Summary
This chapter provides readers with information regarding the nature of neurocognitive impairment in adult patients who have skull base tumors and underscores the importance of neuropsychological evaluation in the multidisciplinary care of patients who have skull base tumors. While the current literature is limited, it suggests that the proximity of skull base tumors to critical brain structures leaves some patients vulnerable to neurocognitive impairment. Necessary treatments, including surgery and radiation, can also give rise to neurocognitive dysfunction. Patients may also exhibit symptoms of affective distress. Ideally, assessment of neurocognitive function should begin prior to intervention and extend well beyond treatment and should use reliable and repeatable measures that are sensitive to even subtle changes, with particular attention to the domains of memory, attention, processing speed, and executive functioning, as well as changes in a patient’s overall mood state. Such an approach helps capture both tumor- and treatment-related neurocognitive sequelae that can impact patients’ independent functioning and successful management of life roles. It also allows for early implementation of interventions, if necessary, that can be personalized to reduce the impact of neurocognitive impairment and improve patients’ quality of life.
12 Neuropsychological Assessment of Patients with Skull Base Tumors
12.1 Introduction
Although neurocognitive compromise has historically been overlooked, a growing body of literature suggests that it is not uncommon in patients who have skull base tumors and that it can arise either secondary to the tumor itself or as a result of subsequent interventions. Neuropsychological evaluation is increasingly being recognized as an important component of the multidisciplinary care required for patients who have tumors of the skull base.1 , 2 Advances in treatment have resulted in longer survival times and lower rates of recurrence, but these successes are not always achieved without some risk of damage to critical proximal neuroanatomical structures, including the frontal and temporal cortices, frontal–subcortical circuits, hypothalamus, and mammillary bodies. There is relatively limited literature regarding the neurocognitive and neurobehavioral sequelae associated with tumors of the skull base, and the majority of data reviewed in this chapter are gleaned from studies that had small sample sizes. However, available data do suggest that patients who have tumors of the skull base are vulnerable to development of a variety of neurocognitive deficits, particularly in the domains of memory and executive functioning. Even when neurocognitive impairment is relatively subtle, impacts on functional well-being can be significant. A mean loss of health-related work productivity of 6.15%, as assessed by the Work Limitations Questionnaire, was reported in one study of patients who had skull base tumors.3 Although overall mean neurocognitive performance was within one standard deviation of normative expectation, there was a significant association between lower learning/memory and greater work productivity loss. In addition, although very few participants reported symptoms that met the criteria for clinical depression, there was also an association between higher levels of reported depressive symptoms and greater work productivity loss. These findings highlight the need for identification of and interventions for the neurocognitive sequelae of skull base tumors.
12.2 Neurocognitive Impairment Associated with Skull Base Tumors
12.2.1 Tumor-Related Neurocognitive Impairment
It is well established that patients who have primary supratentorial brain tumors are very likely to exhibit neurocognitive impairment, even prior to treatment with surgery, chemotherapy, or radiation; in fact, neurocognitive complaints are secondary only to headache as a presenting symptom.4 Indeed, 60 to 100% of patients who have supratentorial brain tumors exhibit at least some degree of neurocognitive impairment prior to intervention, with variability in the nature and severity of this impairment depending on lesion location and lesion momentum, or tumor growth rate. In patients who have brain metastases, pretreatment neurocognitive impairment has been observed in up to 90% of patients, with volume (rather than number) of metastases being an important factor in the severity of impairment.5 The location of many skull base tumors also leaves patients at inherent risk for the development of neurocognitive impairment secondary to the compression or impingement of critical proximal brain structures as tumors in and around the cranial vault grow and crowd healthy brain tissue.
