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AbstractGlioma patients carry the burden of having both a progressive neurological disease and cancer, and may face a variety of symptoms, including depression and anxiety. These symptoms are highly prevalent in glioma patients (median point prevalence ranging from 16–41% for depression and 24–48% for anxiety when assessed by self-report questionnaires) and have a major impact on health-related quality of life and even overall survival time. A worse overall survival time for glioma patients with depressive symptoms might be due to tumor progression and/or its supportive treatment causing depressive symptoms, an increased risk of suicide or other (unknown) factors. Much is still unclear about the etiology of depressive and anxiety symptoms in glioma. These psychiatric symptoms often find their cause in a combination of neurophysiological and psychological factors, such as the tumor and/or its treatment. Although these patients have a particular idiosyncrasy, standard treatment guidelines for depressive and anxiety disorders apply, generally recommending psychological and pharmacological treatment. Only a few nonpharmacological trials have been conducted evaluating the efficacy of psychological treatments (eg, a reminiscence therapy-based care program) in this population, which significantly reduced depressive and anxiety symptoms. No pharmacological trials have been conducted in glioma patients specifically. More well-designed trials evaluating the efficacy of nonpharmacological treatments for depressive and anxiety disorders in glioma are urgently needed to successfully treat psychiatric symptoms in brain tumor patients and to improve (health-related) quality of life.

BackgroundElectroconvulsive therapy is a fast, safe, and effective treatment for severe clinical depression but there is an ongoing search for mechanistic insights.MethodsWe used a mouse neuro-endocrine model of depression to examine behavioral, cellular, and molecular effects of electroconvulsive stimuli (ECS).ResultsThe behavioral response to repeated ECS correlated with adult neurogenesis, more strongly in the ventral than dorsal hippocampus. Subsequent RNA-seq analysis targeting the ventral subgranular zone (SGZ) delineated ECS-responsive molecular pathways that were shared between naive and depressive-state conditions, and which may represent core biological responses to seizure induction. Other pathways responded to ECS preferentially in the depressive state, suggesting further state- specific mechanisms. By comparing gene set pathways reciprocally altered in depressed-state animals then reversed by ECS, we identified and validated neuro-inflammation as a candidate regulator of the antidepressant response. We further identified 56 novel candidate ‘antidepressant response’ genes in the ventral SGZ that may contribute to recovery, half of which have been implicated in human neuropsychiatric phenotypes.ConclusionsElectroconvulsive stimuli reverse neuro-inflammation in a mouse model of depression. The results offer a detailed molecular characterization of potential SGZ antidepressant response-specific genes and pathways in brain regions implicated in depression.

BACKGROUND: Neuropsychiatric presentations of monkeypox (MPX) infection have not been well characterised, despite evidence of nervous system involvement associated with the related smallpox infection. METHODS: In this pre-registered (PROSPERO ID 336649) systematic review and meta-analysis, we searched MEDLINE, EMBASE, PsycINFO, AMED and the preprint server MedRxiv up to 31/05/2022. Any study design of humans infected with MPX that reported a neurological or psychiatric presentation was included. For eligible symptoms, we calculated a pooled prevalence using an inverse variance approach and corresponding 95% confidence intervals. The degree of variability that could be explained by between-study heterogeneity was assessed using the I 2 statistic. Risk of bias was assessed with the Newcastle Ottawa Scale and the Joanna Briggs Institute quality assessment tool. FINDINGS: From 1705 unique studies, we extracted data on 19 eligible studies (1512 participants, 1031 with confirmed infection using CDC criteria or PCR testing) most of which were cohort studies and case series with no control groups. Study quality was generally moderate. Three clinical features were eligible for meta-analysis: seizure 2.7% (95% CI 0.7-10.2%, I2 0%), confusion 2.4% (95% CI 1.1-5.2%, I2 0%) and encephalitis 2.0% (95% 0.5-8.2%, I2 55.8%). Other frequently reported symptoms included myalgia, headache and fatigue, where heterogeneity was too high for estimation of pooled prevalences, possibly as a result of differences in viral clades and study methodology. INTERPRETATION: There is preliminary evidence for a range of neuropsychiatric presentations including severe neurological complications (encephalitis and seizure) and nonspecific neurological features (confusion, headache and myalgia). There is less evidence regarding the psychiatric presentations or sequelae of MPX. This may warrant surveillance within the current MPX outbreak, with prospective longitudinal studies evaluating the mid- to long-term sequelae of the virus. Robust methods to evaluate the potential causality of MPX with these clinical features are required. More evidence is necessary to explain heterogeneity in prevalence estimates. FUNDING: UKRI/MRC (MR/V03605X/1), MRC-CSF (MR/V007181/1), MRC/AMED (MR/T028750/1) and the Wellcome Trust (102186/B/13/Z) and (102186/B/13/Z) and UCLH BRC.

ObjectivesNeuropsychiatric presentations of monkeypox (MPX) infection have not been well characterised, Despite evidence of nervous system involvement associated with two relatedOrthopoxviruses, in the case of smallpox infection (with the variola virus) and smallpox vaccination (which contains live vaccinia virus). In this systematic review and meta-analysis, we aim to determine the prevalence and describe the spectrum of neurological and psychiatric presentations of MPX.DesignSystematic review and meta-analysisData sourcesMEDLINE, EMBASE, PsycINFO, AMED and pre-print server (MedRxiv) searched up to 31/05/2022Eligibility criteria for study selection and analysisAny study design of humans infected with MPX that reported neurological or psychiatric presentation. Studies which included more than ten individuals, and symptoms that were reported in a minimum of two separate studies were eligible for meta-analysisData synthesisResults were pooled with random-effects meta-analysis to calculate generalised linear mixed models and corresponding 95% confidence intervals for each prevalence outcome. Heterogeneity was measured with the I2statistic. All included studies are summarised through a narrative synthesis. Risk of bias was assessed with the Newcastle Ottawa Scale and the Joanna Briggs Institute quality assessment tool.ResultsFrom 1,702 unique studies, we extracted data on 19 eligible studies (1,512 participants, 1,031 with confirmed infection using CDC criteria or PCR testing) most of which were cohort studies and case series with no controlled populations. Study quality was generally moderate. Six clinical features were eligible for meta-analysis, of which the most prevalent were myalgia in 55.5% [95%CI 12.1-91.9%], headache 53.8% [30.6-75.4%], fatigue 36.2% [2.0-94.0%], seizure 2.7% [0.6-10.2%], confusion 2.4% [1.1-5.2%] and encephalitis 2.0% [0.5-8.2%]. Heterogeneity significantly varied across clinical features (I2=0%-98.7%). Other reported presentations not eligible for meta-analysis included sensory-perceptual disturbance (altered vision, dizziness, and photophobia) and psychiatric symptoms (anxiety and depression).ConclusionsThere is preliminary evidence for a range of neurological and psychiatric presentations of MPX, ranging from commonly reported and nonspecific neurological symptoms (myalgia and headache) to rarer but more severe neurological complications, such as encephalitis and seizures. There is less evidence regarding the psychiatric sequelae of MPX, and although there are multiple reports of anxiety and depression the prevalence of these symptoms is unknown. MPX-related nervous system presentations may warrant surveillance within the current MPX outbreak, with prospective longitudinal studies evaluating the mid to long-term sequelae of the virus. Robust methods to evaluate the potential causality of MPX with these clinical features are required at an individual and epidemiological level.Systematic review registrationPROSPERO ID 336649SUMMARY BOXWhat is already known on this topicNeuropsychiatric symptoms can be highly disabling and have a detrimental effect on quality of life.Neuropsychiatric manifestations of monkeypox virus infection have not been well characterised, however, there is evidence of nervous system involvement with the related smallpox virus and vaccinia vaccine.What this study addsPreliminary evidence for a range of neurological and psychiatric presentations of monkeypox infection, ranging from commonly reported and nonspecific neurological symptoms (myalgia and headache) to rarer but more severe neurological complications, such as encephalitis and seizures.There is less evidence regarding the psychiatric sequelae of monkeypox infection, and although there are multiple reports of anxiety and depression the prevalence of these symptoms is unknown.This preliminary suspicion that there are monkeypox-related nervous system manifestations may warrant both surveillance within the current monkeypox outbreak and robust methods to evaluate the potential causality.

