Chemo brain

by matt bridgman

Chemo brain, aka chemo fog, aka chemo-related cognitive dysfunction, aka cancer-related cognitive dysfunction.
What is it? What causes it? What can be done about it? Read More to see what I have been learning in my attempt to answer these questions.   

    
Chemo Brain/Chemo Fog/Cancer-related cognitive dysfunction

1.    What is it? - Symptoms (Mayo clinic; MD Anderson; Evens and Eschiti, 2009)
     a.    Feeling unusually disorganized
     b.    Having moments of confusion
     c.     Increased difficulty Concentrating
     d.    Trouble finding the right words
     e.    Difficulty learning new skills
     f.     Difficulty multitasking
     g.    Fatigue
     h.   Mental fogginess
     i.    Shortened attention span
     j.    Short term memory trouble
     k.   Taking longer to complete routine tasks
     l.    Reduced or slowed information processing/processing speed
     m.  Trouble with verbal memory (like remembering a conversation)
     n.   Trouble with visual memory (like recalling an image or a location)

2.    What causes it? - Physiology (Mayo Clinic; MD Anderson; Evans and Eschiti, 2009; Raffa, 2011; Cui, Kong, and Zhang, 2012; Ho, 2015)
     a.    This is not entirely clear, but is not simply the chemo or radiation itself. Cause of chemo-brain is multifactorial; many factors combining to contribute to the symptoms of chemo brain. 
     b.    Possible factors/contributors: 
          i.    Cancer itself – particularly cancers of the brain
          ii.   Cancer treatments
               1.    Chemotherapy
               2.    Hormone therapy
               3.    Immunotherapy
               4.    Radiation therapy
               5.    Stem cell transplant
               6.    Surgery (post-operative cognitive dysfunction)
          iii. Complications of cancer treatment
               1.    Anemia (which is thought to contribute possibly to ischemic injury)
               2.    Fatigue
               3.    Infection
               4.    Menopause or other hormonal changes 
               5.    Nutritional deficiencies
               6.    Sleep problems/insomnia
               7.    Pain 
          iv. Emotional reactions to cancer diagnosis and treatment
               1.    Anxiety
               2.    Depression
               3.    Stress – stress is not just emotional. Stress is a medical condition. Stress affects physiology – evidence of stress induced telomere shortening; hormone changes, blood flow changes, changes in heart rate, etc.
                    a.    Epel et al 2004, study found association between psychological stress and indicators of accelerated aging (oxidative stress, telomere length, and telomerase activity).  (Telomeres are the protective endcaps of our chromosomes.)
          v. Other causes
               1. Inherited susceptibility to chemo brain
                     a.    Some indication that individuals with APOE 4 allele (which is implicated in Alzheimer’s) also confers increase risk of chemobrain 
               2. Medications for other cancer-related signs and symptoms, such as: 
                    a.    Pain medications, 
                    b.    Antiemetic, 
                    c.    glucocorticosteroids – which are for nausea, vomiting, and hypersensitivity reactions; appetite stimulant; alleviate pain; anticancer effects. (Wooldridge et al 2001). 
               3. Recurrent cancer that has spread to brain
         vi.  Inflammation and oxidative stress – (Raffa 2011; Cui, Kong, and Zhang 2012)
               1.    Inflammation and oxidative stress caused by chemo (but potentially exacerbated by any number of the issues above – the cancer itself, radiation, infection).
               2.    Inflammation and oxidative stress disrupt normal mitochondrial functioning (therefore affecting mental energy and working memory!) and leads to cell death by various complicated pathways (stimulates FOXO3 transcription factor, and blocking neuroprotection by IGF-1 (insulin like growth factor-1) (Davila and Torres-Aleman 2008). 
          vii.    Alterations in Blood brain barrier (which leads to inflammation and increased oxidative injury)
          viii.    Vascular injury
          ix.    Myelination changes
          x.    Decreases in grey matter and demyelination of white matter fibers after systemic chemo

