Cognitive disorders and delirium are often multifactorial, especially in the setting of advanced cancer. General etiologic factors include the following:[1-10]

• Direct effects of cancer on the central nervous system (CNS). For example, an exploratory study of 54 patients newly diagnosed with myelodysplastic syndrome or acute myelogenous leukemia indicates a correlation between levels of circulating cytokines at diagnosis and specific types of cognitive dysfunction. Higher levels of IL-6 were associated with poorer executive function, and higher levels of IL-8 correlated with improved memory.[9]



• Indirect CNS effects related to systemic complications of cancer such as organ failure (e.g., hepatic or renal failure), metabolic or electrolyte disturbance (e.g., hypoglycemia, hypercalcemia, hyponatremia, or dehydration), infection, and paraneoplastic syndromes (e.g., bulbar encephalitis).[11]



• Exogenous substances such as the wide variety of medications and treatments used in these patients, including most of the commonly used chemotherapeutic agents,[12-17] bone marrow or stem cell transplantation, biologic response modifiers (e.g., interleukin and interferon), glucocorticoids, and especially psychoactive agents such as opioid analgesics, antidepressants, benzodiazepines, antihistamines, and other sedating agents.



• Withdrawal phenomena associated with substances such as alcohol and benzodiazepines.

Despite the very limited systematic study of risk factors for delirium in patients with cancer, risk factors have been identified in general medical patients (some of them with cancer) and include severe illness, level of comorbidity, advanced age, prior dementia, hypoalbuminemia, infection, azotemia, and psychoactive medications.[18-20] Studies in elderly medical patients suggest that the level of risk is proportionate to the number of risk factors present.[21] Cancer is particularly prevalent in the elderly population. Many patients with cancer, particularly those with advanced disease, are likely to have a high level of baseline vulnerability. Such vulnerability leaves them predisposed to precipitants such as psychoactive medications.[22] It is also likely that the predictors of poor pain control in cancer patients (neuropathic pain, incidental pain, opioid tolerance, somatization, and a history of drug or alcohol abuse) result in higher opioid doses and thereby increase the risk of delirium.[23] Distinct from delirium, older (65 years or older), long-term (>5 years) cancer survivors are also at increased risk of cognitive deficits and possibly dementia, as noted in a co-twin control design study of 702 Swedish cancer survivors.[10]

References

1. Lawlor PG, Gagnon B, Mancini IL, et al.: Occurrence, causes, and outcome of delirium in patients with advanced cancer: a prospective study. Arch Intern Med 160 (6): 786-94, 2000.  [PUBMED Abstract]
   
   
2. Agostini JV, Leo-Summers LS, Inouye SK: Cognitive and other adverse effects of diphenhydramine use in hospitalized older patients. Arch Intern Med 161 (17): 2091-7, 2001 Sep 24.  [PUBMED Abstract]
   
   
3. Fann JR, Roth-Roemer S, Burington BE, et al.: Delirium in patients undergoing hematopoietic stem cell transplantation. Cancer 95 (9): 1971-81, 2002.  [PUBMED Abstract]
   
   
4. Prieto JM, Blanch J, Atala J, et al.: Psychiatric morbidity and impact on hospital length of stay among hematologic cancer patients receiving stem-cell transplantation. J Clin Oncol 20 (7): 1907-17, 2002.  [PUBMED Abstract]
   
   
5. Morita T, Tei Y, Tsunoda J, et al.: Underlying pathologies and their associations with clinical features in terminal delirium of cancer patients. J Pain Symptom Manage 22 (6): 997-1006, 2001.  [PUBMED Abstract]
   
   
6. Morita T, Tei Y, Tsunoda J, et al.: Increased plasma morphine metabolites in terminally ill cancer patients with delirium: an intra-individual comparison. J Pain Symptom Manage 23 (2): 107-13, 2002.  [PUBMED Abstract]
   