Purpose: To determine the prevalence and predictors of fatigue in clinically stable primary brain tumor patients, we used objective and subjective measures and a cross-sectional design. Methods: Eighty-five brain tumor patients completed self-report measures of fatigue, sleep disturbance, mood and growth hormone deficiency. Objective measures of sleep, cognition and neurological function were carried out. Comparisons were made between patients with no-mild, moderate and severe fatigue. Results: Sixty-seven per cent of patients (n=57) were experiencing moderate or severe fatigue at the time of assessment. Statistically significant differences between no-mild, moderate and severe fatigue groups were found when examining percentage daytime activity (p=0.035), processing speed (p = 0.0006), anxiety (p=0.008), depression (p

Background Glioma patients may experience behavioral and personality changes (BPC), negatively impacting their lives and that of their relatives. However, there is no clear definition of BPC for adult glioma patients, and here we aimed to determine which characteristics of BPC are relevant to include in this definition. Methods Possible characteristics of BPC were identified in the literature and presented to patients and (former) caregivers in an online survey launched via the International Brain Tumour Alliance. Participants had to rate the relevance of each presented characteristic of BPC, the three characteristics with the most impact on their lives, and possible missing characteristics. A cluster analysis and discussions with experts provided input to categorize characteristics and propose a definition for BPC. Results Completed surveys were obtained from 140 respondents; 35% patients, 50% caregivers, and 15% unknown. Of 49 proposed characteristics, 35 were reported as relevant by at least 25% (range: 7%-44%) of respondents. Patients and caregivers rated different characteristics as most important. Common characteristics included in the top 10 of both patients and caregivers were lack of motivation, change in being socially active, not able to finish things, and change in the level of irritation. No characteristics were reported missing by ≥5 respondents. Three categories of BPC were identified: (1) emotions, needs, and impulses (2) personality traits, and (3) poor judgement abilities. Conclusion The work resulted in a proposed definition for BPC in glioma patients, for which endorsement from the neuro-oncological community will be sought. A next step is to identify or develop an instrument to evaluate BPC in glioma patients.

There is accumulating evidence of the neurological and neuropsychiatric features of infection with SARS-CoV-2. In this systematic review and meta-analysis, we aimed to describe the characteristics of the early literature and estimate point prevalences for neurological and neuropsychiatric manifestations. We searched MEDLINE, Embase, PsycINFO and CINAHL up to 18 July 2020 for randomised controlled trials, cohort studies, case-control studies, cross-sectional studies and case series. Studies reporting prevalences of neurological or neuropsychiatric symptoms were synthesised into meta-analyses to estimate pooled prevalence. 13 292 records were screened by at least two authors to identify 215 included studies, of which there were 37 cohort studies, 15 case-control studies, 80 cross-sectional studies and 83 case series from 30 countries. 147 studies were included in the meta-analysis. The symptoms with the highest prevalence were anosmia (43.1% (95% CI 35.2% to 51.3%), n=15 975, 63 studies), weakness (40.0% (95% CI 27.9% to 53.5%), n=221, 3 studies), fatigue (37.8% (95% CI 31.6% to 44.4%), n=21 101, 67 studies), dysgeusia (37.2% (95% CI 29.8% to 45.3%), n=13 686, 52 studies), myalgia (25.1% (95% CI 19.8% to 31.3%), n=66 268, 76 studies), depression (23.0% (95% CI 11.8% to 40.2%), n=43 128, 10 studies), headache (20.7% (95% CI 16.1% to 26.1%), n=64 613, 84 studies), anxiety (15.9% (5.6% to 37.7%), n=42 566, 9 studies) and altered mental status (8.2% (95% CI 4.4% to 14.8%), n=49 326, 19 studies). Heterogeneity for most clinical manifestations was high. Neurological and neuropsychiatric symptoms of COVID-19 in the pandemic’s early phase are varied and common. The neurological and psychiatric academic communities should develop systems to facilitate high-quality methodologies, including more rapid examination of the longitudinal course of neuropsychiatric complications of newly emerging diseases and their relationship to neuroimaging and inflammatory biomarkers.

SUMMARYBackgroundThe nature and extent of persistent neuropsychiatric symptoms after COVID-19 are not established. To help inform mental health service planning in the pandemic recovery phase, we systematically determined the prevalence of neuropsychiatric symptoms in survivors of COVID-19.MethodsFor this pre-registered systematic review and meta-analysis (PROSPERO ID CRD42021239750) we searched PubMed, EMBASE, CINAHL and PsycINFO to 20th February 2021, plus our own curated database. We included peer-reviewed studies reporting neuropsychiatric symptoms at post-acute or later time-points after COVID-19 infection, and in control groups where available. For each study a minimum of two authors extracted summary data. For each symptom we calculated a primary pooled prevalence using generalised linear mixed models. Heterogeneity was measured withI2. Subgroup analyses were conducted for COVID-19 hospitalisation, severity, and duration of follow-up.FindingsFrom 2,844 unique titles we included 51 studies (n=18,917 patients). The mean duration of follow-up after COVID-19 was 77 days (range 14-182 days). Study quality was generally moderate. The most frequent neuropsychiatric symptom was sleep disturbance (pooled prevalence=27·4% [95%CI 21·4- 34·4%]), followed by fatigue (24·4% [17·5-32·9%]), objective cognitive impairment (20·2% [10·3-35·7%]), anxiety (19·1%[13·3-26·8%]), and post-traumatic stress (15·7% [9·9-24·1%]). Only two studies reported symptoms in control groups, both reporting higher frequencies in Covid-19 survivors versus controls. Between-study heterogeneity was high (I2=79·6%-98·6%). There was little or no evidence of differential symptom prevalence based on hospitalisation status, severity, or follow-up duration.InterpretationNeuropsychiatric symptoms are common and persistent after recovery from COVID-19. The literature on longer-term consequences is still maturing, but indicates a particularly high frequency of insomnia, fatigue, cognitive impairment, and anxiety disorders in the first six months after infection.FundingJPR is supported by the Wellcome Trust (102186/B/13/Z).IK is funded through the NIHR (Oxford Health Biomedical Research Facility, Development and Skills Enhancement Award) and the Medical Research Council (Dementias Platform UK and Deep and Frequent Phenotyping study project grants).HH is funded by the German Research Foundation (DFG, Grant: HO 1286/16-1). The funders played no role in the design, analysis or decision to publish.RESEARCH IN CONTEXTEvidence before this studyNeuropsychiatric symptoms like cognitive impairment, fatigue, insomnia, depression and anxiety can be highly disabling. Recently there has been increasing awareness of persistent neuropsychiatric symptoms after COVID-19 infection, but a systematic synthesis of these symptoms is not available. In this review we searched five databases up to 20th February 2021, to establish the pooled prevalence of individual neuropsychiatric symptoms up to six months after COVID-19.Added value of this studyThis study establishes which of a range of neuropsychiatric symptoms are the most common after COVID-19. We found high rates in general, with little convincing evidence that these symptoms lessen in frequency during the follow-up periods studied.ImplicationsPersistent neuropsychiatric symptoms are common and appear to be limited neither to the post-acute phase, nor to recovery only from severe COVID-19. Our results imply that health services should plan for high rates of requirement for multidisciplinary services (including neurological, neuropsychiatric and psychological management) as populations recover from the COVID-19 pandemic.

ObjectivesThere is accumulating evidence of the neurological and neuropsychiatric features of infection with SARS-CoV-2. In this systematic review and meta-analysis, we aimed to describe the characteristics of the early literature and estimate point prevalences for neurological and neuropsychiatric manifestations.MethodsWe searched MEDLINE, Embase, PsycInfo and CINAHL up to 18 July 2020 for randomised controlled trials, cohort studies, case-control studies, cross-sectional studies and case series. Studies reporting prevalences of neurological or neuropsychiatric symptoms were synthesised into meta-analyses to estimate pooled prevalence.Results13,292 records were screened by at least two authors to identify 215 included studies, of which there were 37 cohort studies, 15 case-control studies, 80 cross-sectional studies and 83 case series from 30 countries. 147 studies were included in the meta-analysis. The symptoms with the highest prevalence were anosmia (43.1% [35.2—51.3], n=15,975, 63 studies), weakness (40.0% [27.9—53.5], n=221, 3 studies), fatigue (37.8% [31.6—44.4], n=21,101, 67 studies), dysgeusia (37.2% [30.0—45.3], n=13,686, 52 studies), myalgia (25.1% [19.8—31.3], n=66.268, 76 studies), depression (23.0 % [11.8—40.2], n=43,128, 10 studies), headache (20.7% [95% CI 16.1—26.1], n=64,613, 84 studies), anxiety (15.9% [5.6—37.7], n=42,566, 9 studies) and altered mental status (8.2% [4.4—14.8], n=49,326, 19 studies). Heterogeneity for most clinical manifestations was high.ConclusionsNeurological and neuropsychiatric symptoms of COVID-19 in the pandemic’s early phase are varied and common. The neurological and psychiatric academic communities should develop systems to facilitate high-quality methodologies, including more rapid examination of the longitudinal course of neuropsychiatric complications of newly emerging diseases and their relationship to neuroimaging and inflammatory biomarkers.

