Treatment of cognitive deficits in brain tumour patients:Current status and future directions

Purpose of review Increased life expectancy in brain tumour patients had led to the need for strategies that preserve and improve cognitive functioning, as many patients suffer from cognitive deficits. The tumour itself, as well as antitumor treatment including surgery, radiotherapy and chemotherapy, supportive treatment and individual patient factors are associated with cognitive problems. Here, we review the recent literature on approaches that preserve and improve cognitive functioning, including pharmacological agents and rehabilitation programs. Recent findings Minimizing cognitive dysfunction and improving cognitive functioning in brain tumour patients may be achieved both by preserving cognitive functioning during antitumor treatment, including techniques such as awake brain surgery, less invasive radiation therapies such as stereotactic radiotherapy and proton therapy, as well as with interventions including cognitive rehabilitation programmes. Novel rehabilitation programs including computer-based cognitive rehabilitation therapy (CRT) programmes that can be adjusted to the specific patient needs and can be administered at home are promising. Furthermore, personalized/precision medicine approaches to identify patients who are at risk for cognitive decline may facilitate effective treatment strategies in the future. Cognitive functioning has gained greater awareness in the neuro-oncological community, and methods to preserve and improve cognitive functioning have been explored. Rehabilitation programmes for brain tumour patients should be further developed and referred to in clinical practice.Neurolog

Prevalence and correlates of fatigue in patients with meningioma before and after surgery

Background Fatigue is a common symptom in patients with brain tumors, but comprehensive studies on fatigue in patients with meningioma specifically are lacking. This study examined the prevalence and correlates of fatigue in meningioma patients. Methods Patients with grade I meningioma completed the Multidimensional Fatigue Inventory (MFI-20) before and 1 year after neurosurgery. The MFI consists of 5 subscales: General Fatigue, Physical Fatigue, Mental Fatigue, Reduced Motivation, and Reduced Activity. Patients’ scores were compared with normative data. Preoperative fatigue was compared with postoperative fatigue. Correlations with sex, age, education, tumor hemisphere, preoperative tumor volume, antiepileptic drugs (AEDs), symptoms of anxiety/depression, and self-reported cognitive complaints were explored. Results Questionnaires were completed by 65 patients preoperatively, and 53 patients postoperatively. Of 34 patients, data from both time points were available. Patients had significantly higher fatigue levels on all subscales compared to normative values at both time points. Mean scores on General Fatigue, Physical Fatigue, and Mental Fatigue remained stable over time and improvements were observed on Reduced Motivation and Reduced Activity. Preoperatively, the prevalence of high fatigue (Z-score ≥ 1.3) varied between 34% for Reduced Motivation and 43% for General Fatigue/Mental Fatigue. The postoperative prevalence ranged from 19% for Reduced Activity to 49% on Mental Fatigue. Fatigue was associated with cognitive complaints, anxiety and depression, but not with education, tumor lateralization, tumor volume, or AEDs. Conclusion Fatigue is a common and persistent symptom in patients with meningioma undergoing neurosurgery. Findings emphasize the need for more research and appropriate care targeting fatigue for meningioma patients

Cognitive impairment three months after surgery is an independent predictor of survival time in glioblastoma patients

