insomnia. This patient was educated on good sleep hygiene, particularly keeping a regular sleep/wake schedule, avoiding use of electronic devices overnight, and eliminating daytime naps, thus improving sleep consolidation. She was prescribed pramipexole at a dose of 0.25 mg every evening for her RLS. Her ferritin level was less than 30 ng/mL, so daily iron supplementation was also prescribed for treatment of RLS. She was instructed to keep a sleep diary and was referred to a psychologist who specialized in cognitive-behavioral therapy for insomnia (CBT-I) and sleep restriction therapy (SRT). Her SRT goal was to reduce current 9 to 13 hours in bed to 8 hours and to achieve a minimum of 6 to 7 hours of good-quality sleep initially. We recommended she continue to follow up with her psychiatrist and therapist for her psychiatric conditions. Her current medications of eszopiclone, mirtazapine, and clonazepam were continued without dose changes or additional medications; however, we recommended delaying the timing of her current sedative-hypnotics to be closer to bedtime. An attended polysomnogram (PSG) was scheduled to rule out sleep-disordered breathing as a contributor to her insomnia, objectively assess her sleep architecture, and evaluate for periodic limb movements of sleep.
The PSG results showed a sleep latency of 16.5 minutes and a low sleep efficiency at 83%. This reduced sleep efficiency was largely due to a prolonged terminal awakening at approximately 4:30 am. Her rapid eye movement (REM) sleep latency was prolonged at 213 minutes and REM sleep was reduced, comprising only 3% of sleep time (normal REM sleep is 20%–25% total sleep time). There was no evidence of clinically significant obstructive sleep apnea (apnea-hypopnea index of 0.3/hour), and significant hypoxemia was not present (average oxygen saturation of 96%). The periodic limb movement index was 0.0/hour. Her electroencephalogram showed excessive beta activity throughout the study, but no epileptiform discharges or seizures were noted.
At 1-month follow-up, she endorsed improvement in RLS symptoms and had implemented sleep restriction with a more regular wake time, although her bedtime remained slightly variable (usually between midnight and 1 am). She was now falling asleep within 30 minutes of going to bed with less frequent awakenings and reported an average sleep time of about 7 hours a night per her sleep diary data. The patient was unable to return for her 6-month follow-up due to having been admitted for inpatient psychiatric care, the details of which were not disclosed to the clinic staff at the time of scheduling contact.
Diagnosis: Chronic Insomnia Disorder and Restless Legs Syndrome
The International Classification of Sleep Disorders (ICSD), second edition,6 divided insomnia into clinical subtypes of primary and secondary insomnias. The most recent edition of the ICSD (the third edition)7 changed the classification of chronic insomnia disorder (CID) to a single diagnosis that is given to all patients who have persistent and frequent insomnia complaints whether they occur with or without a potentially sleep-disruptive medical disorder, psychiatric illness, or substance abuse history.