Background Brain tumor patients are at high risk of impaired medical decision-making capacity (MDC), which can be ethically challenging because it limits their ability to give informed consent to medical treatments or participation in research. The European Association of Neuro-Oncology Palliative Care Multidisciplinary Task Force performed a systematic review to identify relevant evidence with respect to MDC that could be used to give recommendations on how to cope with reduced MDC in brain tumor patients. Methods A literature search in several electronic databases was conducted up to September 2019, including studies with brain tumor and other neurological patients. Information related to the following topics was extracted: tools to measure MDC, consent to treatment or research, predictive patient- and treatment-related factors, surrogate decision making, and interventions to improve MDC. Results A total of 138 articles were deemed eligible. Several structured capacity-assessment instruments are available to aid clinical decision making. These instruments revealed a high incidence of impaired MDC both in brain tumors and other neurological diseases for treatment- and research-related decisions. Incapacity appeared to be mostly determined by the level of cognitive impairment. Surrogate decision making should be considered in case a patient lacks capacity, ensuring that the patient’s “best interests” and wishes are guaranteed. Several methods are available that may help to enhance patients’ consent capacity. Conclusions Clinical recommendations on how to detect and manage reduced MDC in brain tumor patients were formulated, reflecting among others the timing of MDC assessments, methods to enhance patients’ consent capacity, and alternative procedures, including surrogate consent.

BACKGROUND Most brain tumour patients report clinically significant fatigue. Here, we aimed to explore patients’ views of the experience, acceptability and usefulness of participating in a trial of novel lifestyle interventions for fatigue. METHODS Qualitative sub-study within the ‘BT-LIFE’ multi-centre phase II RCT (submitted separately). Fatigued adult primary brain tumour patients in receipt of one of the trial interventions (‘Health Coaching’: eight coaching sessions targeting lifestyle behaviours; plus or minus ‘Activation Coaching’: two additional interviews targeting motivation to change) took part in a semi-structured interview following completion of the interventions. A realist approach to the ‘framework’ method was used to analyse verbatim transcripts, with inductive and deductive codes assigned to the realist domains of Context-Mechanism-Outcome. RESULTS Twenty themes and 53 sub-themes were derived from the data. Patients’ (n= 21) understanding of and engagement with the interventions were influenced by their expectations, attitudes to life, and experience of living with a brain tumour. Behaviour change was supported by goal-setting, monitoring using a weekly diary, the motivational ‘push’ by coaches, and family/ social support where available. Barriers to engagement included technical diary difficulties, time limitations including work and holiday schedules, and interference from life events. Most patients described beneficial changes in health behaviours, self-efficacy, and general health and wellbeing. About half indicated actual improvement in fatigue levels; others reported no direct change but they could now cope better with fatigue. A minority experienced no change or worsening fatigue. CONCLUSION Most fatigued brain tumour patients were able to make positive changes after lifestyle coaching, despite physical and cognitive impairments. However, their experiences were varied. Those for whom the interventions were a good ‘fit’ with their pre-existing outlook, lifestyle, and physical and emotional capabilities, appeared to achieve most benefit. These qualitative findings will inform further work addressing the disabling symptom of brain tumour-related fatigue.

Objectives Validated diagnostic interviews are required to classify depression status and estimate prevalence of disorder, but screening tools are often used instead. We used individual participant data meta-analysis to compare prevalence based on standard Hospital Anxiety and Depression Scale – depression subscale (HADS-D) cutoffs of ≥8 and ≥11 versus Structured Clinical Interview for DSM (SCID) major depression and determined if an alternative HADS-D cutoff could more accurately estimate prevalence. Methods We searched Medline, Medline In-Process & Other Non-Indexed Citations via Ovid, PsycINFO, and Web of Science (inception-July 11, 2016) for studies comparing HADS-D scores to SCID major depression status. Pooled prevalence and pooled differences in prevalence for HADS-D cutoffs versus SCID major depression were estimated. Results 6005 participants (689 SCID major depression cases) from 41 primary studies were included. Pooled prevalence was 24.5% (95% Confidence Interval (CI): 20.5%, 29.0%) for HADS-D ≥8, 10.7% (95% CI: 8.3%, 13.8%) for HADS-D ≥11, and 11.6% (95% CI: 9.2%, 14.6%) for SCID major depression. HADS-D ≥11 was closest to SCID major depression prevalence, but the 95% prediction interval for the difference that could be expected for HADS-D ≥11 versus SCID in a new study was −21.1% to 19.5%. Conclusions HADS-D ≥8 substantially overestimates depression prevalence. Of all possible cutoff thresholds, HADS-D ≥11 was closest to the SCID, but there was substantial heterogeneity in the difference between HADS-D ≥11 and SCID-based estimates. HADS-D should not be used as a substitute for a validated diagnostic interview.

Importance The Patient Health Questionnaire depression module (PHQ-9) is a 9-item self-administered instrument used for detecting depression and assessing severity of depression. The Patient Health Questionnaire-2 (PHQ-2) consists of the first 2 items of the PHQ-9 (which assess the frequency of depressed mood and anhedonia) and can be used as a first step to identify patients for evaluation with the full PHQ-9. Objective To estimate PHQ-2 accuracy alone and combined with the PHQ-9 for detecting major depression. Data sources MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, PsycINFO, and Web of Science (January 2000-May 2018). Study selection Eligible data sets compared PHQ-2 scores with major depression diagnoses from a validated diagnostic interview. Data extraction and synthesis Individual participant data were synthesized with bivariate random-effects meta-analysis to estimate pooled sensitivity and specificity of the PHQ-2 alone among studies using semistructured, fully structured, or Mini International Neuropsychiatric Interview (MINI) diagnostic interviews separately and in combination with the PHQ-9 vs the PHQ-9 alone for studies that used semistructured interviews. The PHQ-2 score ranges from 0 to 6, and the PHQ-9 score ranges from 0 to 27. Results Individual participant data were obtained from 100 of 136 eligible studies (44 318 participants; 4572 with major depression [10%]; mean [SD] age, 49 [17] years; 59% female). Among studies that used semistructured interviews, PHQ-2 sensitivity and specificity (95% CI) were 0.91 (0.88-0.94) and 0.67 (0.64-0.71) for cutoff scores of 2 or greater and 0.72 (0.67-0.77) and 0.85 (0.83-0.87) for cutoff scores of 3 or greater. Sensitivity was significantly greater for semistructured vs fully structured interviews. Specificity was not significantly different across the types of interviews. The area under the receiver operating characteristic curve was 0.88 (0.86-0.89) for semistructured interviews, 0.82 (0.81-0.84) for fully structured interviews, and 0.87 (0.85-0.88) for the MINI. There were no significant subgroup differences. For semistructured interviews, sensitivity for PHQ-2 scores of 2 or greater followed by PHQ-9 scores of 10 or greater (0.82 [0.76-0.86]) was not significantly different than PHQ-9 scores of 10 or greater alone (0.86 [0.80-0.90]); specificity for the combination was significantly but minimally higher (0.87 [0.84-0.89] vs 0.85 [0.82-0.87]). The area under the curve was 0.90 (0.89-0.91). The combination was estimated to reduce the number of participants needing to complete the full PHQ-9 by 57% (56%-58%). Conclusions and relevance In an individual participant data meta-analysis of studies that compared PHQ scores with major depression diagnoses, the combination of PHQ-2 (with cutoff ≥2) followed by PHQ-9 (with cutoff ≥10) had similar sensitivity but higher specificity compared with PHQ-9 cutoff scores of 10 or greater alone. Further research is needed to understand the clinical and research value of this combined approach to screening.

Objectives: Depression symptom questionnaires are not for diagnostic classification. Patient Health Questionnaire-9 (PHQ-9) scores >= 10 are nonetheless often used to estimate depression prevalence. We compared PHQ-9 >= 10 prevalence to Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (SCID) major depression prevalence and assessed whether an alternative PHQ-9 cutoff could more accurately estimate prevalence. Study Design and Setting: Individual participant data meta-analysis of datasets comparing PHQ-9 scores to SCID major depression status. Results: A total of 9,242 participants (1,389 SCID major depression cases) from 44 primary studies were included. Pooled PHQ-9 >= 10 prevalence was 24.6% (95% confidence interval [CI]: 20.8%, 28.9%); pooled SCID major depression prevalence was 12.1% (95% CI: 9.6%, 15.2%); and pooled difference was 11.9% (95% CI: 9.3%, 14.6%). The mean study-level PHQ-9 >= 10 to SCID-based prevalence ratio was 2.5 times. PHQ-9 >= 14 and the PHQ-9 diagnostic algorithm provided prevalence closest to SCID major depression prevalence, but study-level prevalence differed from SCID-based prevalence by an average absolute difference of 4.8% for PHQ-9 >= 14 (95% prediction interval: -13.6%, 14.5%) and 5.6% for the PHQ-9 diagnostic algorithm (95% prediction interval: -16.4%, 15.0%). Conclusion: PHQ-9 >= 10 substantially overestimates depression prevalence. There is too much heterogeneity to correct statistically in individual studies. (C) 2020 Elsevier Inc. All rights reserved.

