Transcript Effects of Lesion Location

Neurocognitive Dysfunction
in Brain Tumor Patients
Renee Hinsley Raynor, Ph.D.
Clinical Neuropsychologist
The Preston Robert Tisch Brain Tumor Center at Duke
The Neurocognitive Impact of
Brain Tumors: A Growing Problem
 In 2012, an estimated 688,000+ people in the US
were living with a primary brain or CNS tumor
diagnosis (138,000 malignant and 550,000 benign)
 An estimated 69,720 new cases of primary brain
tumors were expected to be diagnosed in 2013 and
includes both malignant (24,620) and nonmalignant (45,100) brain tumors
 CBTRUS Statistical Report (2012)
The Neurocognitive Impact of
Brain Tumors: A Growing Problem
 Agencies funding cancer research are calling
for a increased emphasis on disease-related
symptoms and/or quality of life (in addition
to survival and response rates)
 As cancer treatment becomes more
successful, more patients will live longer and
expect to return to their baseline level of
functioning
Brain Tumors: Impact of
Neurocognitive Impairment
 Personal loss of independence and dignity
for patients
 Caregiver demand on family and friends
 Financial burden on patient and family to
supply adequate care
 Financial burden on society due to lost
productivity of patients and caregivers
Sound familiar?
Neurocognitive Impairment
in Brain Tumor Patients
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Memory loss
Distractibility and inattention
Difficulty with multi-tasking
Mood disturbance
Decreased executive control
Decreased initiative, increased apathy
Decreased inhibition, behavioral
dysregulation
Etiology of these
Neurocognitive Deficits
 Direct effects of cancer within CNS
 Indirect effects of certain cancers
(paraneoplastic disorders)
 Effects of cancer treatments on brain
(surgical and medical)
 Effects of pharmacological treatments for
the cancer and related complications
 Co-existing neurologic or psychiatric
disorders
Effects of Lesion Location
 Although cognitive symptoms caused by
brain tumors may exhibit relatively focal
effects, they tend to be less dramatic than
those seen in patients with more acute
onset lesions
 Cognitive impairment is often associated
with tumors of either hemisphere in any
lobe (cortical and subcortical)
Effects of Lesion Location
 Neurocognitive impairment tends to be less
localized in brain tumor patients than in
patients with more acute neurologic lesions
 This may be due to destruction of collateral
tissue by the tumor or may be related to
diffuse effects of treatment modalities and
agents
Effects of Lesion Location
 Impairment in frontal lobe function is
ubiquitous in brain tumor patients
• (decreased mental flexibility, abstraction,
motivation, planning, organizational skills, ability
to benefit from experience; increased personality
changes)
• Large proportion of patients have frontal lobe
tumors
• Frontal lobes have rich afferent and efferent
connections with all other brain regions
Effects of Neurosurgery
 Whether patients undergo biopsy or
resection, neurosurgery is an invasive
procedure and neurocognitive recovery time
is measured in months
 While some patients eventually return to
near baseline cognitive functioning post-op,
many do not due to the tumor’s invasion of
previously normal brain
Wouldn’t this be nice?
Effects of Histology
 Level of impairment varies depending on lesion
location, treatment modalities used, and host
characteristics (e.g., age, concurrent medical
problems)
 Higher grade tumors are associated with
greater cognitive impairment in most cases, but
it is unclear whether this is inherently related to
histology or perhaps more due to degree of
progression and associated destruction
of normal brain tissue
Effects of Histology
 Patients with low grade tumors that have
been present for many years may have little
to no cognitive change because of cerebral
plasticity and reorganization
 Alternatively, patients with large low grade
tumor burden or with low grade tumors in
critical cognitive areas may show
devastating cognitive/behavioral decline
Effects of Lesion Location
and Histology
 Patients with left hemisphere tumors and
GBM demonstrated testable differences in
neuropsychologic functioning and QOL*
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Hahn CA, Dunn RH, Logue PE, King JH, Edwards CL, Halperin EC.
A Prospective Study of Neuropsychologic Testing and Quality of Life
Assessment of Adults with Primary Malignant Brain Tumors.
International Journal of Radiation Oncology, Biology,
Physics 55(4):992-999, 2003.
Effects of Lesion Location and
Histology
 Female gender, lower tumor grade,
presence of comorbidities, and lower
education level were associated with
generalized anxiety and depressive
mood symptoms*
*
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. Neurooncology. 10(2):171, 2008.
