Successful Treatment of Insomnia with Melatonin in a Patient with Malignant Glioma after Radiotherapy-Involving the Pineal Gland
Andrea Reim1, David Strobl2, Gerda Saletu-Zyhlarz3, Matthias Preusser2,5, Maria Theresia Schmook4, Karin Dieckmann1,5, Christoph C Zielinski2 and Christine Marosi2,5*
1Department of Radiotherapy and Radiobiology, Medical University of Vienna, Austria
2Department of Medicine I, Division of Oncology, Medical University of Vienna, Austria
3Department of Psychiatry, Medical University of Vienna, Austria
4Department of Radiology, Medical University of Vienna, Austria
5Comprehensive Cancer Center, Medical University of Vienna, Austria
*Corresponding author: Prof. Christine Marosi, Department of Medicine I and Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria, Tel: 0043-1-40400-4457, Fax: 0043-1-40400-4451, E-mail: email@example.com
Clin Med Rev Case Rep, CMRCR-3-112, (Volume 3, Issue 6), Case Report; ISSN: 2378-3656
Received: April 21, 2016 | Accepted: June 23, 2016 | Published: June 25, 2016
Citation: Reim A, Strobl D, Saletu-Zyhlarz G, Preusser M, Schmook MT, et al. (2016) Successful Treatment of Insomnia with Melatonin in a Patient with Malignant Glioma after Radiotherapy-Involving the Pineal Gland. Clin Med Rev Case Rep 3:112. 10.23937/2378-3656/1410112
Copyright: © 2016 Reim A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
A 29-years-old female patient suffering from a biopsy proven anaplastic astrocytoma in the right basal ganglia was treated by conformal radiation therapy with 2 Gy/fraction up to 60 Gy. Near the end of radiotherapy she complained about insomnia. Her previous sleep pattern had been inconspicuous, but now - despite high dose benzodiazepines provided by her family physician - she was unable falling asleep until 2 a.m. and to stay asleep for longer than two hours. Following the hypothesis that melatonin secretion had been impaired by radiotherapy, the patient was given oral 3 mg of melatonin at bedtime with immediate and ongoing restauration of sleep pattern.
A recent survey reported on conspicuous prevalence and severity of sleep disorders in patients with cancer. Insomnia is defined as difficulty falling asleep, difficulty staying asleep - with wake episodes of more than half an hour, unintended early awakening and/or non restorative sleep. This symptom complex qualifies as insomnia when it occurs at least three times a week, results in distress and impairs day time functioning. In cancer patients, especially in patients complaining about fatigue, insomnia is under diagnosed and undertreated [1-7]. Insomnia is also very common in patients with malignant gliomas, although not frequently as striking as in the patient reported here .
A female patient aged 29 years was diagnosed with anaplastic glioma of 3 cm diameter in the basal ganglia of the right hemisphere (Figure 1). The tumor was biopsied. Subsequently the patient underwent conformal radiotherapy with 2 Gy single doses up to 60 Gy. Because of headache three weeks after the start of radiation, she was treated with dexamethasone up to 12 mg daily.
Figure 1: Initial radiologic findings. Brain MRI demonstrates 3.2 × 2.8 cm lesion without contrast enhancement in the T1 weighted image. A) and with edema on flair image; B) before biopsy and radiation therapy. MRI: magnetic resonance imaging. View Figure 1
Two weeks later, she reported that her headache was gone, but that she was continuously active day and night, felt restlessly "driven from outside". She was unable to fall asleep before 2 o'clock a.m. and woke up 1.5 to 2 hours later. Because of sleep deprivation, her family physician prescribed nitrazepam 5 mg taken at bedtime. Despite an increase of the nitrazepam dose of up to 4 tablets her sleep lasted not longer than two hours. Her sleep pattern before the start of radiotherapy had been inconspicuous.
A capsule with 3 mg of melatonin taken at 10 p.m. allowed her again to fall asleep and to stay asleep for five to six hours without benzodiazepine medication. She had again regenerative sleep and felt active at day time. Unfortunately, no quantification of salivary or plasmatic melatonin at bedtime was done prior to starting melatonin substitution.
