neurocognitive dysfunction in brain tumor patients renee hinsley raynor, ph.d. clinical...
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Neurocognitive Dysfunction Neurocognitive Dysfunction in Brain Tumor Patientsin Brain Tumor Patients
Renee Hinsley Raynor, Ph.D.Renee Hinsley Raynor, Ph.D.Clinical NeuropsychologistClinical Neuropsychologist
The Preston Robert Tisch Brain Tumor Center at DukeThe Preston Robert Tisch Brain Tumor Center at Duke
The Neurocognitive Impact of The Neurocognitive Impact of Brain Tumors: A Growing Brain Tumors: A Growing ProblemProblem In 2012, an estimated 688,000+ people in the US In 2012, an estimated 688,000+ people in the US
were living with a primary brain or CNS tumor were living with a primary brain or CNS tumor diagnosis (138,000 malignant and 550,000 diagnosis (138,000 malignant and 550,000 benign)benign)
An estimated 69,720 new cases of primary brain An estimated 69,720 new cases of primary brain
tumors were expected to be diagnosed in 2013 tumors were expected to be diagnosed in 2013 and includes both malignant (24,620) and non-and includes both malignant (24,620) and non-malignant (45,100) brain tumorsmalignant (45,100) brain tumors
CBTRUS Statistical Report (2012)CBTRUS Statistical Report (2012)
The Neurocognitive Impact of The Neurocognitive Impact of Brain Tumors: A Growing Brain Tumors: A Growing ProblemProblem Agencies funding cancer research are Agencies funding cancer research are
calling for a increased emphasis on calling for a increased emphasis on disease-related symptoms and/or disease-related symptoms and/or quality of life (in addition to survival quality of life (in addition to survival and response rates)and response rates)
As cancer treatment becomes more As cancer treatment becomes more successful, more patients will live successful, more patients will live longer and expect to return to their longer and expect to return to their baseline level of functioningbaseline level of functioning
Brain Tumors: Impact of Brain Tumors: Impact of Neurocognitive ImpairmentNeurocognitive Impairment
Personal loss of independence and Personal loss of independence and dignity for patientsdignity for patients
Caregiver demand on family and Caregiver demand on family and friendsfriends
Financial burden on patient and family Financial burden on patient and family to supply adequate careto supply adequate care
Financial burden on society due to lost Financial burden on society due to lost productivity of patients and caregiversproductivity of patients and caregivers
Sound familiar?Sound familiar?
Neurocognitive Impairment Neurocognitive Impairment in Brain Tumor Patientsin Brain Tumor Patients
Memory lossMemory loss Distractibility and inattentionDistractibility and inattention Difficulty with multi-taskingDifficulty with multi-tasking Mood disturbanceMood disturbance Decreased executive controlDecreased executive control Decreased initiative, increased apathyDecreased initiative, increased apathy Decreased inhibition, behavioral Decreased inhibition, behavioral
dysregulationdysregulation
Etiology of these Etiology of these Neurocognitive DeficitsNeurocognitive Deficits
Direct effects of cancer within CNSDirect effects of cancer within CNS Indirect effects of certain cancers Indirect effects of certain cancers
(paraneoplastic disorders)(paraneoplastic disorders) Effects of cancer treatments on brain Effects of cancer treatments on brain
(surgical and medical)(surgical and medical) Effects of pharmacological treatments Effects of pharmacological treatments
for the cancer and related complicationsfor the cancer and related complications Co-existing neurologic or psychiatric Co-existing neurologic or psychiatric
disordersdisorders
Effects of Lesion LocationEffects of Lesion Location
Although cognitive symptoms caused Although cognitive symptoms caused by brain tumors may exhibit relatively by brain tumors may exhibit relatively focal effects, they tend to be less focal effects, they tend to be less dramatic than those seen in patients dramatic than those seen in patients with more acute onset lesionswith more acute onset lesions
Cognitive impairment is often Cognitive impairment is often associated with tumors of either associated with tumors of either hemisphere in any lobe (cortical and hemisphere in any lobe (cortical and subcortical)subcortical)
Effects of Lesion LocationEffects of Lesion Location
Neurocognitive impairment tends to be Neurocognitive impairment tends to be less localized in brain tumor patients less localized in brain tumor patients than in patients with more acute than in patients with more acute neurologic lesionsneurologic lesions