Objective Two previous individual participant data meta-analyses (IPDMAs) found that different diagnostic interviews classify different proportions of people as having major depression overall or by symptom levels. We compared the odds of major depression classification across diagnostic interviews among studies that administered the Depression subscale of the Hospital Anxiety and Depression Scale (HADS-D). Methods Data accrued for an IPDMA on HADS-D diagnostic accuracy were analysed. We fit binomial generalized linear mixed models to compare odds of major depression classification for the Structured Clinical Interview for DSM (SCID), Composite International Diagnostic Interview (CIDI), and Mini International Neuropsychiatric Interview (MINI), controlling for HADS-D scores and participant characteristics with and without an interaction term between interview and HADS-D scores. Results There were 15,856 participants (1942 [12%] with major depression) from 73 studies, including 15,335 (97%) non-psychiatric medical patients, 164 (1%) partners of medical patients, and 357 (2%) healthy adults. The MINI (27 studies, 7345 participants, 1066 major depression cases) classified participants as having major depression more often than the CIDI (10 studies, 3023 participants, 269 cases) (adjusted odds ratio [aOR] = 1.70 (0.84, 3.43)) and the semi-structured SCID (36 studies, 5488 participants, 607 cases) (aOR = 1.52 (1.01, 2.30)). The odds ratio for major depression classification with the CIDI was less likely to increase as HADS-D scores increased than for the SCID (interaction aOR = 0.92 (0.88, 0.96)). Conclusion Compared to the SCID, the MINI may diagnose more participants as having major depression, and the CIDI may be less responsive to symptom severity.

Background: Screening for major depression with the Patient Health Questionnaire-9 (PHQ-9) can be done using a cutoff or the PHQ-9 diagnostic algorithm. Many primary studies publish results for only one approach, and previous meta-analyses of the algorithm approach included only a subset of primary studies that collected data and could have published results. Objective: To use an individual participant data meta-analysis to evaluate the accuracy of two PHQ-9 diagnostic algorithms for detecting major depression and compare accuracy between the algorithms and the standard PHQ-9 cutoff score of ≥10. Methods: Medline, Medline In-Process and Other Non-Indexed Citations, PsycINFO, Web of Science (January 1, 2000, to February 7, 2015). Eligible studies that classified current major depression status using a validated diagnostic interview. Results: Data were included for 54 of 72 identified eligible studies (n participants = 16,688, n cases = 2,091). Among studies that used a semi-structured interview, pooled sensitivity and specificity (95% confidence interval) were 0.57 (0.49, 0.64) and 0.95 (0.94, 0.97) for the original algorithm and 0.61 (0.54, 0.68) and 0.95 (0.93, 0.96) for a modified algorithm. Algorithm sensitivity was 0.22–0.24 lower compared to fully structured interviews and 0.06–0.07 lower compared to the Mini International Neuropsychiatric Interview. Specificity was similar across reference standards. For PHQ-9 cutoff of ≥10 compared to semi-structured interviews, sensitivity and specificity (95% confidence interval) were 0.88 (0.82–0.92) and 0.86 (0.82–0.88). Conclusions: The cutoff score approach appears to be a better option than a PHQ-9 algorithm for detecting major depression.

BackgroundItem 9 of the Patient Health Questionnaire-9 (PHQ-9) queries about thoughts of death and self-harm, but not suicidality. Although it is sometimes used to assess suicide risk, most positive responses are not associated with suicidality. The PHQ-8, which omits Item 9, is thus increasingly used in research. We assessed equivalency of total score correlations and the diagnostic accuracy to detect major depression of the PHQ-8 and PHQ-9.MethodsWe conducted an individual patient data meta-analysis. We fit bivariate random-effects models to assess diagnostic accuracy.Results16 742 participants (2097 major depression cases) from 54 studies were included. The correlation between PHQ-8 and PHQ-9 scores was 0.996 (95% confidence interval 0.996 to 0.996). The standard cutoff score of 10 for the PHQ-9 maximized sensitivity + specificity for the PHQ-8 among studies that used a semi-structured diagnostic interview reference standard (N = 27). At cutoff 10, the PHQ-8 was less sensitive by 0.02 (−0.06 to 0.00) and more specific by 0.01 (0.00 to 0.01) among those studies (N = 27), with similar results for studies that used other types of interviews (N = 27). For all 54 primary studies combined, across all cutoffs, the PHQ-8 was less sensitive than the PHQ-9 by 0.00 to 0.05 (0.03 at cutoff 10), and specificity was within 0.01 for all cutoffs (0.00 to 0.01).ConclusionsPHQ-8 and PHQ-9 total scores were similar. Sensitivity may be minimally reduced with the PHQ-8, but specificity is similar.

BackgroundDifferent diagnostic interviews are used as reference standards for major depression classification in research. Semi-structured interviews involve clinical judgement, whereas fully structured interviews are completely scripted. The Mini International Neuropsychiatric Interview (MINI), a brief fully structured interview, is also sometimes used. It is not known whether interview method is associated with probability of major depression classification.AimsTo evaluate the association between interview method and odds of major depression classification, controlling for depressive symptom scores and participant characteristics.MethodData collected for an individual participant data meta-analysis of Patient Health Questionnaire-9 (PHQ-9) diagnostic accuracy were analysed and binomial generalised linear mixed models were fit.ResultsA total of 17 158 participants (2287 with major depression) from 57 primary studies were analysed. Among fully structured interviews, odds of major depression were higher for the MINI compared with the Composite International Diagnostic Interview (CIDI) (odds ratio (OR) = 2.10; 95% CI = 1.15–3.87). Compared with semi-structured interviews, fully structured interviews (MINI excluded) were non-significantly more likely to classify participants with low-level depressive symptoms (PHQ-9 scores ≤6) as having major depression (OR = 3.13; 95% CI = 0.98–10.00), similarly likely for moderate-level symptoms (PHQ-9 scores 7–15) (OR = 0.96; 95% CI = 0.56–1.66) and significantly less likely for high-level symptoms (PHQ-9 scores ≥16) (OR = 0.50; 95% CI = 0.26–0.97).ConclusionsThe MINI may identify more people as depressed than the CIDI, and semi-structured and fully structured interviews may not be interchangeable methods, but these results should be replicated.Declaration of interestDrs Jetté and Patten declare that they received a grant, outside the submitted work, from the Hotchkiss Brain Institute, which was jointly funded by the Institute and Pfizer. Pfizer was the original sponsor of the development of the PHQ-9, which is now in the public domain. Dr Chan is a steering committee member or consultant of Astra Zeneca, Bayer, Lilly, MSD and Pfizer. She has received sponsorships and honorarium for giving lectures and providing consultancy and her affiliated institution has received research grants from these companies. Dr Hegerl declares that within the past 3 years, he was an advisory board member for Lundbeck, Servier and Otsuka Pharma; a consultant for Bayer Pharma; and a speaker for Medice Arzneimittel, Novartis, and Roche Pharma, all outside the submitted work. Dr Inagaki declares that he has received grants from Novartis Pharma, lecture fees from Pfizer, Mochida, Shionogi, Sumitomo Dainippon Pharma, Daiichi-Sankyo, Meiji Seika and Takeda, and royalties from Nippon Hyoron Sha, Nanzando, Seiwa Shoten, Igaku-shoin and Technomics, all outside of the submitted work. Dr Yamada reports personal fees from Meiji Seika Pharma Co., Ltd., MSD K.K., Asahi Kasei Pharma Corporation, Seishin Shobo, Seiwa Shoten Co., Ltd., Igaku-shoin Ltd., Chugai Igakusha and Sentan Igakusha, all outside the submitted work. All other authors declare no competing interests. No funder had any role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.

The National Cancer Research Institute (NCRI) is a partnership of charity and government research funders whose purpose is to improve health and quality of life by accelerating progress in cancer-related research through collaboration. Under this umbrella, the NCRI Brain Tumor Clinical Studies Group is focused on improving clinical outcomes for adult patients with brain and central nervous system tumors, including those with brain metastasis from other primary sites. This document discusses the current state of clinical brain tumor research in the United Kingdom and the challenges to increasing study and trial opportunities for patients. The clinical research priorities are defined along with a strategy to strengthen the existing brain tumor research network, improve access to tissue and imaging and to develop the future leadership for brain tumor research in the United Kingdom. This strategy document may serve as a framework for other organizations and countries.