Effects of Radiation Therapy
 Cognitive areas impaired may include
processing speed, executive function,
memory, sustained attention, and
psychomotor coordination
 Some of these deficits are thought to be
related to periventricular white matter
damage; hyperintensities observed on
neuro-imaging
Effects of Radiation Therapy
 Pattern of cognitive deficits is not unlike that
seen in other subcortical diseases of the
white matter such as MS
 Children are particularly vulnerable to
radiation injury; even relatively low doses
of cranial irradiation is associated with mild
intellectual declines in older children
(younger children show more severe
deficits)
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Effects of Radiation Therapy
 Literature presents conflicting evidence as to
whether concomitant chemotherapy increases
the neurotoxicity of radiation therapy
 Fatigue from radiation therapy can be physical
and mental and may cause a deleterious effect
on cognition for a period of time that extends
far beyond completion of treatment
 With relatively recent dramatic improvements in
the delivery of radiation therapy, we expect to
see increased sparing of neurocognitive
functioning
Effects of Chemotherapy
 Neurocognitive effects of chemotherapy
were previously thought to be reversible;
growing literature suggests persistent
cognitive deficits in patients who have
received standard-dose chemotherapy
 The risk appears greater after high-dose
chemotherapy such as with bone marrow
transplant (long term effects unknown)
Effects of Chemotherapy
 Most impairment related to chemotherapy
tends to be relatively diffuse, affecting
sustained attention and speed of processing
 Fatigue and hematologic toxicity related to
chemotherapy likely negatively impact
cognition, but evidence suggests persistent
deficits for considerable time after treatment
concludes
Effects of Chemotherapy
 Mechanisms underlying chemotherapyrelated cognitive impairment
• Metabolic disturbances secondary to other organ
toxicities
• Differences between human subjects and
animals used in pre-clinical toxicity studies
• Unanticipated breach of the blood-brain-barrier
• Pre-existing host characteristics
Effects of Other Cancer
Therapies
 Immunotherapy-cytokines such as
Interferon-alpha appear to cause a wide
range of persistent cognitive deficits;
perhaps due to proinflammatory actions
and/or stress hormone cascade
 Hormone ablation therapies-Tamoxifen has
been associated with depression, decreased
concentration, and irritability; perhaps due
to effects on dopamine and
serotonin
Effects of Other Cancer
Therapies-Avastin
 Avastin (bevacizamab) is an antiangiogenesis compound that received FDA
accelerated approval in GBM in 2009
 Conflicting data between AVAglio and RTOG
0825 as to impact on neurocognitive
functioning and QOL
 PRTBTC clinical results more in line with
AVAglio study showing longer PFS and
improved cognition and QOL (reduced
steroid reliance)
Effects of Adjuvant Medical
Treatment
 In addition to the primary cancer therapy
agents, many brain tumor patients require
a number of medications to manage disease
and treatment-related symptoms
 Many of these drugs have cognitive and
mood effects which further complicate the
picture of neurocognitive decline
Effects of Adjuvant Medical
Treatment — Common Drugs
 Steroids
 Anti-convulsants
 Pain meds/narcotics
 Psychotropics
 Anti-emetics
 Immunosuppressive agents
Effects of Comorbid Conditions
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Age-related neurocognitive disorders
Cerebrovascular disease/hypertension
Traumatic brain injury
Attention Deficit Hyperactivity Disorder
Developmental disorders
Learning disorders
Mood/Psychiatric disorders
Metabolic disorders, infections, etc.
Role of Neuropsychological
Assessment
 For treatment options that may offer only
slightly different survival/response rates, the
rationale for selecting a particular therapy
may be highly related to impact on cognitive
function and quality of life
 “Baseline” neurocognitive evaluation can
provide data useful in monitoring disease
progression/response to treatment (in
addition to scans, neurologic
exams, etc.)
Role of Neuropsychological
Assessment
 The specific cause (or causes) underlying
cognitive dysfunction is important in guiding
interventions and treatment planning
 The type of intervention recommended may
be quite different depending on the specific
pattern of the cognitive deficit and/or the
etiology of the deficit
Role of Neuropsychological
Assessment
Role of Neuropsychological
Assessment
 Repeat neuropsychological evaluations can
quantify the potential efficacy of any
interventions implemented
 Neuropsychological assessment is often
crucial in assisting patients in obtaining
disability benefits, or alternatively, in
helping them maintain or return to their
jobs if they are cognitively intact
Neuropsychological
Interventions — Rehabilitation
 Supportive and solution-focused
psychotherapy
• Adjustment to disability/grief for losses
• Problem solving to increase independence
 Cognitive retraining
• Restoring the impaired cognitive skill
• Learning strategies to compensate for the
impaired cognitive ability
• Self cognitive rehab (e.g., Lumosity)
Neuropsychological
Interventions — Rehabilitation
 Memory strategies
 Attention strategies
 Problem solving strategies
 Organizational strategies
 Behavior management (for impulsivity,
emotional dysregulation, etc.)