This may be due to destruction of This may be due to destruction of collateral tissue by the tumor or may collateral tissue by the tumor or may be related to diffuse effects of be related to diffuse effects of treatment modalities and agentstreatment modalities and agents
Effects of Lesion LocationEffects of Lesion Location
Impairment in frontal lobe function is Impairment in frontal lobe function is ubiquitous in brain tumor patientsubiquitous in brain tumor patients• (decreased mental flexibility, abstraction, (decreased mental flexibility, abstraction,
motivation, planning, organizational skills, motivation, planning, organizational skills, ability to benefit from experience; increased ability to benefit from experience; increased personality changes)personality changes)
• Large proportion of patients have frontal Large proportion of patients have frontal lobe tumorslobe tumors
• Frontal lobes have rich afferent and efferent Frontal lobes have rich afferent and efferent connections with all other brain regionsconnections with all other brain regions
Effects of Neurosurgery Effects of Neurosurgery
Whether patients undergo biopsy or Whether patients undergo biopsy or resection, neurosurgery is an invasive resection, neurosurgery is an invasive procedure and neurocognitive procedure and neurocognitive recovery time is measured in monthsrecovery time is measured in months
While some patients eventually return While some patients eventually return to near baseline cognitive functioning to near baseline cognitive functioning post-op, many do not due to the post-op, many do not due to the tumor’s invasion of previously normal tumor’s invasion of previously normal brainbrain
Wouldn’t this be nice?Wouldn’t this be nice?
Effects of HistologyEffects of Histology
Level of impairment varies depending on lesion Level of impairment varies depending on lesion location, treatment modalities used, and host location, treatment modalities used, and host characteristics (e.g., age, concurrent medical characteristics (e.g., age, concurrent medical problems)problems)
Higher grade tumors are associated with Higher grade tumors are associated with greater cognitive impairment in most cases, but greater cognitive impairment in most cases, but it is unclear whether this is inherently related to it is unclear whether this is inherently related to histology or perhaps more due to degree of histology or perhaps more due to degree of progression and associated destruction progression and associated destruction of normal brain tissueof normal brain tissue
Effects of HistologyEffects of Histology
Patients with low grade tumors that have Patients with low grade tumors that have been present for many years may have been present for many years may have little to no cognitive change because of little to no cognitive change because of cerebral plasticity and reorganizationcerebral plasticity and reorganization
Alternatively, patients with large low Alternatively, patients with large low grade tumor burden or with low grade grade tumor burden or with low grade tumors in critical cognitive areas may tumors in critical cognitive areas may show devastating cognitive/behavioral show devastating cognitive/behavioral declinedecline
Effects of Lesion Location Effects of Lesion Location and Histologyand Histology
Patients with left hemisphere tumors and Patients with left hemisphere tumors and GBM demonstrated testable differences in GBM demonstrated testable differences in neuropsychologic functioning and QOL*neuropsychologic functioning and QOL*
• Hahn CA, Dunn RH, Logue PE, King JH, Edwards CL, Halperin EC. Hahn CA, Dunn RH, Logue PE, King JH, Edwards CL, Halperin EC.
A Prospective Study of Neuropsychologic Testing and Quality of A Prospective Study of Neuropsychologic Testing and Quality of Life Assessment of Adults with Primary Malignant Brain Tumors. Life Assessment of Adults with Primary Malignant Brain Tumors. International Journal of Radiation Oncology, Biology, International Journal of Radiation Oncology, Biology, Physics 55(4):992-999, 2003.Physics 55(4):992-999, 2003.
Effects of Lesion Location Effects of Lesion Location and Histologyand Histology
Female gender, lower tumor Female gender, lower tumor grade, presence of grade, presence of comorbidities, and lower comorbidities, and lower education level were associated education level were associated with generalized anxiety and with generalized anxiety and depressive mood symptoms*depressive mood symptoms*
** Arnold, SD, Arnold, SD, Forman, LM, Brigidi, BD, Carter, KE, Schweitzer, HA, Quinn, HE, Guill, AB, Herndon II, JE, and Raynor, RH. Evaluation and Characterization of Neuropsychiatric Symptoms in Patients with Primary Brain Tumors. Neuro-oncology. 10(2):171, 2008.