Evidence of pretreatment neurocognitive impairment has been documented in multiple small studies of patients who had tumors in the anterior and middle cranial fossae. In a group of nine patients who had nasopharyngeal carcinoma and who underwent neuropsychological evaluation before receiving paranasal sinus radiation, several patients exhibited abnormal performance even prior to treatment.6 Another study of patients who had craniopharyngioma revealed that half (n = 6 of 12) exhibited significant impairments in memory and executive functioning prior to surgical resection, hypothesized to be related to interruption of frontal–hypothalamic connections.7 In a 2016 study, patients with meningiomas in the skull base (anterior and middle fossa, n = 26) were compared with patients who had meningiomas in the convexity (n = 28), as well as to a control group of matched healthy volunteers (n = 52). At preoperative baseline, overall patient performance was significantly lower than for the control group across measures assessing delayed recall, verbal fluency, and executive functioning. Patients who had skull base meningioma exhibited greater difficulty with memory than those who had convexity tumors, and those who had tumors in the middle cranial fossa exhibited even greater memory impairment than those who had tumors in the anterior cranial fossa, likely reflecting the proximity of the middle cranial fossa to the temporal lobes, which are known to be critical for memory function.8
A case study provided evidence of the untoward effects of damage due to compression by a skull base tumor: a 57-year-old man was found to have a cystic lesion above the suprasellar region (later identified as a craniopharyngioma) that compressed the base of the hypothalamus and damaged the mammillary bodies. Formal neuropsychological evaluation conducted prior to any intervention revealed an isolated but dense anterograde amnesia.9 These reports suggest that even without invasion of brain tissue, skull base tumors result in neurocognitive dysfunction secondary to compression of critical brain structures, including the temporal lobes, hypothalamus, and mammillary bodies, or to disruption of subcortical networks.
12.2.2 Treatment-Related Neurocognitive Impairment
Surgical Morbidity
Detecting and understanding the neurocognitive impact of surgical resection requires an understanding of the potential transient hazards associated with these procedures as well as of the potentially chronic effects secondary to either focal damage of nearby structures or more diffuse dysfunction related to disruption of larger distributed networks. Fortunately, acute postoperative declines are often due primarily to reactive edema and therefore are transient in nature. This appeared to be the case in results reported by Ichimura et al in 2010; they described transient decline on both traditional paper-and-pencil neuropsychological measures of learning/memory and on computerized tests of reaction time 1 month after resection of posterior cranial fossa tumors via the middle fossa. These changes had recovered by 3-month follow-up.10
If healthy tissue is damaged during the surgical procedure, however, some long-term neurocognitive impairment is possible, and at least some studies have raised concerns about neurocognitive impairment after surgery for resection of skull base tumors. Steinvorth et al observed abnormally slowed speed of processing in a study of 40 patients who had base of skull meningiomas assessed after surgery but prior to initiation of radiation therapy. They also reported that patients who had undergone three or more surgical resections exhibited greater difficulty on tests that assessed attention than did the group as a whole.11 Schick et al reported that 1 to 6 years after middle fossa vestibular schwannoma surgery, approximately 35% of patients exhibited evidence of memory impairment, with particularly poor performance noted for a patient who had evidence of temporal lobe gliosis.12 Dijkstra et al reported that an average of 3.4 years after treatment, patients who had surgically treated skull base meningiomas performed significantly worse on tests assessing verbal memory, information processing, and psychomotor speed than did patients who had convexity meningiomas.13 Not only neurocognitive functioning but also behavioral functioning may be affected after surgical resection. Evaluation of patients who had anterior skull base meningiomas after resection found that those patients who had lesions involving the ventromedial prefrontal cortex were rated as having a greater decline in adaptive functioning (i.e., employment, independence, and self-care).14 In patients who had craniopharyngioma, it appears that hypothalamic involvement leaves patients at greater risk for cognitive impairment, including memory loss, attentional deficits, and reduced information processing speed.15