 Social skills retraining
Neuropsychological
Interventions — Rehabilitation
 Internal aids – emphasize conscious
utilization of cognitive facilitation techniques
(e.g., rehearsal training)
• Perceptual grouping (e.g., clustering)
• Organization (e.g., categorizing)
• Mediation (e.g., mnemonics)
• Mental imagery/association (e.g., linking)
Neuropsychological
Interventions — Rehabilitation
 External aids – incorporating external
cues/props already familiar to the patient
into the overall assistive device planning
(e.g., “memory notebook”)
• Autobiographical data/important numbers
• Daily events log/schedule
• Calendar
• To-do list
• Transportation/medication
information
Resources for Rehabilitation
 Neuropsychologists (evaluation based
cognitive retraining modules/programs)
 Speech/occupational/physical therapists
 Vocational rehabilitation programs
 Brain injury treatment programs
 Self-study and caregiver interventions with
commercial workbooks, computer
programs, etc.
Neuropsychological
Interventions — Pharmacologic
 Stimulants (RitalinTM, AdderallTM, etc.) – may
improve fatigue, somnolence, slowed speed
of processing, inattention, decreased
motivation, mood, etc.
 Best to titrate the dose up slowly over time;
our typical dose is 10-15 mgs bid for
RitalinTM but some patients can tolerate
fairly high doses (30 to 40 mg bid)
 Possible Complications – lowered seizure
threshold, agitation, irritability,
weight loss
Neuropsychological
Interventions — Pharmacologic
 Memory Agents (e.g., AriceptTM,
NamendaTM, etc.) – clinical trial at PRTBTC
at Duke showed subtle clinical efficacy of
AriceptTM in brain tumor patients with
documented memory deficits
 Promising results with these agents in other
neurologic populations (TBI, VAD) in
addition to Alzheimer’s disease
Neuropsychological
Interventions — Pharmacologic
 Psychotropics (antidepressants,
antipsychotics, anxiolytics, etc.) – may be
useful in controlling mood and/or behavioral
dysfunction associated with cancer and/or
related treatment
• Anecdotal responses in brain tumor patients for
reducing depression, anxiety, perseverative
thoughts, irritability, disinhibition, etc.
Neuropsychological
Interventions — Pharmacologic
 Other agents with CNS effects and potential
efficacy in treating cognitive deficits in brain
tumor patients:
• Dopamine agonists (e.g., Amantadine)
• Narcolepsy meds (e.g., ProvigilTM)
• Hormone replacement (e.g., Testosterone)
• Other (e.g., Vitamin E, antioxidants)
Patient/Family Interventions —
Education and Support
 Educating patients and caregivers early
about possible cognitive deficits/mood and
behavioral disturbances helps them cope
and plan for such changes
 Support groups/websites help patients with
cognitive deficits related to their brain
tumors (and their caregivers) feel less
isolated and alone
Patient/Family Interventions —
Education and Support
 Simple strategies such as using memory
lists, taking brief naps, and using written
reminders instead of verbal “nagging” can
improve the quality of life for patients and
caregivers
 Providing hope, while helping patients and
caregivers adjust to their “new normal”, is
crucial for improved coping
Embracing the “new normal” is
not easy, but we can try to help
Sample References
 Weitzner, M.A. & Meyer, C.A. (1997).
Cognitive functioning and quality of life in
malignant glioma patients: A review of
the literature. Psycho-oncology,
6, 169-177.
 Meyers, C.A., Hess, K.R., Yung, W.K., &
Levin, V.A. (2000). Cognitive function as a
predictor of survival in patients with
recurrent malignant glioma. Journal of
Clinical Oncology, 18, 646-650.
Sample References
 Carlson, R.H. (2000). ‘Chemobrain’
Cognitive loss confirmed in adult cancer
patients receiving systemic chemotherapy.
OncologyTimes, 22, 35-38.
 Meyers, C.A. (2000). Neurocognitive
dysfunction in cancer patients.
Oncology, 14, 75-79.
 Meyers, C.A. (2001). Neurocognitive aspects
of cancer and cancer treatment.
Presentation at the International
Neuropsychology Society, Chicago.
Sample References
 Meyers, CA, Hess, KR (2003) Multifaceted
end points in brain tumor clinical trials:
cognitive deterioration precedes MRI
progression. Neuro Oncol 5(2): 89-95.
 Zuccharella C, Bartolo M, Di Lorenzo C,
Villani V, Pace A (2013) Cognitive
impairment in primary brain tumors
outpatients: a prospective cross-sectional
survey. J Neurooncol 112: 455-460.
Sample References
 Wefel, JS, Schagen, AB (2012)
Chemotherapy-Related Cognitive
Dysfunction. Curr Neurol Neurosci Rep 12:
267-275.
 Breindl, A (ed.) ASCO 2013: GBM Trials
Bring Frustrating Answers and New
Questions. Bioworld.com.
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The Preston Robert Tisch Brain
Tumor Center at Duke
 Contact Info for Renee Raynor, PhD:
• [email protected]
• www.cancer.duke.edu/btc
• (919) 684-1832