Effects of Radiation TherapyEffects of Radiation Therapy
Cognitive areas impaired may include Cognitive areas impaired may include processing speed, executive function, processing speed, executive function, memory, sustained attention, and memory, sustained attention, and psychomotor coordinationpsychomotor coordination
Some of these deficits are thought to Some of these deficits are thought to be related to periventricular white be related to periventricular white matter damage; hyperintensities matter damage; hyperintensities observed on neuro-imagingobserved on neuro-imaging
Effects of Radiation TherapyEffects of Radiation Therapy
Pattern of cognitive deficits is not unlike Pattern of cognitive deficits is not unlike that seen in other subcortical diseases of that seen in other subcortical diseases of the white matter such as MSthe white matter such as MS
Children are particularly vulnerable to Children are particularly vulnerable to radiation injury; even relatively low doses radiation injury; even relatively low doses of cranial irradiation is associated with of cranial irradiation is associated with mild intellectual declines in older children mild intellectual declines in older children (younger children show more severe (younger children show more severe deficits)deficits)
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Effects of Radiation TherapyEffects of Radiation Therapy
Literature presents conflicting evidence as Literature presents conflicting evidence as to whether concomitant chemotherapy to whether concomitant chemotherapy increases the neurotoxicity of radiation increases the neurotoxicity of radiation therapytherapy
Fatigue from radiation therapy can be Fatigue from radiation therapy can be physical and mental and may cause a physical and mental and may cause a deleterious effect on cognition for a period deleterious effect on cognition for a period of time that extends far beyond completion of time that extends far beyond completion of treatmentof treatment
With relatively recent dramatic With relatively recent dramatic improvements in the delivery of radiation improvements in the delivery of radiation therapy, we expect to see increased therapy, we expect to see increased sparing of neurocognitive functioningsparing of neurocognitive functioning
Effects of ChemotherapyEffects of Chemotherapy
Neurocognitive effects of chemotherapy Neurocognitive effects of chemotherapy were previously thought to be reversible; were previously thought to be reversible; growing literature suggests persistent growing literature suggests persistent cognitive deficits in patients who have cognitive deficits in patients who have received standard-dose chemotherapyreceived standard-dose chemotherapy
The risk appears greater after high-dose The risk appears greater after high-dose chemotherapy such as with bone marrow chemotherapy such as with bone marrow transplant (long term effects unknown)transplant (long term effects unknown)
Effects of ChemotherapyEffects of Chemotherapy
Most impairment related to Most impairment related to chemotherapy tends to be relatively chemotherapy tends to be relatively diffuse, affecting sustained attention and diffuse, affecting sustained attention and speed of processingspeed of processing
Fatigue and hematologic toxicity related Fatigue and hematologic toxicity related to chemotherapy likely negatively to chemotherapy likely negatively impact cognition, but evidence suggests impact cognition, but evidence suggests persistent deficits for considerable time persistent deficits for considerable time after treatment concludesafter treatment concludes
Effects of ChemotherapyEffects of Chemotherapy
Mechanisms underlying Mechanisms underlying chemotherapy-related cognitive chemotherapy-related cognitive impairmentimpairment• Metabolic disturbances secondary to other Metabolic disturbances secondary to other
organ toxicitiesorgan toxicities• Differences between human subjects and Differences between human subjects and