It has been argued that patients who have tumors in the skull base may be more vulnerable to neurocognitive change than those who have meningiomas in the convexity secondary to the inherently difficult nature of the surgery.13 It must be noted, however, that the aforementioned studies did not include preoperative baseline evaluations; thus it cannot be determined with certainty whether the neurocognitive impairment noted postoperatively truly resulted from the surgical resection or rather had been present preoperatively, secondary to the effect of the tumor on surrounding brain tissue. Prospective studies that include preoperative baseline evaluations have provided needed insight into the nature of postoperative impairment. One such study evaluated 58 patients who had skull base meningioma evaluated prior to and at intervals after resection. Results revealed that compared with preoperative baseline performance, patients exhibited acute declines in verbal memory, working memory, and executive functioning that were noted at the follow-up evaluation 3 to 5 months postoperatively. These declines were generally transient, with the majority of patients’ performance being stable to improved relative to baseline 1 year after surgery; only a small minority exhibited persistent deficits.16
Another prospective study of skull base meningioma patients found no neurocognitive decline relative to preoperative baseline 1 year after resection and in fact found improvement on tasks assessing verbal fluency, processing speed, and fine motor dexterity. However, impairments in memory that were present preoperatively persisted.8 This suggests that much of the neurocognitive impairment observed postoperatively is likely secondary to the impact of the tumor itself rather than an untoward effect of surgical resection, and it stresses the importance of baseline neuropsychological evaluation to appropriately interpret the presence and nature of neurocognitive impairment for skull base tumor patients.
Taken together, these studies provide evidence that although patients can recover from the acute effects of surgical resection, neurocognitive deficits may persist if damage to healthy brain occurred preoperatively secondary to the tumor itself or if the required surgical approach injures surrounding tissue.
Radiation-Induced Morbidity
Radiation therapy for skull base tumors may also pose a risk to neurocognitive function, as some treatment plans necessarily include exposure to structures critical for neurocognitive functioning. Of particular concern is late-delayed toxicity, which can develop months to years after completion of radiation therapy. Several factors have been identified as being associated with greater risk for the development of radiation-induced neurocognitive impairment, including age (younger than 5 or older than 60), dose per fraction (greater than 2 Gy), higher total dose, hyperfractionated schedules, shorter overall treatment time, comorbid vascular risk factors, concurrent or subsequent chemotherapy, and greater total volume of brain exposed to radiation.17 With regard to memory specifically, an association has been reported between greater exposure to the bilateral hippocampi and greater impairment in long-term memory.18 Studies investigating the neurocognitive impact of radiation therapy for skull base tumors have yielded mixed findings, perhaps in part due to the heterogeneity of skull base tumors and associated treatment plans, with different tumor types involving different risk to critical brain structures. In 1997 Glosser et al found only a mild decline in motor speed in the chronic and delayed periods after irradiation for chondrosarcoma (mean 25.4 and 47.4 months, respectively). They otherwise reported no evidence of adverse neurocognitive effects despite radiation dose of 50 to 60 CGE involving midline and temporal lobe structures.19 A prospective 1-year follow-up study of 40 patients who had skull base meningiomas also suggested the relative safety of radiation therapy. This study showed a significant but transient decline in memory after the first radiation fraction. No further declines were noted thereafter; rather, improvements were noted in attention after the first radiation fraction, with further significant improvements in attention and memory after 6 months and still further improvements at 1 year.11
In contrast to the preceding findings, in 2000 Meyers et al reported that patients who completed radiation for tumors of the paranasal sinus exhibited impairment in memory, executive functioning, and motor functioning in a pattern suggestive of frontal–subcortical dysfunction. Degree of impairment was associated with total dose of radiation therapy and time since treatment; average time since radiation to testing was 6 years.6 Notably, Steinvorth et al11 followed patients for only up to 1 year, so late delayed effects might not yet have developed. Although Glosser et al19 had a longer follow-up time, that study also eliminated patients who had radiation necrosis and thus failed to account for those patients who might have experienced the most toxic effects of their radiation therapy.