Purpose Cognitive functioning is increasingly investigated for its prognostic value in glioblastoma (GBM) patients, but the association of cognitive status during early adjuvant treatment with survival time is unclear. The aim of this study was to determine whether cognitive performance three months after surgical resection predicted survival time, while using a clinically intuitive time ratio (TR) statistic. Methods Newly diagnosed patients with GBM undergoing resection between November 2010 and February 2018 completed computerized cognitive assessment 3 months after surgery with the CNS Vital Signs battery (8 measures). The association of cognitive performance (continuous Z scores and dichotomous impairment status; impaired vs. unimpaired) with survival time was assessed with multivariate Accelerated Failure Time (AFT) models that also included clinical prognostic factors and covariates related to cognitive performances. Results 114 patients were included in the analyses (median survival time 16.4 months). Of the clinical factors, postoperative Karnofsky Performance Status (TR 1.51), surgical (TR 2.20) and non-surgical (TR 1.94) salvage treatment, and pre-surgical tumor volume (cm3, TR 1.003) were significant independent predictors of survival time. Independently of the base model factors and covariates, impairment on Stroop test I and Stroop test III estimated 23% and 26% reduction of survival time (TR 0.77, TR 0.74) respectively, as compared to unimpaired performance. Conclusion These findings suggest that impaired performances on tests of executive control and processing speed in the early phase of adjuvant treatment can reflect a worse prognostic outlook rather than an early treatment effect, and their assessment might allow for early refinement of current prognostic stratification. This study was approved by the local Medical Ethics Committee Brabant (file number NL41351.008.12)

Health-related quality of life in adult patients with brain metastases after stereotactic radiosurgery:A systematic, narrative review

Purpose A growing number of patients with brain metastases (BM) are being treated with stereotactic radiosurgery (SRS), and the importance of evaluating the impact of SRS on the health-related quality of life (HRQoL) in these patients has been increasingly acknowledged. This systematic review summarizes the current knowledge about the HRQoL of patients with BM after SRS. Methods We searched EMBASE, Medline Ovid, Web-of-Science, the Cochrane Database, PsycINFO Ovid, and Google Scholar up to November 15, 2018. Studies in patients with BM in which HRQoL was assessed before and after SRS and analyzed over time were included. Studies including populations of several types of brain cancer and/or several types of treatments were included if the results for patients with BM and treatment with SRS alone were described separately. Results Out of 3638 published articles, 9 studies met the eligibility criteria and were included. In 4 out of 7 studies on group results, overall HRQoL of patients with BM remained stable after SRS. In small study samples of longer-term survivors, overall HRQoL remained stable up to 12 months post-SRS. Contradictory results were reported for physical and general/global HRQoL, which might be explained by the different questionnaires that were used. Conclusions In general, SRS does not have significant negative effects on patients’ overall HRQoL over time. Future research is needed to analyze different aspects of HRQoL, differences in individual changes in HRQoL after SRS, and factors that influence these changes. These studies should take into account several methodological issues as discussed in this review

Cognitive effects of stereotactic radiosurgery in adult patients with brain metastases:A systematic review

Purpose:  Stereotactic radiation surgery (SRS) is increasingly applied in patients with brain metastases (BM) and is expected to have fewer adverse effects on cognitive functioning than whole brain radiation therapy (WBRT). Patients with BM are often confronted with a relatively short life expectancy, and the prevention or delay of cognitive decline to maintain quality of life is a clinically and highly relevant treatment goal. This review systematically and specifically evaluates the current literature on the cognitive effects of SRS in patients with BM. Methods and materials:  Published trials on SRS alone or in combination with WBRT, including objective assessment of cognitive functioning, were identified through a systematic search of the PubMed database up to March 2018. Results:  Of the 241 records screened, 14 studies matched the selection criteria: 2 pilot studies, 7 single-group/observational trials (1 study update), and 5 randomized trials (1 secondary analysis). Conclusions:  In general, the results show little to no objective cognitive decline up to 4 months after SRS compared with WBRT. However, most trials suffered from methodologic limitations that hindered reliable conclusions. Most importantly, few studies investigated the specific cognitive effects of SRS alone or versus WBRT. Furthermore, disentangling the cognitive effects of SRS from the effects of the disease itself and from the effects of other treatments remains very difficult. By presenting this comprehensive review, we aim to encourage researchers to probe deeper into this area and to do so in a standardized and methodologically optimal manner. The ultimate objective of this line of research is to inform both doctors and patients more precisely about the cognitive effects they can expect from treatment. This study is expected to improve the quality of decision-making and maximize clinical outcomes for each individual patient