animals used in pre-clinical toxicity studiesanimals used in pre-clinical toxicity studies• Unanticipated breach of the blood-brain-Unanticipated breach of the blood-brain-
barrierbarrier• Pre-existing host characteristicsPre-existing host characteristics
Effects of Other Cancer Effects of Other Cancer TherapiesTherapies
Immunotherapy-cytokines such as Immunotherapy-cytokines such as Interferon-alpha appear to cause a wide Interferon-alpha appear to cause a wide range of persistent cognitive deficits; range of persistent cognitive deficits; perhaps due to proinflammatory actions perhaps due to proinflammatory actions and/or stress hormone cascadeand/or stress hormone cascade
Hormone ablation therapies-Tamoxifen Hormone ablation therapies-Tamoxifen has been associated with depression, has been associated with depression, decreased concentration, and irritability; decreased concentration, and irritability; perhaps due to effects on dopamine and perhaps due to effects on dopamine and serotonin serotonin
Effects of Other Cancer Effects of Other Cancer Therapies-AvastinTherapies-Avastin
Avastin (bevacizamab) is an anti-Avastin (bevacizamab) is an anti-angiogenesis compound that received FDA angiogenesis compound that received FDA accelerated approval in GBM in 2009accelerated approval in GBM in 2009
Conflicting data between AVAglio and Conflicting data between AVAglio and RTOG 0825 as to impact on neurocognitive RTOG 0825 as to impact on neurocognitive functioning and QOLfunctioning and QOL
PRTBTC clinical results more in line with PRTBTC clinical results more in line with AVAglio study showing longer PFS and AVAglio study showing longer PFS and improved cognition and QOL (reduced improved cognition and QOL (reduced steroid reliance)steroid reliance)
Effects of Adjuvant Medical Effects of Adjuvant Medical TreatmentTreatment
In addition to the primary cancer In addition to the primary cancer therapy agents, many brain tumor therapy agents, many brain tumor patients require patients require a number of medications to manage a number of medications to manage disease and treatment-related disease and treatment-related symptomssymptoms
Many of these drugs have cognitive and Many of these drugs have cognitive and mood effects which further complicate mood effects which further complicate the picture of neurocognitive declinethe picture of neurocognitive decline
Effects of Adjuvant Medical Effects of Adjuvant Medical Treatment — Common DrugsTreatment — Common Drugs
SteroidsSteroids Anti-convulsantsAnti-convulsants Pain meds/narcoticsPain meds/narcotics PsychotropicsPsychotropics Anti-emeticsAnti-emetics Immunosuppressive agentsImmunosuppressive agents
Effects of Comorbid Effects of Comorbid ConditionsConditions
Age-related neurocognitive disordersAge-related neurocognitive disorders Cerebrovascular disease/hypertensionCerebrovascular disease/hypertension Traumatic brain injuryTraumatic brain injury Attention Deficit Hyperactivity DisorderAttention Deficit Hyperactivity Disorder Developmental disordersDevelopmental disorders Learning disordersLearning disorders Mood/Psychiatric disordersMood/Psychiatric disorders Metabolic disorders, infections, etc.Metabolic disorders, infections, etc.
Role of Neuropsychological Role of Neuropsychological AssessmentAssessment
For treatment options that may offer only For treatment options that may offer only slightly different survival/response rates, slightly different survival/response rates, the rationale for selecting a particular the rationale for selecting a particular therapy may be highly related to impact therapy may be highly related to impact on cognitive function and quality of lifeon cognitive function and quality of life
““Baseline” neurocognitive evaluation can Baseline” neurocognitive evaluation can provide data useful in monitoring disease provide data useful in monitoring disease progression/response to treatment (in progression/response to treatment (in addition to scans, neurologic addition to scans, neurologic exams, etc.)exams, etc.)