3.    Risk factors (Mayo Clinic; Gordon and Haut, 2014)
     a.    Brain cancer
     b.    Chemotherapy given directly to CNS (central nervous system, which is the brain and spinal cord)
     c.    Chemotherapy combined with whole-brain radiation
     d.    Higher doses of chemo or radiation
     e.    Combination chemotherapy (multiple chemotherapy agents)
     f.    Radiation to the brain
     g.    Younger age at time of cancer diagnosis and treatment
     h.    Increasing age
     i.    Pre-cancer heath issues, such as: head injuries, depression, learning disabilities, and other neurologic disorders. These probably increase risk of chemo/cancer-related cognitive dysfunction, but confirming this is challenging, as individuals with such histories are typically excluded from research studies. 

4.    Diagnosis 
     a.    No clear definition or criteria for diagnosing chemo brain, so therefore no definitive tests exist. Cancer survivors who do experience cognitive symptoms often score normally on memory tests, but not always (depending on the tests used) (Mayo Clinic). (Jim et al 2012 metaanalysis did find consistent post treatment effects on verbal abilities and visuospatial abilities). 
     b.    Comprehensive neuropsychological testing is more sensitive to deficits than screeners such as MMSE/MoCA. 
     c.    Objective deficits are often subtle (so easily missed by cognitive screenings), or the decline is from an above average or average level, to an average or low average level (so test results are still “normal” even though they are a decline from pre-treatment). Having a pre-treatment neuropsychological evaluation can be helpful in this regard, to therefore provide comparison of pre-treatment and post-treatment scores, which is a more sensitive way of measuring a cognitive change. 
     d.    May undergo tests to rule out other causes/reversible causes of cognitive difficulty (i.e. B12 deficiency, anemia, electrolyte issues, nutritional deficiencies, etc.) (Mayo Clinic)