BACKGROUND: Item 9 of the Patient Health Questionnaire-9 (PHQ-9) queries about thoughts of death and self-harm, but not suicidality. Although it is sometimes used to assess suicide risk, most positive responses are not associated with suicidality. The PHQ-8, which omits Item 9, is thus increasingly used in research. We assessed equivalency of total score correlations and the diagnostic accuracy to detect major depression of the PHQ-8 and PHQ-9. METHODS: We conducted an individual patient data meta-analysis. We fit bivariate random-effects models to assess diagnostic accuracy. RESULTS: 16,742 participants (2,097 major depression cases) from 54 studies were included. The correlation between PHQ-8 and PHQ-9 scores was 0·996 (95% confidence interval 0·996 to 0·996). The standard cutoff score of 10 for the PHQ-9 maximized sensitivity + specificity for the PHQ-8 among studies that used a semi-structured diagnostic interview reference standard (N = 27). At cutoff 10, the PHQ-8 was less sensitive by 0·02 (−0·06 to 0·00) and more specific by 0·01 (0·00 to 0·01) among those studies (N = 27), with similar results for studies that used other types of interviews (N = 27). For all 54 primary studies combined, across all cutoffs, the PHQ-8 was less sensitive than the PHQ-9 by 0·00 to 0·05 (0·03 at cutoff 10), and specificity was within 0·01 for all cutoffs (0·00 to 0·01). CONCLUSIONS: PHQ-8 and PHQ-9 total scores were similar. Sensitivity may be minimally reduced with the PHQ-8, but specificity is similar.

Background The diagnosis and treatment of a brain or spinal cord tumour can have a huge impact on the lives of patients and their families with family caregiving often resulting in considerable burden and distress. Meeting the support needs of family caregivers is critical to maintain their emotional and physical health. Although support for caregivers is becoming more widely available, large‐scale implementation is hindered by a lack of high‐quality evidence for its effectiveness in the neuro‐oncology caregiver population. Objectives To assess the effectiveness of supportive interventions at improving the well‐being of caregivers of people with a brain or spinal cord tumour. To assess the effects of supportive interventions for caregivers in improving the physical and emotional well‐being of people with a brain or spinal cord tumour and to evaluate the health economic benefits of supportive interventions for caregivers. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 7), MEDLINE via Ovid, and Embase via Ovid. We also handsearched relevant published conference abstracts (previous five years), publications in the two main journals in the field (previous year), searched for ongoing trials via ClinicalTrials.gov, and contacted research groups in the field. The initial search was in March 2017 with an update in August 2018 (handsearches completed in January 2019). Selection criteria We included all randomised controlled trials (RCTs) where caregivers of neuro‐oncology patients constituted more than 20% of the sample and which evaluated changes in caregiver well‐being following any supportive intervention. Data collection and analysis Two review authors independently selected studies and carried out risk of bias assessments. We aimed to extract data on the outcomes of psychological distress, burden, mastery, quality of patient–caregiver relationship, quality of life, and physical functioning. Main results In total, the search identified 2102 records, of which we reviewed 144 in full text. We included eight studies. Four interventions focused on patient–caregiver dyads and four were aimed specifically at the caregiver. Heterogeneity of populations and methodologies precluded meta‐analysis. Risk of bias varied, and all studies included only small numbers of neuro‐oncology caregivers (13 to 56 participants). There was some evidence for positive effects of caregiver support on psychological distress, mastery, and quality of life (low to very low certainty of evidence). No studies reported significant effects on caregiver burden or quality of patient–caregiver relationship (low to very low certainty of evidence). None of the studies assessed caregiver physical functioning. For secondary outcomes (patient emotional or physical well‐being; health economic effects), we found very little to no evidence for the effectiveness of caregiver support. We identified five ongoing trials. Authors' conclusions The eight small‐scale studies included employed different methodologies across different populations, with low certainty of evidence overall. It is not currently possible to draw reliable conclusions regarding the effectiveness of supportive interventions aimed at improving neuro‐oncology caregiver well‐being. More high‐quality research is needed on support for family caregivers of people diagnosed, and living, with a brain or spinal cord tumour.

Background: The objective of this study was to develop and validate a short form of the Patient Health Questionnaire-9 (PHQ-9), a self-report questionnaire for assessing depressive symptomatology, using objective criteria. Methods: Responses on the PHQ-9 were obtained from 7,850 English-speaking participants enrolled in 20 primary diagnostic test accuracy studies. PHQ unidimensionality was verified using confirmatory factor analysis, and an item response theory model was fit. Optimal test assembly (OTA) methods identified a maximally precise short form for each possible length between one and eight items, including and excluding the ninth item. The final short form was selected based on prespecified validity, reliability, and diagnostic accuracy criteria. Results: A four-item short form of the PHQ (PHQ-Dep-4) was selected. The PHQ-Dep-4 had a Cronbach's alpha of 0.805. Sensitivity and specificity of the PHQ-Dep-4 were 0.788 and 0.837, respectively, and were statistically equivalent to the PHQ-9 (sensitivity = 0.761, specificity = 0.866). The correlation of total scores with the full PHQ-9 was high (r = 0.919). Conclusion: The PHQ-Dep-4 is a valid short form with minimal loss of information of scores when compared to the full-length PHQ-9. Although OTA methods have been used to shorten patient-reported outcome measures based on objective, prespecified criteria, further studies are required to validate this general procedure for broader use in health research. Furthermore, due to unexamined heterogeneity, there is a need to replicate the results of this study in different patient populations.

BACKGROUND Fatigue is common and disabling for brain tumour patients. We studied the feasibility of two innovative lifestyle coaching interventions for high fatigue. METHODS Multi-centre phase II feasibility RCT (ISRCTN17883425). Adult primary brain tumour outpatients reporting significant fatigue (Brief Fatigue Inventory [BFI] score 4+), were randomised to one of three arms: Control; Health Coaching (“HC”, comprising eight structured coaching sessions on lifestyle behaviours); or HC plus Activation Coaching (“HC+AC”, adding two structured interviews targeting motivation to change). Outcomes were measured at baseline (T0), after interventions (T1), and at 16 weeks (T2). The primary outcome of feasibility was required for both recruitment (aim: average n= 5 fatigued patients recruited/month) and retention (aim: minimum 60% retention at T2). Secondary pilot outcomes included change in fatigue, depressive symptom, and QOL measures. RESULTS Over a nine-month recruitment period, n= 46 fatigued brain tumour patients were recruited (average n=5.1/month) and n= 34 were retained to endpoint (retention at T2= 73%), meeting the primary outcome of feasibility. Surprisingly, fatigue reduced significantly after HC (T1 mean change in BFI score from T0 baseline, relative to the equivalent change in control group: HC= -2.3 points [95%CI -3.4/-0.3]; HC+AC= -2.0 [-2.9/+0.1]; ANOVA p= 0.02) and was reduced in magnitude in both intervention groups at T2 (p= N.S). Both interventions also improved depressive symptoms (T1 mean change in HADS-Depression: HC= -2.0 points [-5.6/-0.1]; HC+AC= -2.9 [-6.5/-1.0]; Kruskal-Wallis p= 0.02). Patient-nominated QOL outcomes improved persistently after HC+AC (T2 mean change in PSYCHLOPS score: HC= -2.4 points [-5.4/+2.8]; HC+AC= -6.1 [-9.2/-0.8]; ANOVA p= 0.01). CONCLUSION Innovative coaching interventions, focused on lifestyle factors, are feasible to deliver to fatigued brain tumour patients. Preliminary signals suggest that these non-drug approaches may benefit several mediators of quality of life and warrant further study.