Role of Neuropsychological Role of Neuropsychological AssessmentAssessment
The specific cause (or causes) The specific cause (or causes) underlying cognitive dysfunction is underlying cognitive dysfunction is important in guiding interventions and important in guiding interventions and treatment planningtreatment planning
The type of intervention recommended The type of intervention recommended may be quite different depending on may be quite different depending on the specific pattern of the cognitive the specific pattern of the cognitive deficit and/or the etiology of the deficitdeficit and/or the etiology of the deficit
Role of Neuropsychological Role of Neuropsychological AssessmentAssessment
Role of Neuropsychological Role of Neuropsychological AssessmentAssessment
Repeat neuropsychological evaluations Repeat neuropsychological evaluations can quantify the potential efficacy of can quantify the potential efficacy of any interventions implementedany interventions implemented
Neuropsychological assessment is Neuropsychological assessment is often crucial in assisting patients in often crucial in assisting patients in obtaining disability benefits, or obtaining disability benefits, or alternatively, in helping them maintain alternatively, in helping them maintain or return to their jobs if they are or return to their jobs if they are cognitively intactcognitively intact
Neuropsychological Neuropsychological Interventions — Interventions — RehabilitationRehabilitation Supportive and solution-focused Supportive and solution-focused
psychotherapypsychotherapy• Adjustment to disability/grief for lossesAdjustment to disability/grief for losses• Problem solving to increase independenceProblem solving to increase independence
Cognitive retrainingCognitive retraining• Restoring the impaired cognitive skillRestoring the impaired cognitive skill• Learning strategies to compensate for the Learning strategies to compensate for the
impaired cognitive abilityimpaired cognitive ability• Self cognitive rehab (e.g., Lumosity)Self cognitive rehab (e.g., Lumosity)
Neuropsychological Neuropsychological Interventions — Interventions — RehabilitationRehabilitation Memory strategiesMemory strategies Attention strategiesAttention strategies Problem solving strategiesProblem solving strategies Organizational strategiesOrganizational strategies Behavior management (for impulsivity, Behavior management (for impulsivity,
emotional dysregulation, etc.)emotional dysregulation, etc.) Social skills retrainingSocial skills retraining
Neuropsychological Neuropsychological Interventions — Interventions — RehabilitationRehabilitation Internal aids – emphasize conscious Internal aids – emphasize conscious
utilization of cognitive facilitation utilization of cognitive facilitation techniques (e.g., rehearsal training)techniques (e.g., rehearsal training)• Perceptual grouping (e.g., clustering)Perceptual grouping (e.g., clustering)• Organization (e.g., categorizing)Organization (e.g., categorizing)• Mediation (e.g., mnemonics)Mediation (e.g., mnemonics)• Mental imagery/association (e.g., linking)Mental imagery/association (e.g., linking)
Neuropsychological Neuropsychological Interventions — Interventions — RehabilitationRehabilitation External aids – incorporating external External aids – incorporating external
cues/props already familiar to the cues/props already familiar to the patient into the overall assistive device patient into the overall assistive device planning (e.g., “memory notebook”)planning (e.g., “memory notebook”)• Autobiographical data/important numbersAutobiographical data/important numbers• Daily events log/scheduleDaily events log/schedule• CalendarCalendar• To-do listTo-do list• Transportation/medication Transportation/medication
informationinformation
Resources for RehabilitationResources for Rehabilitation
Neuropsychologists (evaluation based Neuropsychologists (evaluation based cognitive retraining modules/programs)cognitive retraining modules/programs)
Speech/occupational/physical therapistsSpeech/occupational/physical therapists Vocational rehabilitation programsVocational rehabilitation programs Brain injury treatment programsBrain injury treatment programs Self-study and caregiver interventions Self-study and caregiver interventions
with commercial workbooks, computer with commercial workbooks, computer programs, etc.programs, etc.
Neuropsychological Neuropsychological Interventions — Interventions — PharmacologicPharmacologic StimulantsStimulants (Ritalin (RitalinTMTM, Adderall, AdderallTMTM, etc.) – , etc.) –
may improve fatigue, somnolence, may improve fatigue, somnolence, slowed speed of processing, inattention, slowed speed of processing, inattention, decreased motivation, mood, etc.decreased motivation, mood, etc.