5.    Treatment (Mayo Clinic; MD Anderson; Evans and Eschiti, 2009)
     a.    No standard treatment exists for chemo-brain. Because chemo brain is the result of many factors, no single treatment will be sufficient. Effective treatment will require addressing as many of the responsible factors as possible.
     b.    Addressing treatable factors
           i.    Insomnia – treatment using medications, sleep hygiene, guided imagery 
               1.    Collaborate with your family doctor or other providers regarding possible medications or alternative therapies (i.e. melatonin). 
               2.    Behavioral therapy for insomnia (such as Cognitive Behavioral Therapy for Insomnia, or CBT-i, which is a formalized psychotherapeutic approach to treating insomnia) see the following site for an introduction to CBT-I http://www.mayoclinic.org/diseases-conditions/insomnia/in-depth/insomnia-treatment/art-20046677 
               3.    This is a good resource discussing sleep and sleep hygiene: http://www.med.umich.edu/painresearch/patients/Sleep.pdf 
               4.    This is also a great page: http://healthysleep.med.harvard.edu/healthy/getting/overcoming/tips 
               5.    Guided imagery: search YouTube for various guided imagery for sleep exercises. They are not all of equal quality or effectiveness, so check out several to see which may be helpful for you.
               6.    www.marc.ucla.edu click on the link for Free Guided Meditations, on which you will find several mindfulness meditation audio files, one of which is a body scan meditation for sleep
          ii.    Anemia – if your medical provider has tested and discovered anemia, they will advise you on how to treat this. 
          iii.    Depression/anxiety – medications, individual psychotherapy
          iv.    Hormone changes (e.g. menopause); your medical provider will advise you on how to address this. 
          v.    Pain: this is tricky, as the pain itself interferes with cognition, but medications to treat pain can also interfere with cognition. Finding an appropriate balance is tricky, but important. Consider treating pain not just with medication, but also with behavioral strategies. Much has been written recently about the benefits of meditation (such as mindfulness meditation) for chronic pain management (research has been not just related to cancer/chemo, but especially related to conditions such as Fibromyalgia) (find information about mindfulness and pain management through links/websites elsewhere in this outline). Also see the information on Pacing, below. 
     c.    Cognitive exercises
           i.    Cognitive rehabilitation, such as with a speech therapist: a formalized approach to learning and practicing specific exercises for strengthening memory and other cognitive abilities. Obtaining speech therapy for cognitive rehabilitation usually requires an order or prescription from your family doctor or other medical provider. 
           ii.    Meditation for improving cognition (Biegler et al 2009).  (see section on meditation below). 
     d.    Learning to adapt and cope
           i.    Tracking and understanding what influences memory problems
               1.    i.e. if concentration/memory worsen when hungry, be more purposeful about eating regularly, or doing more mentally demanding tasks shortly after eating
               2.    If concentration/memory issues worsen when tired, schedule/plan to do more demanding tasks at times when energy is typically highest
          ii.    Compensatory strategies
               1.    Taking notes
               2.    Organization
               3.    Routines
               4.    Using calendar more
               5.    Using reminders/alarms on a phone or other device
               6.    Take frequent breaks – Pacing!
                    a.    A good overview/strategy for pacing (meant for fibromyalgia, but applies to any condition involving chronic fatigue and chronic pain issues) http://www.med.umich.edu/painresearch/patients/Pacing.pdf 
                    b.    If cognition, and particularly mental fatigue is a problem for us, we need to consider pacing not just for physical tasks, but also for mentally demanding tasks and situations (as well as for emotionally taxing tasks and situations). 
               7.    Reducing distractions/multitasking
               8.    Work accommodations (adjustments to environment and/or work demands)
          iii. Memorization strategies
               1.    Association
               2.    Visual imagery
               3.    Appointments/tasks: Elaborative encoding/adding meaning
               4.    Information or lists of things: Method of loci (aka Memory Palace) https://www.youtube.com/watch?v=s2zUIw1ESbE (YouTube video on Method of Loci/Memory Palace, by aceblade – a quick 6:45 minute intro to using this strategy)
               5.    Names: https://www.youtube.com/watch?v=m2GI0huaV5s 
(Ronnie White – “How to Memorize/How to Remember Names/Memory Speaker”)
          iv.    Stress relief strategies
               1.    Relaxation techniques
               2.    Guided imagery
               3.    (and other things listed elsewhere, like exercise and meditation)
     e.    Meditation
           i.    In almost any form, such as mindfulness meditation, yoga, or tai chi. This assists with stress management, but also evidence of cognitive benefits, and evidence of benefits for telomere length (meditation is good for our genes!) 
          ii.    Biegler et al 2009 – meditation is an important treatment for cancer-related cognitive dysfunction (evidence that it can help cognition and psychological effects of cancer and cancer treatments).
          iii.    Epel et al 2009 – meditation may promote cell longevity by decreasing stress hormones and oxidative stress, and by increasing hormones that may protect the telomere (telomere = the protective endcaps of our chromosomes). 
          iv.    MBSR – Mindfulness Based Stress Reduction – a formalized program of using mindfulness meditation for the purpose of managing stress 
          v.    Resources:
               1.    www.marc.ucla.edu - contains much, much information on mindfulness meditation – videos, podcasts, articles, etc. on the background research, how do learn it, how to practice it, and how to apply it for different purposes (such as for pain, sleep, mood, etc.)
               2.    www.palousemindfulness.com - All you need to learn and benefit from Mindfulness Based Stress Reduction
     f.    Medications
          i.    No medications have been approved specifically for Chemo brain, but others are used “off-label” 
          ii.    Methylphenidate (Concerta, Ritalin, etc.) used for ADHD
          iii.   Donepezil – for AD
          iv.   Modafinil (Provigil) sleep disorders
          v.    Memantine – memory/AD
     g.    Alternative medicine/Nutrition
          i.    Ginkgo – some promise, but more study needed
          ii.   Vitamin E – may be beneficial for brain cells, but more study is needed
          iii.  Anti-inflammatory interventions (Cui, Kong, and Zhang, 2012), such as an anti-inflammatory diet.
          iv.    Zuniga et al 2015 provides some indication that intake of fruits and vegetables is positively associated with cognitive control for more cognitively demanding tasks
          v.    I am sure there is much more to be included in this section, hopefully to be added in the future. 
     h.    Exercise – helps with stress, sleep, energy, memory, neuroplasticity, neurogenesis
          i.    Again, keep in mind the importance of pacing (see http://www.med.umich.edu/painresearch/patients/Pacing.pdf 
          ii.    What is meant by “exercise”?
               1.    Aerobic exercise – gets your heart rate up, but not too high; activity that warms you up, makes you breathe a little heavier, but you can still carry on a conversation
               2.    Such as walking, biking, swimming, elliptical, etc.
               3.    Ideal: 30 minutes a day, 5 days a week
               4.    As always "check with your doctor before starting a new exercise program", always being careful to engage in activities that will not exacerbate pre-existing conditions or put you at risk of injury. 
          iii.    Why?
               1.    Improves depression and facilitates neurogenesis (Ernst et al 2006). 
               2.    Reduces brain tissue loss in aging (Colcombe et al 2003). 
               3.    Neuroprotection, and brain growth (neurogenesis, neuroplasticity) through mechanisms such as increasing BDNF’s – brain derived neurotrophic factors (Cotman and Berchtold, 2002)
               4.    Mitochondrial biogenesis (Hood, 2009; Vina et al 2009) 
               5.    Reduced inflammation (Woods et al 2009)
               6.    And of course, well-documented improvements in learning, memory, sleep, and stress management.
     i.    Support – support groups and support from family and friends is of course extremely important for navigating the challenges and stresses of cancer and chemo related cognitive dysfunction. 


