45 Quality of Life and Neurocognitive Function

Kyle Richard Noll and Jeffrey Scott Wefel

The natural history of malignant brain tumors is often a relentless neurologic deterioration to death. The tumor, the type of antineoplastic treatment the patient receives, adjuvant medications, and medical complications can all affect neurocognitive function, psychological well-being, and the ability to perform daily activities. However, a great deal can be done to improve the quality of life (QOL) of the patient and the caregiving system. Understanding the specific contribution of the effects of the tumor, of the treatment, and of other factors to the functioning of the brain and the patient’s life guides the development of intervention strategies, both therapeutic and palliative.

The impact of a primary brain tumor on the individual is best conceptualized by the three-tiered system developed by the World Health Organization: impairment is the deficit of brain function caused by the disease and is assessed by neurologic and neuropsychological evaluations; disability is the impact the deficit has on the patient’s ability to perform activities and is assessed by performance status and functional status measures; and handicap is the impact the disability has on the patient’s subjective well-being and social functioning and is generally assessed by QOL questionnaires.

Similar impairments can cause greater or lesser disabilities and handicaps depending on the patient’s developmental stage in life, work demands, and support systems. For instance, a young woman with a left frontal glioma was found to have a mild impairment of working memory, characterized by a reduced capacity to hold and manipulate information mentally. Because of the tumor she was more vulnerable to distraction, had difficulty performing tasks with multiple steps, and had difficulty handling more than one source of information at once (e.g., being in a room with more than one conversation going on). However, her memory, in terms of learning and retaining new information, was completely normal, as were her intellectual abilities, visuospatial and visuomotor abilities, and bilateral motor functions. Consistent with the site of her tumor, she also had mildly reduced verbal fluency and mild right visual field inattention. The impairments that this patient experienced in working memory capacity and verbal fluency were a great disability to her as a school teacher.

In addition, the disability was a great handicap because she loved her work and had difficulty adjusting to the fact that she could not maintain her previous level of performance. If she had a different career or if she did not like her job so much, the level of disability and handicap caused by the tumor might have been quite different.

Thus, interventions must be individually tailored to the patient’s specific needs. This patient had the cognitive abilities necessary to successfully deal with these deficits. It is not known if she will be able to return to her former teaching occupation or if she will need to consider careers that do not place as high a demand on her areas of deficit, but it is likely that she will be able to function at a reasonable level with appropriate assistance. The assistance in this case included pharmacological treatment (stimulant therapy) and cognitive-vocational rehabilitation.

Contributions to Neurocognitive Impairment

Tumor Effects

In adult patients with primary brain cancer, presentation of neurocognitive deficits is associated with tumor location, tumor-related epilepsy, lesion type, lesion momentum (i.e., speed of tumor growth), and lesion volume. Although manifestations of the disease vary significantly across patients, glioma patients with lesions in the temporal or frontal lobes were assessed before initiation of any treatment, and neuro-cognitive dysfunction was found in 90% of patients. Executive functions were impaired in 78% and memory and attention were impaired in 60%.¹ Patients with newly diagnosed glioblastoma having tumor in heterogeneous locations who participated in a large phase 3 cooperative clinical trial demonstrated median cognitive performances that were generally 1 standard deviation (SD) below the healthy population’s normative mean.²

Cognitive dysfunction tends to correspond with the hemispheric site of a tumor. Left hemisphere tumors are often associated with more frequent and severe deficits in verbal learning and memory, language functions, and verbally based intellectual functions. Right hemisphere tumors more frequently produce difficulties with visuospatial and visuoperceptual functions. Frontal tumors may cause marked personality changes and impairments of executive function, including problems with social judgment, frustration tolerance, ability to plan and organize activities, and working memory capacity. However, the specificity and severity of cognitive impairments related to tumor site are often less pronounced than those observed with sudden-onset neurologic conditions such as stroke.^3,4

The adverse effects of chemotherapy are usually presumed to be acute and reversible except in the cases of intra-arterial or intraventricular administration. The neurobehavioral effects of most cancer therapy agents tend to be nonspecific and diffuse, except for those that have a mechanism of action that is expected to affect focal brain regions5 or immunologic agents that are known to affect particular inflammatory cytokines, neurotransmitters, and neuroendocrine hormones.⁶ Cognitive and emotional changes reported during and after chemotherapy include memory loss, decrease in information-processing speed, reduced attention, anxiety, depression, and fatigue. These changes are most pronounced and long lasting after high-dose treatment.⁷

Although newer agents such as temozolomide appear to enhance survival with fewer adverse symptoms,⁸ emerging research has demonstrated that some patients experience worsening cognitive function while progression free and receiving temozolomide.^9,10 Specifically, a large phase 3 intergroup trial demonstrated that up to 30% of newly diagnosed glioblastoma multiforme (GBM) patients who received temozolomide evidenced decline in cognitive function across all domains assessed, despite remaining progression free on imaging.⁸ Further, a small, single-institution study of standard-dose temozolomide reported cognitive decline in 3 of 13 progression-free patients after concurrent chemoradiation and three cycles of adjuvant chemotherapy.¹⁰ It remains to be determined if this represents the adverse effect of subclinical tumor progression or treatment-related neurotoxicity. Nonetheless, recent animal modeling suggests that such effects may be attributable, as least in part, to disruption of learning via decreased hippocampal neurogenesis and theta activity.¹¹ Although preliminary, these findings reflect the need for continued development of targeted chemotherapies that provide benefit with reduced toxicity.