The essential feature of CID is frequent and persistent difficulty in initiating and maintaining sleep that results in sleep dissatisfaction accompanied by distress about poor sleep and/or impairment in family, social, work, academic, or another important area of functioning. Common waking symptoms include fatigue, reduced motivation, decreased concentration/attention, irritability, and poor mood. Sleep disturbances and waking symptoms occur despite having adequate time and circumstances to obtain the necessary sleep. Symptoms must be present for at least 3 days per week for at least 3 months.7
RLS was also diagnosed based on the defining features of an urge to move the legs that was accompanied by an uncomfortable sensation in the legs that begins or worsens during periods of rest and is most predominant in the evening and night. Furthermore, the urge and sensation are at least partially relieved by movement. Symptoms of RLS may disrupt sleep and cause impairment in important areas of function.7
Chronic insomnia is a condition developed over time in patients who have a predisposition to sleep disruptions due to genetic or environmental factors that can be precipitated by physical and psychiatric illnesses and perpetuated by multiple stressors. CID occurs in approximately 10% of the population, but the prevalence of transient insomnia symptoms is much higher at about 30% to 35%, particularly among cancer survivors. CID is more common among women, people in lower socioeconomic classes, and in patients with comorbid medical, psychiatric, or substance abuse disorders.7
In patients with brain tumors, sleep disturbances can potentially be caused due to direct effects on structures and neurochemicals responsible for the regulation of sleep, such as the hypothalamus or brainstem, as well as indirect effects due to elevated intracranial pressure or dysregulation of the hypothalamic-pituitary-axis. Other predisposing factors may include surgical impediments, side effects of cranial radiation and chemotherapy, or young age during cancer treatment.8 In the absence of surgical interventions, treatment options for insomnia are limited and remain geared toward symptom management.9,10
Inadequate sleep hygiene, as noted in this patient, is defined by activities that are inconsistent with the maintenance of good quality sleep and normal daytime alertness. Contributing factors include irregular sleep/wake schedules, sedentary lifestyle, using the bedroom for nonsleep activities, being mentally or physically stimulated close to bedtime, or partaking in sleep-disruptive substances (alcohol, nicotine, caffeine). Treatment involves behavioral modifications that correct sleep-disruptive behaviors.7
Depression and anxiety are known to be associated with sleep onset and sleep maintenance insomnia. Sleep architecture changes are noted on PSG in patients with anxiety and depression. Typically, untreated depression will cause increased REM density and decreased REM latency on PSG. However, many antidepressants (including mirtazapine, which this patient was taking) may cause REM suppression and increased REM latency, as seen in our patient's PSG. Patients with depression and insomnia classically have terminal awakenings, such as the one noted on our patient's PSG. Treatment of the underlying mood disturbance often results in positive sleep benefits.11–13
CBT-I and sleep hygiene education, as recommended for our patient, provide behavioral means to combat insomnia, whereas SRT is targeted at a physiologic mechanism that induces mild sleep deprivation, thereby strengthening homeostatic sleep pressure and resulting in more consolidated and restorative sleep. Educating patients to avoid attempting sleep during the “forbidden zone of sleep” or “wake maintenance zone” (which is a physiologic period of heightened wakefulness typically occurring 1 to 3 hours before natural sleep onset as determined by a person's circadian rhythm) reduces failure at sleep initiation and decreases anxiety associated with sleep.
Other sleep disorders, such as RLS, obstructive sleep apnea, parasomnias, bruxism, and circadian rhythm sleep disorders, can contribute to insomnia and require further evaluation and treatment.14,15 Treating these sleep disorders will often improve and sometimes completely resolve chronic insomnia.
CID is a clinical diagnosis. There are many tools commonly used by most sleep psychologists and behavioral therapists for evaluation of insomnia and its adverse effects on functioning. These include the Insomnia Severity Index, Pittsburgh Sleep Quality Index, Functional Outcomes Sleep Questionnaire, and Sleep Glasgow Questionnaires. These short surveys were not used for evaluation of this patient as these are not routinely used at our sleep center by sleep clinicians.
As a single case report of a rare presentation, this is not representative of most CID patients; therefore, treatment recommendations cannot be generalized.
The psychologic effects of a cancer diagnosis, the disease burden on patients and families, the nature of the treatments (surgery, chemotherapy, radiation), and the life-long adverse effects of these therapies have a significant impact on a cancer survivor's physical, mental, and emotional well-being. This case provides insight into a challenging instance of CID in a unique at-risk person. In addition to the typical psychophysiological factors of the general population, one must consider the risks for brain structure abnormalities and/or post-treatment effects that may contribute to sleep disturbance in brain tumor survivors. Treatment-refractory insomnia should also raise concern for what was formally called secondary insomnia (insomnia due to a medical or psychiatric disorder), particularly in a patient with significant chronic illness, which can be a predisposing risk factor for depression and anxiety. Treatment options must be customized to address the most distressing symptoms and may include any combination of lifestyle modification, sedative-hypnotic medications, and behavioral therapies as well as management of comorbid contributing conditions.