References

Mayo Clinic website: http://www.mayoclinic.org/diseases-conditions/chemo-brain/home/ovc-20170224 Retrieved 5/21/16.

MD Anderson website:  https://www.mdanderson.org/patients-family/diagnosis-treatment/emotional-physical-effects/chemobrain.html Retrieved 5/21/16.

Biegler, K. A., Alejandro Chaoul, M., & Cohen, L. (2009). Cancer, cognitive impairment, and meditation. Acta Oncologica, 48(1), 18–26. http://doi.org/10.1080/02841860802415535

Colcombe, S. J., Erickson, K. I., Raz, N., Webb, A. G., Cohen, N. J., McAuley, E., & Kramer, A. F. (2003). Aerobic Fitness Reduces Brain Tissue Loss in Aging Humans. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 58(2), M176–M180. http://doi.org/10.1093/gerona/58.2.M176

Cotman, C., & Berchtold, N. (2002). Exercise: a behavioral intervention to enhance brain health and plasticity. TRENDS in Neurosciences, 25(6), 295–301.

Cui, H., Kong, Y., & Zhang, H. (2012). Oxidative stress, mitochondrial dysfunction, and aging. Journal of Signal Transduction, 2012, 646354. http://doi.org/10.1155/2012/646354

Dávila, D., & Torres-Aleman, I. (2008). Neuronal death by oxidative stress involves activation of FOXO3 through a two-arm pathway that activates stress kinases and attenuates insulin-like growth factor I signaling. Molecular Biology of the Cell, 19(5), 2014–25. http://doi.org/10.1091/mbc.E07-08-0811

Epel, E. S., Blackburn, E. H., Lin, J., Dhabhar, F. S., Adler, N. E., Morrow, J. D., & Cawthon, R. M. (2004). Accelerated telomere shortening in response to life stress. Proceedings of the National Academy of Sciences of the United States of America, 101(49), 17312–5. http://doi.org/10.1073/pnas.0407162101

Epel, E., Daubenmier, J., Moskowitz, J. T., Folkman, S., & Blackburn, E. (2009). Can Meditation Slow Rate of Cellular Aging? Cognitive Stress, Mindfulness, and Telomeres. Annals of the New York Academy of Sciences, 1172(1), 34–53. http://doi.org/10.1111/j.1749-6632.2009.04414.x