Radiotherapy can also have deleterious effects on cognition due to a combination of vascular injury, inflammation, and damage to neuronal progenitor cells affecting neurogenesis and oligodendroglial formation.¹² Preferential disruption of frontal subcortical networks in the brain is common secondary to the effects of radiation on white matter tracts, which are particularly dense in frontal and subcortical areas. Within the first 2 weeks of treatment, patients can develop fatigue and exacerbation of preexisting neurologic deficits. Early delayed effects often develop 1 to 4 months after completion of radiation and include slowed information processing speed, executive dysfunction, diminished memory function, and motor deficits.¹³ These symptoms are believed to result from transient demyelination and subsequent remyelination with variable symptom improvement.

Neuropsychological studies of patients before and after radiation treatment document neurocognitive impairments that are consistent with frontal network systems, including impaired information-processing speed, attention (e.g., working memory), mental flexibility, learning, memory, and, frequently, a decline in motor functioning bilaterally, even in patients with no evidence of disease recurrence.^14,15 Unfortunately, some patients experience late delayed encephalopathy that can involve progressive neurologic decline, dementia, leukoencephalopathy, and brain necrosis. Such late delayed problems typically emerge 6 months to 3 years following radiotherapy, though cases have reportedly occurred as early as 3 months to as late as 13 years posttreatment.¹⁶ Several factors that contribute to the occurrence of radiation encephalopathy have been identified, including age > 60, higher total dose, dose per fraction > 2 Gy, greater brain volume irradiated, hyperfractionation schedules, shorter overall treatment time, concomitant or subsequent use of chemotherapy, and the presence of comorbid vascular risk factors.¹⁵

Effects of Adjuvant Medications and Medical Complications

Medical complications and adjuvant medications may cause impairments and contribute to disabilities and handicaps. For instance, glucocorticoid use is an extremely common adjuvant treatment for brain tumor patients. There are myriad neuro-behavioral adverse effects of chronic steroid use in addition to the well-described gastrointestinal, dermatologic, musculoskeletal, circulatory, and immune system complications. Glucocorticoids such as dexamethasone bind to receptors in the brain that are important for controlling emotions and memory. Dexamethasone can cause memory difficulties, even in neurologically normal control subjects.¹⁷ Reversible dementia, emotional lability, major depression, paranoia, mania, and delirium are not uncommon and are generally related to dose.

Endocrine dysfunction related to pituitary-hypothalamic injury is also very common following radiotherapy.18 Thyroid dysfunction, loss of libido, and erectile dysfunction are present in a large proportion of patients. In fact, one study found that only 23% of brain tumor patients had normal thyroid, gonadal, and adrenal hormone levels following treatment.¹⁹ The QOL of brain tumor patients with endocrinologic deficiency can improve greatly with replacement therapy.²⁰

Seizures occur in 50 to 70% of patients at some time during their illness and have a significant impact on neurobehavioral functioning and QOL. Persistent, poorly controlled seizures cause neocortical changes, metabolic dysfunction, and hippocampal sclerosis, reducing cognitive efficiency and exacerbating underlying cognitive deficits.²¹ Patients with seizures are often fearful of having them and may become socially isolated because of the possibility of having one in a public place or around people they know. In addition, many antiepileptic drugs (AEDs) have adverse constitutional and cognitive side effects. The use of phenytoin, carbamazepine, and valproic acid has been associated with impairments of attention, processing speed, and memory.²² However, newer anticonvulsant agents including lamotrigine, oxcarbazepine, and gabapentin appear to have more favorable side-effect profiles and fewer neurocognitive side effects.²³

Restricting brain tumor patients’ driving privileges has a large impact on their feeling of independence and may place a burden on families with limited alternatives for transportation. Laws dictate how long after a grand mal seizure a person must refrain from driving, but the situation is much less clear when a person experiences focal or partial seizures without loss of consciousness, or if seizures are not an issue but cognitive impairments are. Patients with right hemisphere tumors may have visuoperceptual problems, including left visual field inattention, and are particularly at risk. If there is a question about driving safety, it is best to have the patient undergo a formal driving evaluation, which can be done by many neuro-psychologists and rehabilitation psychologists. In addition, it is important for the treating physician to be aware of reporting requirements and licensing regulations.