Cognitive outcomes in meningioma patients undergoing surgery: individual changes over time and predictors of late cognitive functioning

Background Meningioma patients are known to face cognitive deficits before and after surgery. We examined individual changes in cognitive performance over time and identified preoperative predictors of cognitive functioning 12 months after surgery in a large sample of meningioma patients. Methods Patients underwent neuropsychological assessment (NPA) using CNS Vital Signs 1 day before (T0), and 3 (T3) and 12 (T12) months after surgery. Patients’ sociodemographically-corrected scores on 7 cognitive domains were compared to performance of a normative sample using one-sample z tests and Chi-square tests of independence. Reliable change indices with correction for practice effects were calculated for individual patients. Linear mixed effects models were used to identify preoperative predictors of performance at T12. Results At T0, 261 patients were assessed, and 229 and 82 patients were retested at T3 and T12, respectively. Patients showed impaired cognitive performance before and after surgery, and although performance improved on the group-level, cognitive scores remained significantly lower than in the normative sample up to T12. On the individual level, performance remained stable in the majority of patients. Better preoperative performance, younger age, male sex, and higher educational level predicted better late cognitive performance. Conclusions Meningioma patients face serious and persistent pre- and postsurgical cognitive deficits. A preoperative NPA together with sociodemographic characteristics may provide valuable information on the late cognitive outcome of individual meningioma patients. These results can help to inform patients and clinicians on late cognitive outcomes at an early stage, and emphasizes the importance of presurgical NPA and timely cognitive rehabilitation

Multidimensional assessment of fatigue in patients with brain metastases before and after Gamma Knife radiosurgery

Purpose  Fatigue is a common and distressing symptom in cancer patients which negatively affects patients' daily functioning and health-related quality of life. The aim of this study was to assess multidimensional fatigue in patients with brain metastases (BM) before, and after Gamma Knife radiosurgery (GKRS).  Methods  Patients with BM, an expected survival > 3 months, and a Karnofsky Performance Status >= 70 and 104 Dutch non-cancer controls were recruited. The Multidimensional Fatigue Inventory (MFI), measuring general fatigue, physical fatigue, mental fatigue, reduced activity and reduced motivation, was used. Baseline levels of fatigue between patients and controls were compared using independent-samples t-tests. The course of fatigue over time, and clinical and psychological predictors thereof, were analyzed using linear mixed models (within-group analyses).  Results  Ninety-two, 67 and 53 patients completed the MFI at baseline, and 3 and 6 months after GKRS. Before GKRS, patients with BM experienced significantly higher levels of fatigue on all subscales compared to controls (medium to large effect sizes). Over 6 months, general and physical fatigue increased significantly (p = .009 and p <.001), and levels of mental fatigue decreased significantly (p = .027). No significant predictors of the course of fatigue over time could be identified.  Conclusions  Fatigue is a major problem for patients with BM. Different patterns over time were observed for the various aspects of fatigue in patients with BM. Information on the various aspects of fatigue is important because fatigue may negatively affect patients' functional independence, health-related quality of life, and adherence to therapy

Subjective cognitive functioning in patients with a meningioma:Its course and association with objective cognitive functioning and psychological symptoms