- Mulrooney DA, Ness KK, Neglia JP, et al. Fatigue and sleep disturbance in adult survivors of childhood cancer: a report from the childhood cancer survivor study (CCSS). Sleep.2008;31(2):271–281. doi:10.1093/sleep/31.2.271 [CrossRef] PMID:18274275
- Clanton NR, Klosky JL, Li C, et al. Fatigue, vitality, sleep, and neurocognitive functioning in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Cancer.2011;117(11):2559–2568. doi:10.1002/cncr.25797 [CrossRef] PMID:21484777
- Daniel LC, Wang M, Mulrooney DA, et al. Sleep, emotional distress, and physical health in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Psychooncology. 2019;28(4):903–912. doi:10.1002/pon.5040 [CrossRef] PMID:30817058
- Rosen G, Brand SR. Sleep in children with cancer: case review of 70 children evaluated in a comprehensive pediatric sleep center. Support Care Cancer. 2011;19(7):985–994. doi:10.1007/s00520-010-0921-y [CrossRef] PMID:20517621
- Central Brain Tumor Registry of the United States. 2018 CBTRUS fact sheet. Accessed October 26, 2020. https://www.cbtrus.org/www.cbtrus.org/factsheet/factsheet.
- American Academy of Sleep Medicine. International Classification of Sleep Disorders. 2nd ed. American Academy of Sleep Medicine; 2006.
- American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd ed. American Academy of Sleep Medicine; 2014.
- Gapstur R, Gross CR, Ness K. Factors associated with sleep-wake disturbances in child and adult survivors of pediatric brain tumors: a review. Oncol Nurs Forum. 2009;36(6):723–731. doi:10.1188/09.ONF.723-731 [CrossRef] PMID:19887361
- Müller HL, Handwerker G, Gebhardt U, et al. Melatonin treatment in obese patients with childhood craniopharyngioma and increased daytime sleepiness. Cancer Causes Control.2006;17(4):583–589. doi:10.1007/s10552-005-9012-7 [CrossRef] PMID:16596314
- Jacola LM, Conklin HM, Scoggins MA, et al. Investigating the role of hypothalamic tumor involvement in sleep and cognitive outcomes among Children treated for craniopharyngioma. J Pediatr Psychol. 2016;41(6):610–622. doi:10.1093/jpepsy/jsw026 [CrossRef] PMID:27189690
- Kalmbach DA, Pillai V, Drake CL. Nocturnal insomnia symptoms and stress-induced cognitive intrusions in risk for depression: a 2-year prospective study. PLoS One. 2018;13(2):e0192088. doi:10.1371/journal.pone.0192088 [CrossRef] PMID:29438400
- Baglioni C, Battagliese G, Feige B, et al. Insomnia as a predictor of depression: a meta-analytic evaluation of longitudinal epidemiological studies. J Affect Disord. 2011;135:10–19. doi:10.1016/j.jad.2011.01.011 [CrossRef] PMID:21300408
- Oh CM, Kim HY, Na HK, Cho KH, Chu MK. The effect of anxiety and depression on sleep quality of individuals with high risk for insomnia: a population-based study. Front Neurol. 2019;13(10):849. doi:10.3389/fneur.2019.00849 [CrossRef] PMID:31456736
- Benetó A, Gomez-Siurana E, Rubio-Sanchez P. Comorbidity between sleep apnea and insomnia. Sleep Med Rev. 2009;13(4):287–293. doi:10.1016/j.smrv.2008.09.006 [CrossRef] PMID:19246219
- Edinger JD. Cognitive and behavioral anomalies among insomnia patients with mixed restless legs and periodic limb movement disorder. Behav Sleep Med. 2003;1(1):37–53. doi:10.1207/S15402010BSM0101_5 [CrossRef] PMID:15600136