   
7. van Steijn JH, Nieboer P, Hospers GA, et al.: Delirium after interleukin-2 and alpha-interferon therapy for renal cell carcinoma. Anticancer Res 21 (5): 3699-700, 2001 Sep-Oct.  [PUBMED Abstract]
   
   
8. Walker LG, Walker MB, Heys SD, et al.: The psychological and psychiatric effects of rIL-2 therapy: a controlled clinical trial. Psychooncology 6 (4): 290-301, 1997.  [PUBMED Abstract]
   
   
9. Meyers CA, Albitar M, Estey E: Cognitive impairment, fatigue, and cytokine levels in patients with acute myelogenous leukemia or myelodysplastic syndrome. Cancer 104 (4): 788-93, 2005.  [PUBMED Abstract]
   
   
10. Heflin LH, Meyerowitz BE, Hall P, et al.: Cancer as a risk factor for long-term cognitive deficits and dementia. J Natl Cancer Inst 97 (11): 854-6, 2005.  [PUBMED Abstract]
    
    
11. Paraneoplastic syndromes. In: Posner JB: Neurologic Complications of Cancer. Philadelphia, Pa: FA Davis, 1995, pp 353-85. 
    
    
12. Eberhardt B, Dilger S, Musial F, et al.: Short-term monitoring of cognitive functions before and during the first course of treatment. J Cancer Res Clin Oncol 132 (4): 234-40, 2006.  [PUBMED Abstract]
    
    
13. Hermelink K, Untch M, Lux MP, et al.: Cognitive function during neoadjuvant chemotherapy for breast cancer: results of a prospective, multicenter, longitudinal study. Cancer 109 (9): 1905-13, 2007.  [PUBMED Abstract]
    
    
14. Nelson CJ, Nandy N, Roth AJ: Chemotherapy and cognitive deficits: mechanisms, findings, and potential interventions. Palliat Support Care 5 (3): 273-80, 2007.  [PUBMED Abstract]
    
    
15. Taillibert S, Voillery D, Bernard-Marty C: Chemobrain: is systemic chemotherapy neurotoxic? Curr Opin Oncol 19 (6): 623-7, 2007.  [PUBMED Abstract]
    
    
16. Bender CM, Sereika SM, Brufsky AM, et al.: Memory impairments with adjuvant anastrozole versus tamoxifen in women with early-stage breast cancer. Menopause 14 (6): 995-8, 2007 Nov-Dec.  [PUBMED Abstract]
    
    
17. Stewart A, Collins B, Mackenzie J, et al.: The cognitive effects of adjuvant chemotherapy in early stage breast cancer: a prospective study. Psychooncology 17 (2): 122-30, 2008.  [PUBMED Abstract]
    
    
18. Schor JD, Levkoff SE, Lipsitz LA, et al.: Risk factors for delirium in hospitalized elderly. JAMA 267 (6): 827-31, 1992.  [PUBMED Abstract]
    
    
19. O'Keeffe ST, Lavan JN: Predicting delirium in elderly patients: development and validation of a risk-stratification model. Age Ageing 25 (4): 317-21, 1996.  [PUBMED Abstract]
    
    
20. Elie M, Cole MG, Primeau FJ, et al.: Delirium risk factors in elderly hospitalized patients. J Gen Intern Med 13 (3): 204-12, 1998.  [PUBMED Abstract]
    
    
21. Inouye SK, Charpentier PA: Precipitating factors for delirium in hospitalized elderly persons. Predictive model and interrelationship with baseline vulnerability. JAMA 275 (11): 852-7, 1996.  [PUBMED Abstract]
    
    
22. Casarett DJ, Inouye SK; American College of Physicians-American Society of Internal Medicine End-of-Life Care Consensus Panel.: Diagnosis and management of delirium near the end of life. Ann Intern Med 135 (1): 32-40, 2001.  [PUBMED Abstract]
    
    
23. Bruera E, Schoeller T, Wenk R, et al.: A prospective multicenter assessment of the Edmonton staging system for cancer pain. J Pain Symptom Manage 10 (5): 348-55, 1995.  [PUBMED Abstract]
    
    

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