Cancer-Related Symptoms

Fatigue and Sleep

Most brain tumor patients experience considerable cancer-related fatigue during the course of their illness. Cancer-related fatigue is a persistent, subjective sense of tiredness secondary to cancer or cancer treatment that is generally unrelieved by rest and interferes with usual functioning.²⁴ It is well accepted that physical, psychological, and medical factors such as anemia, cachexia, systemic illness, pain, and medications can contribute to fatigue. Across a wide variety of cancer patients, 50 to 75% reported fatigue at the time of their diagnosis, 80 to 96% reported fatigue associated with chemotherapy, and 60 to 93% reported fatigue associated with radiotherapy.²⁵ Several treatments can help ameliorate fatigue, including correction of anemia, treatment of depression, exercise, energy conservation, and pharmacological intervention (e.g., psychostimulants).²⁶

Sleep–wake disturbance is understood as alteration in night time sleep followed by daytime impairment.²⁷ Sleep problems are estimated to occur in up to 57% of those with solid tumors, including the brain. Common problems include insomnia, sleep-related breathing disorders, parasomnias, hypersomnias, circadian rhythm disorders, and sleep-related movement disorders. Although the literature regarding sleep disturbance in primary brain tumor patients is limited, insomnias and parasomnias are the most common sleep problems in patients with solid tumors. Additionally, medications commonly used with brain tumor patients like glucocorticoids and anxiolytics may contribute to insomnia or daytime sleepiness. Management of sleep–wake disturbance often includes a combination of behavioral strategies (e.g., sleep hygiene and cognitive-behavioral therapy) as well as pharmacological treatment (i.e., hypnotics).²⁸

Emotional Distress

Comprehensive studies of QOL in brain tumor patients report increased emotional reactivity, lowered frustration tolerance, depression, anxiety, and reduced family functioning in these patients.²⁹ Overall QOL does not appear to be closely correlated with histological diagnosis, prognosis, or age as much as the patient’s social support, personality characteristics, and access to services. Approximately 93% of patients with high-grade glioma reported symptoms of depression prior to surgery and up to 6 months after resection.³⁰ However, physicians detected depression in only 15% of patients preoperatively and in up to 22% of patients after resection. Thus, many patients did not receive a potentially efficacious therapy to address their affective distress, and depressed patients had shorter survival times and more complications.

Special Considerations for Pediatric Brain Tumor Patients

The effects of tumor and treatment in children must be considered in light of the developing brain and body. Pediatric brain tumor survivors are likely to have multiple cognitive and constitutional impairments. Children treated at a young age have significant difficulties learning and acquiring skills at a normal developmental rate.31,32 They tend to have short stature, and, as adults, fewer marry or obtain full-time employment. The full impact of tumor and treatment on pediatric brain tumor survivors is often seen long after treatment has ended. A study of 10-year survivors of childhood medulloblastoma found that more than half of them had significant cognitive and psychosocial deficits that hampered independence as an adult, although they do not tend to report impaired QOL.³³

Many childhood survivors develop cognitive and psychosocial deficits long after their treatments have been completed, either due to the delayed toxicities associated with radiation and chemotherapy or in association with the phenomenon of “growing into deficits.” The principle of this phenomenon is that the impact of cancer and cancer therapies on certain behaviors like executive functions do not manifest themselves until the developing neural networks that subserve those functions become active (i.e., after complete myelination of the frontal lobes). At this time, the prior injury to that system is manifested as a failure to acquire a developmentally appropriate skill or ability. Pediatric brain tumor patients have been reported to demonstrate impairments in visuomotor and visuoperceptual skills, attention, memory, processing speed, language, and executive functions.³⁴ Impairments in core processes like attention, executive function, and processing speed have been demonstrated to be closely associated with failure to achieve expected intellectual and academic gains.³⁵

Assessment Considerations

Assessment of Neurocognitive Impairment

The assessment of impairment includes the traditional neurologic evaluation, which usually focuses on evaluating motor and sensory function as well as the reactivity and appropriateness of response following stimulation of neural subsystems. Assessment of cognition generally involves standardized tests and questionnaires that are relatively sensitive and specific. Assessment of neurocognitive function must take into consideration the fact that tumors in different locations cause different cognitive deficits, and that there are different patterns of cognitive decline associated with radiation and chemotherapy as opposed to focal tumor progression. The particular choice of tests and the length of the assessment battery will depend on the purpose of the examination, with briefer assessments using tests that can be repeated in the clinical trial setting (e.g., tests having alternate forms or little practice effect), and more lengthy comprehensive assessments when decisions regarding issues such as the ability of the patient to go back to work are being addressed.

The Mini-Mental State Examination (MMSE), a brief screening tool for dementia, has often been used in brain tumor clinical trials. However, this tool has several drawbacks that limit its usefulness. Although the MMSE can detect moderate to severe global cognitive impairment, it lacks well-established sensitivity or specificity, overlaps considerably with concurrently used neurologic function scales and performance status measures, fails to measure many of the functions known to be impaired in brain tumor patients, and does not have validated alternate forms for repeated testing.³⁶

Related posts:

Metabolic Imaging Gene Therapy for Gliomas Molecular Markers and Pathways in Brain Tumorigenesis Low-Grade Gliomas Pediatric Supratentorial Tumors Skull Base Meningiomas and Other Tumors

Stay updated, free articles. Join our Telegram channel

Join