Sleep No More: A Case of Severe Insomnia Due to Injury to the Reticular Activating System From Glioblastoma Multiforme

Key Message : Injury to the reticular activating system is a rare, serious cause of insomnia in patients with serious illness. Such cases can manifest with intractable insomnia culminating in complete loss of ability to sleep with poor prognosis and death. Such cases can respond to rational multidrug regimens and interdisciplinary team support.

Abstract: Insomnia is a common symptom among those receiving palliative care, with an estimated prevalence of 40-70%. Almost all cases are due to poor sleep hygiene, suboptimal control of other symptoms, a primary sleep disorder, or adverse effects of medications. These etiologies leave the sleep-wake apparatus, the reticular activating system (RAS) intact, and often respond favorably to treatment of the underlying cause. Complete RAS injury is typically associated with traumatic, metabolic, or ischemic insults, resulting in coma [1]. Incomplete injury to the RAS is rare but can be caused by malignancy, radiation, or surgical injury [2-3]. Such cases are poorly understood but carry a poor prognosis with progressive loss of biologic ability to sleep, eventually resulting in death within weeks to months from delirium once the ability to sleep is completely lost [4-5].

This presentation will discuss a case of insomnia due to injury to the reticular activating system from a large, multifocal, unresectable glioblastoma multiforme (GBM) in a male patient in his 70s. Despite treatment with radiation, temozolomide, bevacizumab, and Tumor Treating Fields, he developed intractable insomnia with complete inability to initiate sleep and failed multiple single-agent hypnotic therapies. He had a favorable response to a rational multidrug regimen targeting multiple sleep systems, including the neurohormonal (ramelteon), orexin (suvorexant), GABA-ergic (temazepam), and histamine (mirtazapine) axes. He and his wife experienced significant distress due to this symptom and responded well to social work support. He had marked functional and cognitive improvement and lived for 7 months, well beyond his initial prognosis, until he eventually had disease progression and death at home with hospice care.

This presentation will review the different neurotransmitters and pathways involved in sleep, imaging findings of RAS injury, selection of medications in the treatment of insomnia, and the role of the interdisciplinary team in managing complex insomnia cases.

References: 1. Young GB. Coma. Ann N Y Acad Sci. 2009 Mar;1157:32-47. doi: 10.1111/j.1749-6632.2009.04471.x. PMID: 19351354.
2. Gong L, He K, Cheng F, Deng Z, Cheng K, Zhang X, Zhou W, Ou J, Wang J, Zhang B, Ding X, Xu R, Xi C. The role of ascending arousal network in patients with chronic insomnia disorder. Hum Brain Mapp. 2023 Feb 1;44(2):484-495. doi: 10.1002/hbm.26072. Epub 2022 Sep 16. PMID: 36111884; PMCID: PMC9842899.
3. Van Someren EJW. Brain mechanisms of insomnia: new perspectives on causes and consequences. Physiol Rev. 2021 Jul 1;101(3):995-1046. doi: 10.1152/physrev.00046.2019. Epub 2020 Aug 13. PMID: 32790576.
4. Vgontzas AN, Fernandez-Mendoza J, Liao D, Bixler EO. Insomnia with objective short sleep duration: the most biologically severe phenotype of the disorder. Sleep Med Rev. 2013 Aug;17(4):241-54. doi: 10.1016/j.smrv.2012.09.005. Epub 2013 Feb 16. PMID: 23419741; PMCID: PMC3672328.
5. Waters F, Chiu V, Atkinson A, Blom JD. Severe Sleep Deprivation Causes Hallucinations and a Gradual Progression Toward Psychosis With Increasing Time Awake. Front Psychiatry. 2018 Jul 10;9:303. doi: 10.3389/fpsyt.2018.00303. PMID: 30042701; PMCID: PMC6048360.