The hormone melatonin (N-acetyl-5-methoxytryptamine) is secreted in the pineal gland during darkness or when the absorption of blue light (484 nm) is blocked. Melatonin is an important factor of the sleep-wake cycle, mainly regulated by the suprachiasmatic nuclei of the hypothalamus [9,10]. In the US, melatonin is widely used as over the counter medicine against sleep disorders, jet lag and various other conditions as it is a powerful antioxidant, whereas in Europe, its medical use focuses on insomnia in persons above the age of 55 years. However, with rare exceptions, melatonin is well tolerated in doses below 5 mg [11-15] and potential anti-tumoral effectiveness of melatonin has been discussed .
In the patient of this report, the radiation field covered the epiphysis as well as both hypothalamic suprachiasmatic nuclei, where the circadian rhythms of waking and sleep are regulated (Figure 2 and Table 1). Radiation therapy is known to cause irreversible depletion of the pituitary hormones [17-19], so in analogia, trying melatonin therapy was obvious - and successful. Thus, in patients with radiation fields covering the hypothalamus or the epiphysis with insomnia, the administration of melatonin may offer restoration of satisfactory sleep patterns.
Figure 2: Irradiation plan showing the isodoses (red-violet-blue), brainstem (green), pineal gland (pink). View Figure 2
Table 1: Minimal, maximal, median and average doses of the risk organs and CTV (clinical target volume), PTV (planning target volume). View Table 1
Savard J, Ivers H, Villa J, Caplette-Gingras A, Morin CM (2011) Natural course of insomnia comorbid with cancer: an 18-month longitudinal study. J Clin Oncol 29: 3580-3586.
Enderlin CA, Coleman EA, Cole C, Richards KC, Kennedy RL, et al. (2011) Subjective sleep quality, objective sleep characteristics, insomnia symptom severity, and daytime sleepiness in women aged 50 and older with nonmetastatic breast cancer. Oncol Nurs Forum 38: E314-325.
Dirksen SR, Epstein DR, Hoyt MA (2009) Insomnia, depression, and distress among outpatients with prostate cancer. Appl Nurs Res 22: 154-158.
Donovan KA, Jacobsen PB (2007) Fatigue, depression, and insomnia: evidence for a symptom cluster in cancer. Semin Oncol Nurs 23: 127-135.
O'Donnell JF (2004) Insomnia in cancer patients. Clin Cornerstone 6: S6-14.
Silberfarb PM, Hauri PJ, Oxman TE, Lash S (1985) Insomnia in cancer patients. Soc Sci Med 20: 849-850.
Beszterczey A, Lipowski ZJ (1977) Insomnia in cancer patients. Can Med Assoc J 116: 355.
Yuile P, Dent O, Cook R, Biggs M, Little N (2006) Survival of glioblastoma patients related to presenting symptoms, brain site and treatment variables. J Clin Neurosci 13: 747-751.
Dubocovich ML (2007) Melatonin receptors: role on sleep and circadian rhythm regulation. Sleep Med 8: 34-42.
Dijk DJ, Cajochen C (1997) Melatonin and the circadian regulation of sleep initiation, consolidation, structure, and the sleep EEG. J Biol Rhythms 12: 627-635.
Lemoine P, Wade AG, Katz A, Nir T, Zisapel N (2012) Efficacy and safety of prolonged-release melatonin for insomnia in middle-aged and elderly patients with hypertension: a combined analysis of controlled clinical trials. Integr Blood Press Control 5: 9-17.
Yousaf F, Seet E, Venkatraghavan L, Abrishami A, Chung F (2010) Efficacy and safety of melatonin as an anxiolytic and analgesic in the perioperative period: a qualitative systematic review of randomized trials. Anesthesiology 113: 968-976.
Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, et al. (2006) Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis. BMJ 332: 385.
Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, et al. (2005) The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis. J Gen Intern Med 20: 1151-1158.
Arendt J (1997) Safety of melatonin in long-term use (?). J Biol Rhythms 12: 673-681.
Wion D, Berger F, Wion-Barbot N (2006) Glioma, melatonin, and radiotherapy. Cancer Res 66: 6457.
Darzy KH (2009) Radiation-induced hypopituitarism after cancer therapy: who, how and when to test. Nat Clin Pract Endocrinol Metab 5: 88-99.
Darzy KH (2013) Radiation-induced hypopituitarism. Curr Opin Endocrinol Diabetes Obes 20: 342-353.
Darzy KH, Shalet SM (2006) Pathophysiology of radiation-induced growth hormone deficiency: efficacy and safety of GH replacement. Growth Horm IGF Res 16: S30-40.