Objective: Although meningioma patients show deficits in objective cognitive functioning (OCF) measured with neuropsychological tests, subjective cognitive functioning (SCF) has received little attention. We investigate SCF from pre- to post-surgery and its associations with OCF, psychological, sociodemographic, and clinical characteristics.Methods: SCF was measured using the Cognitive Failures Questionnaire (CFQ) one day before (T0), and three (T3) and twelve months (T12) after surgery. Patients' scores were compared to normative data and changes over time were assessed. The neuropsychological battery CNS Vital Signs and the Hospital Anxiety and Depression Scale were administered. Correlations of SCF with OCF, psychological, sociodemographic, and clinical characteristics were explored.Results: Patients reported significantly better SCF as compared with controls at T0 (N=54) and T3 (N=242), but not at T12 (N=50). A significant decrease in group level SCF was observed from T0 to T12 (n=24, p&lt;.001). SCF was associated with anxiety at all time points (rs=-0.543 to -0.352) and with depression at T3 and T12 (r=-0.338 and -0.574), but not with OCF, sociodemographic, or clinical characteristics (rs=-0.202 to 0.288).Conclusions: Meningioma patients experienced better SCF as compared to controls before and three months after surgery, which might be the result of phenomena related to disease and recovery. As the findings suggest that cognitive symptoms might increase later on, future studies should further investigate the course of SCF in meningioma patients. In clinical practice, measurements of SCF should be combined with those of OCF and psychological distress in order to determine whether and which interventions are needed.</p

A randomized trial predicting response to cognitive rehabilitation in multiple sclerosis:Is there a window of opportunity?

BACKGROUND: Cognitive training elicits mild-to-moderate improvements in cognitive functioning in people with multiple sclerosis (PwMS), although response heterogeneity limits overall effectiveness. OBJECTIVE: To identify patient characteristics associated with response and non-response to cognitive training. METHODS: Eighty-two PwMS were randomized into a 7-week attention training (n = 58, age = 48.4 ± 10.2 years) or a waiting-list control group (n = 24, age = 48.5 ± 9.4 years). Structural and functional magnetic resonance imaging (MRI) was obtained at baseline and post-intervention. Twenty-one healthy controls (HCs, age = 50.27 ± 10.15 years) were included at baseline. Responders were defined with a reliable change index of 1.64 on at least 2/6 cognitive domains. General linear models and logistic regression were applied. RESULTS: Responders (n = 36) and non-responders (n = 22) did not differ on demographics, clinical variables and baseline cognition and structural MRI. However, non-responders exhibited a higher baseline functional connectivity (FC) between the default-mode network (DMN) and the ventral attention network (VAN), compared with responders (p = 0.018) and HCs (p = 0.001). Conversely, responders exhibited no significant baseline differences in FC compared with HCs. Response to cognitive training was predicted by lower DMN-VAN FC (p = 0.004) and DMN-frontoparietal FC (p = 0.029) (Nagelkerke R(2) = 0.25). CONCLUSION: An intact pre-intervention FC is associated with cognitive training responsivity in pwMS, suggesting a window of opportunity for successful cognitive interventions

A pilot randomized controlled trial of exercise to improve cognitive performance in patients with stable glioma:A proof of concept

BACKGROUND: Patients with glioma often suffer from cognitive deficits. Physical exercise has been effective in ameliorating cognitive deficits in older adults and neurological patients. This pilot randomized controlled trial (RCT) explored the possible impact of an exercise intervention, designed to improve cognitive functioning in glioma patients, regarding cognitive test performance and patient-reported outcomes (PROs). METHODS: Thirty-four clinically stable patients with World Health Organization grades II/III glioma were randomized to a home-based remotely coached exercise group or an active control group. Patients exercised 3 times per week for 20-45 minutes, with moderate to vigorous intensity, during 6 months. At baseline and immediate follow-up, cognitive performance and PROs were assessed with neuropsychological tests and questionnaires, respectively. Linear regression analyses were used to estimate effect sizes of potential between-group differences in cognitive performance and PROs at 6 months. RESULTS: The exercise group (n = 21) had small- to medium-sized better follow-up scores than the control group (n = 11) on several measures of attention and information processing speed, verbal memory, and executive function, whereas the control group showed a slightly better score on a measure of sustained selective attention. The exercise group also demonstrated small- to medium-sized better outcomes on measures of self-reported cognitive symptoms, fatigue, sleep, mood, and mental health-related quality of life. CONCLUSIONS: This small exploratory RCT in glioma patients provides a proof of concept with respect to improvement of cognitive functioning and PROs after aerobic exercise, and warrants larger exercise trials in brain tumor patients