BACKGROUND BT-LIFE is a multi-centre RCT of novel lifestyle coaching treatments for fatigued brain tumour patients. To our knowledge it is also the first example of ‘multi-sectoral research’ to combine healthcare, private, and charity sectors in this population. To maximise learning, the trial team devised a structured reflection opportunity to ask, “What went well and what would we do differently next time?” METHOD After trial closedown we convened a six-hour ‘focus group’ for management, principle investigators, research assistants, interventionists, qualitative researchers, trial statisticians, and the funder. Discussion was structured using a ‘timeline’ wall-chart which attendees freely populated with post-it notes summarising learning points from the trial. Minutes were taken in duplicate. RESULTS In total n=19 team members contributed. Many points were study-specific and will be used internally to plan a larger trial. Among points of wider interest, examples of success included: using regular teleconferences to co-ordinate a cohesive and highly collaborative team; obtaining secure nhs.net email addresses to facilitate multi-sectoral communication; and the clear value of employing one part-time research assistant per centre instead of relying on busy clinical staff to recruit. General future learning points included: speak to the prospective sponsor and ethical committees when writing the grant application to avoid pitfalls and facilitate faster opening if funding is secured; consider preceding emails with a phone call to ‘lay the ground’ in time-sensitive situations; identify staff training requirements as early as possible and cascade aggressively; and be sensitive to the fact that inter-sectoral attitudes and practices may vary widely and need actively monitored and managed. Therefore frequent and secure communication, pro-active problem-spotting, and inter-sectoral value alignment appear critical for success. CONCLUSION BT-LIFE provides many useful lessons for anyone interested in running multi-sectoral research.

Background Symptom management in glioma patients remains challenging, as patients suffer from various concurrently occurring symptoms. This study aimed to identify symptom clusters and examine the association between these symptom clusters and patients’ functioning. Methods Data of the CODAGLIO project was used, including individual patient data from previously published international randomized controlled trials (RCTs) in glioma patients. Symptom prevalence and level of functioning were assessed with European Organisation for Research and Treatment of Cancer (EORTC) quality of life QLQ-C30 and QLQ-BN20 self-report questionnaires. Associations between symptoms were examined with Spearman correlation coefficients and partial correlation networks. Hierarchical cluster analyses were performed to identify symptom clusters. Multivariable regression analyses were performed to determine independent associations between the symptom clusters and functioning, adjusted for possible confounders. Results Included in the analysis were 4307 newly diagnosed glioma patients from 11 RCTs who completed the EORTC questionnaires before randomization. Many patients (44%) suffered from 5–10 symptoms simultaneously. Four symptom clusters were identified: a motor cluster, a fatigue cluster, a pain cluster, and a gastrointestinal/seizures/bladder control cluster. Having symptoms in the motor cluster was associated with decreased (≥10 points difference) physical, role, and social functioning (betas ranged from −11.3 to −15.9, all P < 0.001), independent of other factors. Similarly, having symptoms in the fatigue cluster was found to negatively influence role functioning (beta of −12.3, P < 0.001), independent of other factors. Conclusions Two symptom clusters, the fatigue and motor cluster, were frequently affected in glioma patients and were found to independently have a negative association with certain aspects of patients’ functioning as measured with a self-report questionnaire.

The third Britain/Israel Research and Academic Exchange Partnership Regenerative Medicine conference was recently held in Oxford (UK). This conference report summarizes highlights from the scientific program. There is a particular emphasis on internationally collaborative projects funded by this initiative, the young researchers' symposium, and a lively panel session focused on the relationships between industry and academia.

International audience; Patients with glioma present with complex palliative care needs throughout their disease trajectory. The life-limiting nature of gliomas and the presence of specific symptoms related to neurological deterioration necessitate an appropriate and early palliative care approach. The multidisciplinary palliative care task force of the European Association of Neuro-Oncology did a systematic review of the available scientific literature to formulate the best possible evidence-based recommendations for the palliative care of adult patients with glioma, with the aim to reduce symptom burden and improve the quality of life of patients and their caregivers, particularly in the end-of-life phase. When recommendations could not be made because of the scarcity of evidence, the task force either used evidence from studies of patients with systemic cancer or formulated expert opinion. Areas of palliative care that currently lack evidence and thus deserve attention for further research are fatigue, disorders of behaviour and mood, interventions for the needs of caregivers, and timing of advance care planning.

Brain tumour patients may struggle to express their concerns in the outpatient clinic, creating a physician-focused rather than a shared agenda. We created a simple, practical brain-tumour-specific holistic needs assessment (HNA) tool for use in the neuro-oncology outpatient clinic.We posted the brain tumour Patient Concerns Inventory (PCI) to a consecutive sample of adult brain tumour attendees to a neuro-oncology outpatient clinic. Participants brought the completed PCI to their clinic consultation. Patients and staff provided feedback.Seventy seven patients were eligible and 53 participated (response rate = 68%). The PCI captured many problems absent from general cancer checklists. The five most frequent concerns were fatigue, fear of tumour coming back, memory, concentration, and low mood. Respondents used the PCI to formulate 105 specific questions, usually about the meaning of physical or psychological symptoms. Patients and staff found the PCI to be useful, and satisfaction with the instrument was high.This study demonstrates the clinical utility of the brain tumour PCI in a neuro-oncology clinic. The combination of a brain-tumour-specific concerns checklist and an intervention to focus patient agenda creates a simple and efficient HNA tool.

No depression screening tool is validated for use in cases of cerebral glioma. To address this, we studied the operating characteristics of the Hospital Anxiety and Depression Scale (Depression subscale) (HAD-D), the Patient Health Questionnaire-9 (PHQ-9), and the Distress Thermometer (DT) in glioma patients.We conducted a twin-center prospective observational cohort study of major depressive disorder (MDD), according to the Diagnostic and Statistical Manual, 4th edition, in adults with a new diagnosis of cerebral glioma receiving active management or "watchful waiting." At each of 3 interviews over a 6-month period, patients completed the screening questionnaires and received a structured clinical interview to diagnose MDD. Internal consistency, area under the receiver operating characteristics curve (AUC), sensitivity, specificity, positive predictive value, and positive likelihood ratio were calculated. A maximum of 154 patients completed the DT, 133 completed the HAD-D, and 129 completed the PHQ-9. The HAD-D and PHQ-9 showed good internal consistency (α ≥ 0.77 at all timepoints). Median AUCs were 0.931 ± 0.074 for the HAD-D and 0.915 ± 0.055 for the PHQ-9. The optimal threshold was 7+ for the HAD-D, but 8+ had similar operating characteristics. There was no consistently optimal PHQ-9 threshold, but 10+ was optimal in the largest sample. The DT was inferior to the multi-item instruments. Clinicians can screen for depression in well-functioning glioma patients using the HAD-D at the existing recommended lower threshold of 8+, or the PHQ-9 at a threshold of 10+. Due to a modest positive predictive value of either instrument, patients scoring above these thresholds need a clinical assessment to diagnose or exclude depression.

Fatigue is a common and disabling symptom in people with a primary brain tumour (PBT). The effectiveness of interventions for treating clinically significant levels of fatigue in this population is unclear. This is an updated version of the original Cochrane Review published in Issue 4, 2016.To assess the effectiveness and safety of pharmacological and non-pharmacological interventions for adults with PBT and clinically significant (or high levels) of fatigue.For this updated review, we searched CENTRAL, MEDLINE and Embase, and checked the reference lists of included studies in April 2022. We also searched relevant conference proceedings, and ClinicalTrials.gov for ongoing trials.We included randomised controlled trials (RCTs) that investigated any pharmacological or non-pharmacological intervention in adults with PBT and fatigue, where fatigue was the primary outcome measure. We restricted inclusion specifically to studies that enrolled only participants with clinically significant levels of fatigue to improve the clinical utility of the findings.Two review authors (JD, DC) independently evaluated search results for the updated search. Two review authors (JD, SYK) extracted data from selected studies, and carried out a risk of bias assessment. We extracted data on fatigue, mood, cognition, quality of life and adverse events outcomes.The original review identified one study and this update identified a further two for inclusion. One study investigated the use of modafinil, one study the use of armodafinil and one study the use of dexamfetamine. We identified three ongoing studies. In the original review, the single eligible trial compared modafinil to placebo for 37 participants with a high- or low-grade PBT. One new study compared two doses of armodafinil (150 mg and 250 mg) to placebo for 297 people with a high-grade glioma. The second new study compared dexamfetamine sulfate to placebo for 46 participants with a low- or high-grade PBT. The evidence was uncertain for both modafinil and dexamfetamine regarding fatigue outcome measures, compared to controls, at study endpoint. Two trials did not reach the planned recruitment target and therefore may not, in practice, have been adequately powered to detect a difference. These trials were at a low risk of bias across most areas. There was an unclear risk of bias related to the use of mean imputation for one study because the investigators did not analyse the impact of imputation on the results and information regarding baseline characteristics and randomisation were not clear. The certainty of the evidence measured using GRADE was very low across all three studies. There was one identified study awaiting classification once data are available, which investigated the feasibility of 'health coaching' for people with a PBT experiencing fatigue. There were three ongoing studies that may be eligible for an update of this review, all investigating a non-pharmacological intervention for fatigue in people with PBT.There is currently insufficient evidence to draw reliable and generalisable conclusions regarding potential effectiveness or harm of any pharmacological or non-pharmacological treatments for fatigue in people with PBT. More research is needed on how best to treat people with brain tumours with high fatigue.