Ernst, C., Olson, A., Pinel, J., & Lam, R. (2006). Antidepressant effects of exercise: evidence for an adult-neurogenesis hypothesis? Journal of Psychiatry. Retrieved from http://search.proquest.com/openview/0ab8ef4de3168b3aa059ccad3258505f/1?pq-origsite=gscholar

Evens, K., & Eschiti, V. (2009). Cognitive Effects of Cancer Treatment:“ Chemo Brain” Explained. Clinical Journal of Oncology Nursing. Retrieved from http://search.ebscohost.com/login.aspx?direct=true&profile=ehost&scope=site&authtype=crawler&jrnl=10921095&AN=48882221&h=3JgRcdTtsSxttdfLabaS96BOwjkN2hOZaZxl4TOaSYcvc5Gg%2FGqBAEu1uWlY7oH8%2BXqjld8SqWf%2B9jWcxO6Gsw%3D%3D&crl=c

Gordon, D., & Haut, M. W. (April/May 2014). Chemo Brain: Cognitive problems after cancer treatment are not imaginary. Neurology Now. Retrieved from: http://patients.aan.com/resources/neurologynow/index.cfm?event=home.articlePDF&id=ovid.com%3A%2Fbib%2Fovftdb%2F01222928-201410020-00013 on 6/12/2016. 

Ho, K. (2015). Insights into the mechanism of “chemobrain”: deriving a multi-factorial model of pathogenesis. Novel Oral Anticoagulants. Retrieved from http://www.amsj.org/wp-content/uploads/files/issue/amsj_v6_i1.pdf#page=26

Hood, D. (2009). Mechanisms of exercise-induced mitochondrial biogenesis in skeletal muscle This paper is one of a selection of papers published in this Special Issue, entitled 14th. Applied Physiology, Nutrition, and Metabolism. Retrieved from http://www.nrcresearchpress.com/doi/abs/10.1139/h09-045

Jim, H. S. L., Phillips, K. M., Chait, S., Faul, L. A., Popa, M. A., Lee, Y.-H., … Small, B. J. (2012). Meta-analysis of cognitive functioning in breast cancer survivors previously treated with standard-dose chemotherapy. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 30(29), 3578–87. http://doi.org/10.1200/JCO.2011.39.5640

Raffa, R. B. (2011). A proposed mechanism for chemotherapy-related cognitive impairment (’chemo-fog'). Journal of Clinical Pharmacy and Therapeutics, 36(3), 257–9. http://doi.org/10.1111/j.1365-2710.2010.01188.x

Viña, J., Gomez-Cabrera, M. C., Borras, C., Froio, T., Sanchis-Gomar, F., Martinez-Bello, V. E., & Pallardo, F. V. (2009). Mitochondrial biogenesis in exercise and in ageing. Advanced Drug Delivery Reviews, 61(14), 1369–1374. http://doi.org/10.1016/j.addr.2009.06.006

Woods, J., Vieira, V., & Keylock, K. (2009). Exercise, inflammation, and innate immunity. Immunology and Allergy Clinics of North. Retrieved from http://www.sciencedirect.com/science/article/pii/S0889856109000125

Wooldridge, J., Anderson, C., & Perry, M. (2001). Corticosteroids in Advanced Cancer. Oncology, 15(2), 225–236. Retrieved from http://www.cancernetwork.com/review-article/corticosteroids-advanced-cancer

Zuniga, K. E. ., Mackenzie, M. J. ., Roberts, S. A. ., Raine, L. B. ., Hillman, C. H. ., Kramer, A. F. ., & McAuley, E. . (2015). Relationship between fruit and vegetable intake and interference control in breast cancer survivors. European Journal of Nutrition, (May 2016). http://doi.org/10.1007/s00394-015-0973-3

Disclaimer: Information contained in this outline is intended for educational purposes only, and is not intended for the diagnosis or treatment of any individual, or to replace the services of a qualified medical professional. This information does not constitute medical advice.