Best to titrate the dose up slowly over Best to titrate the dose up slowly over time; our typical dose is 10-15 mgs bid time; our typical dose is 10-15 mgs bid for Ritalinfor RitalinTMTM but some patients can but some patients can tolerate fairly high doses (30 to 40 mg tolerate fairly high doses (30 to 40 mg bid)bid)
Possible Complications – lowered Possible Complications – lowered seizure threshold, agitation, irritability, seizure threshold, agitation, irritability, weight lossweight loss
Neuropsychological Neuropsychological Interventions — Interventions — PharmacologicPharmacologic Memory AgentsMemory Agents (e.g., Aricept (e.g., AriceptTMTM, ,
NamendaNamendaTMTM, etc.) – clinical trial at , etc.) – clinical trial at PRTBTC at Duke showed subtle clinical PRTBTC at Duke showed subtle clinical efficacy of Ariceptefficacy of AriceptTMTM in brain tumor in brain tumor patients with documented memory patients with documented memory deficits deficits
Promising results with these agents in Promising results with these agents in other neurologic populations (TBI, other neurologic populations (TBI, VAD) in addition to Alzheimer’s diseaseVAD) in addition to Alzheimer’s disease
Neuropsychological Neuropsychological Interventions — Interventions — PharmacologicPharmacologic PsychotropicsPsychotropics (antidepressants, (antidepressants,
antipsychotics, anxiolytics, etc.) – may antipsychotics, anxiolytics, etc.) – may be useful in controlling mood and/or be useful in controlling mood and/or behavioral dysfunction associated with behavioral dysfunction associated with cancer and/or related treatmentcancer and/or related treatment• Anecdotal responses in brain tumor Anecdotal responses in brain tumor
patients for reducing depression, anxiety, patients for reducing depression, anxiety, perseverative thoughts, irritability, perseverative thoughts, irritability, disinhibition, etc.disinhibition, etc.
Neuropsychological Neuropsychological Interventions — Interventions — PharmacologicPharmacologic Other agents with CNS effects and Other agents with CNS effects and
potential efficacy in treating cognitive potential efficacy in treating cognitive deficits in brain tumor patients:deficits in brain tumor patients:• Dopamine agonists (e.g., Amantadine)Dopamine agonists (e.g., Amantadine)• Narcolepsy meds (e.g., ProvigilNarcolepsy meds (e.g., ProvigilTMTM))• Hormone replacement (e.g., Testosterone)Hormone replacement (e.g., Testosterone)• Other (e.g., Vitamin E, antioxidants)Other (e.g., Vitamin E, antioxidants)
Patient/Family Patient/Family Interventions — Education Interventions — Education and Supportand Support Educating patients and caregivers Educating patients and caregivers
early about possible cognitive early about possible cognitive deficits/mood and behavioral deficits/mood and behavioral disturbances helps them cope and disturbances helps them cope and plan for such changesplan for such changes
Support groups/websites help patients Support groups/websites help patients with cognitive deficits related to their with cognitive deficits related to their brain tumors (and their caregivers) brain tumors (and their caregivers) feel less isolated and alonefeel less isolated and alone
Patient/Family Patient/Family Interventions — Education Interventions — Education and Supportand Support Simple strategies such as using Simple strategies such as using
memory lists, taking brief naps, and memory lists, taking brief naps, and using written reminders instead of using written reminders instead of verbal “nagging” can improve the verbal “nagging” can improve the quality of life for patients and quality of life for patients and caregiverscaregivers
Providing hope, while helping patients Providing hope, while helping patients and caregivers adjust to their “new and caregivers adjust to their “new normal”, is crucial for improved copingnormal”, is crucial for improved coping
Embracing the “new normal” is Embracing the “new normal” is not easy, but we can try to helpnot easy, but we can try to help
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Wefel, JS, Schagen, AB (2012) Wefel, JS, Schagen, AB (2012) Chemotherapy-Related Cognitive Chemotherapy-Related Cognitive Dysfunction. Curr Neurol Neurosci Rep Dysfunction. Curr Neurol Neurosci Rep 12: 267-275.12: 267-275.
Breindl, A (ed.) ASCO 2013: GBM Trials Breindl, A (ed.) ASCO 2013: GBM Trials Bring Frustrating Answers and New Bring Frustrating Answers and New Questions. Bioworld.com.Questions. Bioworld.com.
Activism Activism Awareness Awareness Funding Funding Research Research CureCure
Angels Among us 5K and Family Fun RunAngels Among us 5K and Family Fun Run
The Preston Robert Tisch The Preston Robert Tisch Brain Tumor Center at DukeBrain Tumor Center at Duke
Contact Info for Renee Raynor, PhD:Contact Info for Renee Raynor, PhD:
• www.cancer.duke.edu/btc
• (919) 684-1832(919) 684-1832