Neurocognitive deficits are common with brain tumors. If assessed at presentation using detailed neurocognitive tests, problems are detected in 80 % of cases. Neurocognition may be affected by the tumor, its treatment, associated medication, mood, fatigue, and insomnia. Interpretation of neurocognitive problems should be considered in the context of these factors. Early post-operative neurocognitive rehabilitation for brain tumor patients will produce rehabilitation outcomes (e.g., quality of life, improved physical function, subjective neurocognition) equivalent to stroke, multiple sclerosis, and head injury, but the effect size and duration of benefit needs further research. In stable patients treated with radiotherapy +/- chemotherapy, the most frequent causes of distress include neurocognitive problems, psychological factors of anxiety, depression, fatigue, and sleep. Exercise, neurocognitive training, neurocognitive behavioral therapy, and medications to treat fatigue, behavior, memory, mood, and removal of drugs that may be associated with neurocognitive side effects (e.g., anti-epileptic drugs) all show promise in helping patients to manage the effects of their neurocognitive impairments better. As these are complex symptoms, multidisciplinary expertise is necessary to evaluate the influence of each variable to plan appropriate support and intervention. Neurocognitive rehabilitation should therefore occur in parallel with disease-centered, medical management from the outset. It should not occur in series, as a restricted phase in a patient's pathway. It should be considered in the pre- and post-operative period where there are good prospects of recovery, as one would for any brain-injured patient, so that the person may reach their optimal physical, sensory, intellectual, psychological, and social functional level. Yet the identification and selection of patients for early neurological rehabilitation and routine evaluation of cognition is uncommon in neurosurgical wards.

INTRODUCTION: The widely used antiepileptic drug (AED) Levetiracetam has previously been associated with behavioural changes. We hypothesised that patients taking Levetiracetam would experience higher levels of fatigue than patients on other AEDs. METHOD: Secondary analysis of a prospective observational study. Clinically stable adult outpatients with cerebral glioma completed a Visual Analogue Scale for fatigue (range 0-100mm, called ‘high' if >60mm). AED prescription was prospectively recorded. RESULTS: N = 166 patients consented to participate in the parent study (61% male; mean age 49yrs; 70% high-grade glioma). Fatigue was commonly reported (high in 43%; 95%CI 35-50%). AEDs were prescribed singly or multiply to most patients (n = 113). Levetiracetam (LEV) was the most frequent AED monotherapy. With clinical and statistical significance, patients on LEV monotherapy reported higher fatigue (n = 33, mean = 57mm, SD 5.2, 95%CI 46-67mm) than those on monotherapy with any other AED (n = 50, mean = 43mm, SD 3.9, 95%CI 35-50mm, t-test p < 0.0001). Surprisingly, this association was independent of functional status (ANCOVA p = 0.04, LR p < 0.0001, R2 = 27.7). Patients on LEV were more than twice as likely to report high fatigue as patients on other AEDs (OR 2.7 [1.1-6.2]). We observed similar findings with polytherapy involving LEV. CONCLUSION: Therapy-related side effects reduce quality of life and treatment compliance while increasing healthcare costs. Our data suggest that fatigue may be more common with Levetiracetam therapy specifically. Specialist review of AED medication may benefit some glioma patients with severe or persistent fatigue. Explanatory biological mechanisms of LEV-specific fatigue could be experimentally pursued.

BACKGROUND: Family caregiving in neuro-oncology is linked to considerable burden and distress. Meeting the support needs of family caregivers is critical to maintain their emotional and physical health, enabling them to continue their caregiving activities for longer. Although support for caregivers is becoming more widely available, large-scale implementation is hindered by a lack of high-quality evidence for its effectiveness in the neuro-oncology caregiver population. We performed a Cochrane systematic review to assess the effectiveness of supportive interventions at improving the wellbeing of caregivers of people with a brain or spinal cord tumour. MATERIAL AND METHODS: In March 2017, we searched for studies in CENTRAL, MEDLINE and Embase. We also handsearched relevant conference abstracts published (past 5 years), publications in the two main journals in the field (past year), searched for ongoing trials via ClinicalTrials.gov, and contacted research groups in this field. We included all randomised studies where caregivers of neuro-oncology patients constituted >20% of the sample and which evaluated changes in caregiver wellbeing following any supportive intervention. Two review authors independently selected studies and carried out risk of bias assessments. We aimed to extract data on the outcomes of psychological distress, burden, mastery, quality of patient-caregiver relationship, quality of life, and physical functioning. RESULTS: In total, 1666 records were identified, of which 122 were reviewed in full-text. We could include five studies (four ongoing trials were also identified). Three interventions focused on patient-caregiver dyads and two were aimed specifically at the caregiver. Heterogeneity of populations and methodologies precluded meta-analysis. Risk of bias varied, but all studies included only small numbers of neuro-oncology caregivers (n range= 13 - 56). Some evidence was found for positive effects of caregiver support on psychological distress and mastery (GRADE quality of evidence: low to very low). No studies reported significant effects on caregiver burden, quality of life, or quality of patient-caregiver relationship (GRADE quality of evidence: low to very low). Caregiver physical functioning was not assessed in the studies. CONCLUSION: The five small-scale studies included employed different methodologies across different populations, with a low quality of evidence overall. It is not currently possible to draw reliable conclusions regarding the effectiveness of supportive interventions aimed at improving neuro-oncology caregiver wellbeing. More high-quality research is needed on support for family caregivers of patients diagnosed with a brain or spinal cord tumour.

The aim of this study was to compare the clinical characteristics of patients with and without abnormal MR imaging admitted to a neurosurgical unit with suspected cauda equina syndrome using a retrospective study of consecutive admissions to a regional neurosurgical unit over a 10-month period. Clinical details were obtained from the case notes. A lumbar spine MR scan to investigate possible cauda equina syndrome was performed in 66 patients. There were no significant differences between those with abnormal imaging (n = 34, 52%) and those with a normal scan (n = 32, 48%) in respect of sex, clinical history or features recorded on examination. Those with normal imaging had a high frequency of weakness (n = 18, 59%), saddle numbness (n = 17, 57%), leg numbness (n = 24, 80%), urinary incontinence (n = 13, 54%) and urinary retention (n = 9, 53%). A large number of patients present to neurosurgical units with symptoms suggestive of cauda equina syndrome without any radiological evidence of structural pathology. While some may have had an alternative organic cause, we propose that these symptoms may have a "functional" origin in many patients.

Patients with primary intrinsic brain tumors can experience neurological, cognitive, and psychiatric symptoms that greatly affect daily life. In this review, we focus on changes in personality and behavior, mood issues, hallucinations, and psychosis, because these are either difficult to recognize, to treat, or are understudied in scientific literature. Neurobehavioral symptoms are common, often multiple, and causation can be multifactorial. Although different symptoms sometimes require a different treatment approach, we advise a comprehensive treatment approach, including pharmacological treatment and/or psychotherapy where appropriate. Further research is needed to obtain a better estimate of the prevalence of psychiatric symptoms in glioma patients, and the extent to which these affect everyday functioning and family life.

Depression is one of the leading causes of global disability, and a considerable hidden morbidity among patients with glioma. In this narrative review, we summarise what is currently known about depression in glioma, the main unanswered questions and the types of studies that should be prioritised in order to find out. We conclude by calling for a prospective Phase II study of antidepressants in depressed glioma patients, to test methodologies for a multicentre randomised controlled trial.

When screening for depression in glioma patients, the utility of proxy carer report is unknown. We studied how patients and proxies differed in the frequency, severity and agreement of reported depressive symptoms, the external validity of these reports, and whether patient-proxy agreement was associated with cognitive function. This was a cross-sectional study within a prospective cohort study of depression in glioma. Eligible patients were adults with a new diagnosis of cerebral glioma whose cohabiting partners chose to attend study interviews. Patients completed the Patient Health Questionnaire-9 (PHQ-9, maximum score 27) to screen for major depressive disorder. Proxies independently completed the PHQ-9 'for the patient'. A structured clinical interview for MDD was then given. From 55 couples attending, 41 participated (74 %). Patient-proxy total PHQ-9 score differed by 3 or more points in 26/41 cases (63.4 %). Disagreement within dyads ranged from -7 to +10 points. Proxies observed more individual depressive symptoms than patients reported (mean 2.7 vs 1.8 symptoms respectively, p = 0.013, Wilcoxon Rank Sum Test), and a greater severity of symptom burden (mean PHQ-9 score 8.4 vs 6.8 respectively, p = 0.016, Wilcoxon Rank Sum Test). Proxies were more reliable than patients on objective behavioural symptoms of depression. Dyadic agreement was not associated with severity of patient cognitive impairment. There was frequent disagreement between glioma patients and proxies reports of depressive symptoms. Proxies reported more depressive symptoms than patients, and were more reliable when reporting observable behavioural symptoms. When diagnosing depression in glioma, collateral history should be obtained.