Much of the available literature regarding neurocognitive functioning after radiation therapy for skull base tumors involves patients who have nasopharyngeal carcinoma, as these patients are particularly vulnerable to the development of temporal lobe necrosis after treatment due to exposure of the temporal lobe(s) to radiation.20 In a study of 30 patients treated using intensity-modulated radiation therapy, 76.7% exhibited significant declines in neurocognitive functioning compared with pretreatment performance on tests assessing memory, language, and verbal fluency. Higher dose generally, and to the temporal lobes specifically, was associated with worse neurocognitive outcome.21 In 2000 Cheung et al compared patients who had nasopharyngeal carcinoma who developed radiation-induced temporal lobe necrosis with those who did not as well as with healthy controls, finding that although patients who did not have necrosis tended to perform worse than controls did, there was not a statistically significant difference. Patients who had necrosis performed significantly worse than both controls and patients who did not have necrosis on tests of memory as well as across measures assessing language, motor functioning, and executive functioning.20
In summary, patients who undergo radiation therapy may be at risk for development of neurocognitive dysfunction if the dose distribution includes critical brain structures; particular concern is raised for late delayed effects, which might not develop until months to years after therapy. In addition to clearly identified radiation necrosis, other imaging biomarkers may be associated with these neurocognitive changes. Alterations in functional network connectivity were identified in patients who had nasopharyngeal carcinoma after radiation therapy using fMRI and were associated with degree of neurocognitive impairment.22 In patients who developed radiation necrosis, a higher number of temporal cerebral microbleeds was also identified as being associated with greater neurocognitive impairment.23
12.3 Affective Distress in Patients Who Have Skull Base Tumors
In addition to neurocognitive changes, patients who have skull base tumors may experience mood disturbance. There is a dearth of strong literature regarding the prevalence of depression and anxiety in cases of skull base tumor. A report on 18 patients who had malignant tumors of the skull base found that post treatment a third reported possible or probable anxiety or depression, as measured by the Hospital Anxiety and Depression Scale (HADS).24 Similarly, 29% of patients who had skull base chordoma and who had undergone surgery and/or radiation were found to have moderate or severe depression, as measured by the Patient Health Questionnaire (PHQ-9).25 Slightly higher estimates were reported in 2008 by Lue et al, who found that of 43 patients posttreatment for nasopharyngeal carcinoma, 51.2% reported significant symptoms of anxiety (as measured by the Beck Anxiety Inventory) and 44.2% reported significant symptoms of depression (as measured by the Beck Depression Inventory–II).26
There is some evidence to suggest that affective distress in patients who have tumors of the skull base may stabilize and/or decline through the disease course. A prospective study investigating neuropsychological functioning in patients who had chordomas and low-grade chondrosarcomas of the skull base found improvements in self-reported symptoms of depression and anxiety over time, with a tendency for mood to stabilize approximately 1 year after radiation therapy.19 Similarly, a study assessing neuropsychological outcomes in patients who had skull base meningiomas after fractionated stereotactic radiotherapy found improvements in overall mood states 6 weeks after completion of treatment, with stabilization thereafter.11 In 2017 Zweckberger et al also reported that in patients who had skull base meningiomas, self-reported symptoms of depression and anxiety remained stable after resection in more than 90% of cases.16 As neurocognitive impairment persisted even in the context of improved mood, these findings suggest that affective distress does not explain the observed neurocognitive impairments in this patient population.
12.4 Neuropsychological Assessment of Patients Who Have Skull Base Tumors
Neuropsychological evaluation is beneficial in determining the impact of the tumor on neurocognitive functioning, as well as to monitor for possible treatment-related changes. Assessment is also helpful in determining the presence and/or impact of neuromedical or psychological/psychiatric comorbidities. Unfortunately, the diagnosis of a skull base tumor does not preclude additional diagnosis of, for example, a comorbid neurodegenerative condition. Neuropsychological assessment may be diagnostically relevant in determining whether observed neurocognitive changes reflect tumor/treatment effects or are secondary to another process.