Purpose There is a need for high-quality evidence regarding the frequency, independent clinical associations, and longitudinal course of depression in patients with cerebral glioma. Patients and Methods This was a twin-center, prospective, observational cohort study with 6-month follow-up. Consenting adults with a new diagnosis of cerebral glioma received the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition to diagnose major depressive disorder (MDD). Interviews occurred shortly after the start of radiotherapy (T1), with follow-up interviews 3 months later (T2) and 6 months later (T3). Independent associations between MDD and clinical variables were analyzed using logistic regression. Results One hundred fifty-five patients participated. The frequency of MDD was 13.5% ± 5.4% at T1 (n = 155); 14.8% ± 6.7% at T2 (n = 108); and 6.8% ± 5.3% at T3 (n = 88). Overall, 32 individuals were diagnosed with MDD during the study period (20.6% ± 6.4%). Inter-rater diagnostic agreement for MDD was good (κ = 0.81; 95% CI, 0.60 to 1.00). Independent predictors of MDD were functional impairment (odds ratio, 3.9; 95% CI, 1.5 to 10.8) and a previous history of depression (odds ratio, 2.7; 95% CI, 0.99 to 7.3). MDD persisted for at least 3 months in half of the patients with adequate follow-up, but many depressed patients also dropped out of the study as a result of clinical deterioration. Conclusion In this longitudinal study, one in five patients with glioma developed clinical depression in the 6 months after starting radiotherapy. Patients with functional impairment or previous depression were at higher risk. MDD often persisted for at least 3 months. Clinicians should seek and treat depression in adults with glioma.

To the Editor:We read Litofsky and Resnick’s timely and useful reviewof depression in brain tumour patients with interest [1]. Theauthors identified screening for depression as an issuerequiring future study. Because screening is often targetedat high-risk groups, it is important to study the risk factorsfor depression in brain tumour patients.The authors state that female gender is a risk factor fordepression in glioma. It is true that some groups have foundwomen with brain tumours to be more likely than men tobecome depressed [2, 3]. However other researchers havenot, including one of the authors of the review [4–6].We sent a questionnaire to the GP of each glioma patienton our hospital database (Edinburgh, UK), asking whethertheir patient had suffered depression both before and sincethe diagnosis of glioma. The diagnosis of depression wasbased on the clinical judgement of each GP. Response ratewas 68% (100/147; 55% male). A pre-glioma (past medi-cal) history of depression was significantly more likely inwomen (12/45 women compared with 3/55 men;P = 0.004, Fisher’s Exact Test). However following gli-oma presentation the sex difference in depression disap-peared and men were equally as likely as women toexperience depression (12/55 and 12/45 respectively;P = 0.64).Female gender is not a proven risk factor for depressionin glioma. Since general population surveys consistentlyreport that depression is twice as common in women [7],studies reporting a more equal sex distribution fordepression in brain tumours may even suggest a relativelyincreased risk for men.We agree that depression in glioma is a fertile field forresearch. For now we suggest that men and women withglioma should be considered at equal risk of developingdepression, and that efforts should therefore be made toinclude them equally in any proposed screeningprogrammes.References

AimsTo identify the frequency and severity of fatigue in adults with cerebral glioma, and its association with anti-epileptic drugs (AED).MethodsCross-sectional study. Stable glioma patients attending Edinburgh Neuro-Oncology clinic completed a fatigue Visual Analogue Scale (range 0-100mm, “high” >=60 mm). AED type and dose were recorded.ResultsOne hundred and sixty six patients were enrolled (61% males; mean age 49 yrs; 70% high-grade glioma). Among all patients, 43% reported high fatigue (95% CI 35–50%). Sixty eight percent were taking AEDs (58% of which were non enzyme inducing). Levetiracetam (LEV) was the most common AED. LEV monotherapy correlated with higher fatigue levels (mean=57 mm, SD 5.2, 95% CI 46–67 mm), compared with other AEDs (mean=43 mm, SD 3.9, 95% CI 35–50 mm, ANCOVA p=0.04). Patients taking LEV had poorer Karnofsky Performance Scores (KPS, Mann–Whitney p=0.03). The effect of LEV on fatigue was independent of KPS (LR pConclusionsGlioma patients on levetiracetam therapy are more fatigued than patients on other or no anti-epileptic therapy. Changes to AED medications may benefit patients with troublesome fatigue.

INTRODUCTION: Fatigue is unusual daytime tiredness not relieved by sleep. It is common and with mixed aetiology in glioma. Annual fatigue assessment in stable patients with glioma is being trialled through a ‘symptoms MDM’ METHOD: Patients aged >18years, diagnosed with a glioma that was clinically stable, and had completed a fatigue study, were offered further clinical evaluation of their results by discussion at a ‘symptoms MDM’. This included a neurologist, clinical psychologist, psychiatrist and sleep consultant. Assessments included self-reported fatigue, mood, cognition, a growth hormone questionnaire, full neurological examination, and 2 week sleep assessment using an Actigraphy Watch and sleep log. RESULTS: 37/50 patients requested further assessment, including 10/10 severely fatigued, 22/24 moderately fatigued, 4/8 mildly fatigued and 1/8 non-fatigued. Of these the HADS depicted 20 patients with abnormal anxiety (8 borderline) and 5 with abnormal depression (11 borderline), 36 had poor cognition in one or more areas, and a sleep consultant reviewed 23 with abnormal sleep.Individual intervention plans included combinations of: referrals to clinical psychology (10), psychiatry (2), endocrinology (17), sleep clinic (5) and anti-epileptic medication review (9). Twelve were offered local support group in formation, and 24 were offered self-guided relaxation and sleep hygiene information. Almost all patients agreed to all interventions; 1 declined clinical psychology referral, 3 declined anti-epileptic review due to regaining a driving licence. CONCLUSION: Fatigue in glioma is common, complex and debilitating, but may be helped by managing symptoms, through annual ‘symptoms MDM’ and individualised treatment plans.

Objective To investigate any association between fatigue and physical impairment/disability in stable cerebral glioma patients. Secondary aims were to explore the association of fatigue severity with sleep problems and depression and distinguishing physical from mental fatigue. Background Fatigue, an abnormal tiredness that negatively impacts daily functioning, is commonly reported in glioma patients and cause may be multi-factorial. It has not been studied in glioma patients. Methods Patients, attending a regional neuro-oncology clinic in Edinburgh, were recruited if they had cerebral glioma, “stable” imaging and were not receiving active treatment. After consent, the Brief Fatigue Inventory, KPS, Kurtzke EDSS, 10Metre Walk test, NHPT, Actiwatch, sleep log, ESS, and the HADs test were completed. Results 38 patients with (WHO grade I-IV) glioma, age range 22–69 year were recruited. Most patients were fatigued (73.7% reported a moderate-severe level). Physical and mental fatigue were equally prevalent and significant correlated. We did not find a significant association between the severity of fatigue and EDSS score or between EDSS and depression. However, an association was found between hours of sleep and fatigue severity. Discussion Assessing fatigue, mood, sleep, and physical status may be useful for better understanding of the needs of brain tumour patients. Although no association was found with physical disability, sleep disturbance where present may be treatable.

Background Brain tumours often cause deficits across multiple cognitive domains. Changes in cognitive function may occur as a result of tumour, treatment or the psychological effects of having cancer. The commonly used mini-mental state examination (MMSE) can be insensitive to cognitive dysfunction and poorly responsive to treatment. The aim of this study was to examine the utility of the Addenbrooke9s Cognitive Examination (ACE), which includes the MMSE, in people with brain tumours. Methods Cognitive assessment was performed using the ACE on 155 people with brain tumours (133 WHO Grade III or IV and 22 WHO Grade I or II). Assessment was performed prior to neuro-surgery and then again after 3 and 6 months. Results Patients found the ACE tolerable and it was a more sensitive test of cognitive dysfunction than the MMSE revealing significant baseline cognitive impairment with 42/155 achieving a score ≤82/100 27%) compared to 10/155 achieving a score of ≤24/30 in the MMSE. Deficits were most commonly identified by tests of verbal fluency and visuospatial abilities. Cognitive impairment was greater in patients with WHO Grade III or IV tumours. Conclusions The utility of the ACE has not been reported in this population. It was well tolerated and is a more sensitive test of cognition than the MMSE.