12.4.1 Clinical Interview
As with any neuropsychological evaluation, the assessment of cognition is incomplete without a thorough clinical interview that can provide context for the acquired neurocognitive test results. Although pretreatment baseline evaluations are ideal, it is not uncommon for patients to present for their first evaluation after the initiation or completion of some treatment. Thus the clinical interview should address factors relevant to a patient’s level of premorbid functioning; this will include information regarding educational and occupational attainment, any developmental delays, and relevant medical comorbidities. In addition to obtaining this background information, the clinician should acquire information from the patient and a collateral informant, if available, regarding the patient’s subjective baseline level of functioning and the chronology of any perceived changes, including the perceived impact on the patient of the tumor and its treatment. The interview is also used to garner information regarding current relative need for supervision and assistance, as well as any functional difficulties in personal and/or occupational responsibilities. This is also a time for identification of any mood or personality changes, as well as discussion of changes to family or occupational roles that might cause distress.
12.4.2 Neurocognitive Test Selection
Screening measures, such as the Mini Mental State Examination (MMSE), generally fail to provide the breadth and sensitivity needed to capture the neurocognitive sequelae of tumors and associated treatment.27 An appropriate neuropsychological assessment is often broad in scope but has a particular focus on those cognitive skills that may be particularly vulnerable to tumor and treatment effects. There is no one “correct” assessment battery that must be used to properly evaluate these abilities, but certain standards of practice should be followed. An objective test robust to brain insult is typically included in the first evaluation to further inform estimates of premorbid functioning. As already noted, patients who have tumors of the skull base may be particularly vulnerable to changes in the domains of memory and executive functioning. Further test selection may thus weigh more heavily in these domains. Accordingly, tests of memory should include both verbal and visual information and should assess multiple aspects of memory, including learning, retrieval, and consolidation. Tests assessing executive functioning often include those tapping working memory, cognitive flexibility, and reasoning. Additional measures may assess basic naming abilities, verbal fluency, visuospatial skills (from simple to complex), processing speed, and fine motor dexterity. The choice of how many tests to administer must take into account the patient’s physical well-being. Fatigue is perhaps the most commonly reported cancer-related symptom, and it is also a common complaint among patients who have skull base tumors.28 , 29 Test batteries must therefore be selected with the patient’s stamina in mind, and/or assessment may need to be distributed across multiple testing sessions.
With these considerations taken into account, neurocognitive assessment is generally well tolerated by patients, as has been demonstrated in clinical trials.30 The possibility of sensory change secondary to tumor effects must also be considered. For example, some skull base tumors may result in visual field deficits or diplopia, whereas others may lead to significant tinnitus and/or hearing loss. If these deficits are severe enough to interfere with a patient’s ability to perform tasks involving visual or auditory stimuli, this will necessarily change the clinician’s test selection to those that can be adequately presented. Clinical experience suggests that skull base tumor–related sensory deficits are rarely so severe as to entirely preclude assessment through one modality or another; however, the clinician should use information regarding any such limitations to guide test selection and interpretation. For example, a visual field deficit is unlikely to prevent administration of all visually mediated measures. However, this may slow performance on speed of processing tasks requiring visual scanning and/or may have an untoward impact on reading abilities. Interpretation in such a case would need to be made accordingly to ensure that potentially weak performance in these other domains is not overinterpreted, with test data perhaps needing to be supplemented by additional information from the clinical interview, behavioral observations, and complementary measures to ensure appropriate clinical analysis. As when evaluating other brain tumor patients, chosen measures should have well-established reliability and validity. Tests that have alternate forms are preferred when available so as to allow for more frequent evaluation with a reduced risk of practice effects.
Related posts:
5 Anesthesia and Intraoperative Monitoring of Patients with Skull Base Tumors
4 Head, Neck, and Neuro-otologic Assessment of Patients with Skull Base Tumors
3 Imaging of Skull Base Neoplasms
10 Management of Benign Skull Base Tumors in Neuro-oncology: Systemic Cytotoxic and Targeted Therapies
9 Clinical Applications of Radiotherapy for Skull Base Tumors
15 Pediatric Skull Base Surgery
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