Cerebellar-Induced Aphasia After Stroke: Evidence for the "Linguistic Cerebellum".

The cerebellum is traditionally known to subserve motor functions. However, for several decades, the concept of the "cerebellar cognitive affective syndrome" has evolved. Studies in healthy participants and patients have confirmed the cerebellar role in language. The exact involvement of the cerebellum regarding cerebellar aphasia remains uncertain. We included 43 cerebellar stroke patients who were tested at 3 months post-onset with the Boston Naming Test (BNT), the Token Test (TT), and the Diagnostic Instrument for Mild Aphasia (DIMA). Lesion side (left/right) and volume (cm3) were investigated. Patients significantly deviated on the following: BNT (p<0.001), TT (p<0.05), DIMA subtests: sentences repetition (p=0.001), semantic odd-picture-out (p<0.05), sentence completion (p<0.05) without an effect of lesion location (left/right) or volume (cm3) (p>0.05). Our clinical study confirms a non-lateralized cerebellar aphasia post-stroke, characterized by impairments in word retrieval, phonology, semantics, and syntax resembling cerebral-induced aphasia. The integral cerebellum appears to interact with eloquent cortico-subcortical language areas.

Cognition and health-related quality of life in long-term survivors of high-grade glioma: an interactive perspective from patient and caregiver.

BACKGROUND: The health-related quality of life (HRQoL) and cognition are important indicators for the quality of survival in patients with high-grade glioma (HGG). However, data on long-term survivors and their caregivers are scarce. We aim to investigate the interaction between cognition and HRQoL in long-term survivors, their caregivers' evaluations, and the effect on caregiver strain and burden. METHODS: 21 long-term HGG (8 WHO grade III and 13 WHO grade IV) survivors (survival ≥ 5 years) and 15 caregivers were included. Cognition (verbal memory, attention, executive functioning, and language), HRQoL, anxiety and depression, caregiver strain, and caregiver burden were assessed with standardized measures. Questionnaires were completed by patients and/or their caregivers. RESULTS: Mean survival was 12 years (grade III) and 8 years (grade IV). Cognition was significantly impaired with a large individual variety. Patients' general HRQoL was not impaired but all functioning scales were deviant. Patient-proxy agreement was found in most HRQoL subscales. Three patients (14%) showed indications of anxiety or depression. One-third of the caregivers reported a high caregiver strain or a high burden. Test scores for attention, executive functioning, language, and/or verbal memory were correlated with perceived global health status, cognitive functioning, and/or communication deficits. Caregiver burden was not related to cognitive deficits. CONCLUSIONS: In long-term HGG survivors maintained HRQoL seems possible even when cognition is impaired in a large variety at the individual level. A tailored approach is therefore recommended to investigate the cognitive impairments and HRQoL in patients and the need for patient and caregiver support.

The CODECS study: COgnitive DEficits in Cerebellar Stroke.

Part of the extra-pyramidal system, the cerebellum is more and more recognized by its non-motor functions known as the cerebellar cognitive affective syndrome. Several studies have identified disturbances specifically in executive and attentional functions after focal cerebellar lesions. However, most studies were performed in small and heterogeneous patient groups. Furthermore, there is a substantial variation in the methodology of assessment. Here, we present the results of a large and homogeneous cohort of patients with isolated uniform cerebellar lesions. After three months post-stroke all patients underwent structural neuroimaging to confirm an isolated lesion and were given neuropsychological testing. The results show that cerebellar lesions relate to mild but long-term cognitive impairment in a broad spectrum of neurocognitive functions compared to normative values. These findings confirm involvement of the cerebellum in cognitive processing and supports the theory of 'dysmetria of thought' based upon uniform cerebellar processing in multiple cognitive domains. This study highlights the following results: 1-Cognitive impairments after isolated cerebellar stroke is confirmed in several cognitive domains. 2-Semantic and phonemic fluency are most affected in cerebellar stroke patients. 3-Verbal deficits show an age-independent long term effect post-stroke and should be studied further in depth. 4-Cognitive disorders after cerebellar stroke are more prominent in women than men.

Localization patterns of speech and language errors during awake brain surgery: a systematic review.

Awake craniotomy with direct electrical stimulation (DES) is the standard treatment for patients with eloquent area gliomas. DES detects speech and language errors, which indicate functional boundaries that must be maintained to preserve quality of life. During DES, traditional object naming or other linguistic tasks such as tasks from the Dutch Linguistic Intraoperative Protocol (DuLIP) can be used. It is not fully clear which speech and language errors occur in which brain locations. To provide an overview and to update DuLIP, a systematic review was conducted in which 102 studies were included, reporting on speech and language errors and the corresponding brain locations during awake craniotomy with DES in adult glioma patients up until 6 July 2020. The current findings provide a crude overview on language localization. Even though subcortical areas are in general less often investigated intraoperatively, still 40% out of all errors was reported at the subcortical level and almost 60% at the cortical level. Rudimentary localization patterns for different error types were observed and compared to the dual-stream model of language processing and the DuLIP model. While most patterns were similar compared to the models, additional locations were identified for articulation/motor speech, phonology, reading, and writing. Based on these patterns, we propose an updated DuLIP model. This model can be applied for a more adequate "location-to-function" language task selection to assess different linguistic functions during awake craniotomy, to possibly improve intraoperative language monitoring. This could result in a better postoperative language outcome in the future.

Effect of awake craniotomy in glioblastoma in eloquent areas (GLIOMAP): a propensity score-matched analysis of an international, multicentre, cohort study.

BACKGROUND: Awake mapping has been associated with decreased neurological deficits and increased extent of resection in eloquent glioma resections. However, its effect within clinically relevant glioblastoma subgroups remains poorly understood. We aimed to assess the benefit of this technique in subgroups of patients with glioblastomas based on age, preoperative neurological morbidity, and Karnofsky Performance Score (KPS). METHODS: In this propensity score-matched analysis of an international, multicentre, cohort study (GLIOMAP), patients were recruited at four tertiary centres in Europe (Erasmus MC, Rotterdam and Haaglanden MC, The Hague, Netherlands, and UZ Leuven, Leuven, Belgium) and the USA (Brigham and Women's Hospital, Boston, MA). Patients were eligible if they were aged 18-90 years, undergoing resection, had a histopathological diagnosis of primary glioblastoma, their tumour was in an eloquent or near-eloquent location, and they had a unifocal enhancing lesion. Patients either underwent awake mapping during craniotomy, or asleep resection, as per treating physician or multidisciplinary tumour board decision. We used propensity-score matching (1:3) to match patients in the awake group with those in the asleep group to create a matched cohort, and to match patients from subgroups stratified by age (<70 years vs ≥70 years), preoperative National Institute of Health Stroke Scale (NIHSS) score (score of 0-1 vs ≥2), and preoperative KPS (90-100 vs ≤80). We used Cox proportional hazard regressions to analyse the effect of awake mapping on the primary outcomes including postoperative neurological deficits (measured by deterioration in NIHSS score at 6 week, 3 months, and 6 months postoperatively), overall survival, and progression-free survival. We used logistic regression to analyse the predictive value of awake mapping and other perioperative factors on postoperative outcomes. FINDINGS: Between Jan 1, 2010, and Oct 31, 2020, 3919 patients were recruited, of whom 1047 with tumour resection for primary eloquent glioblastoma were included in analyses as the overall unmatched cohort. After propensity-score matching, the overall matched cohort comprised 536 patients, of whom 134 had awake craniotomies and 402 had asleep resection. In the overall matched cohort, awake craniotomy versus asleep resection resulted in fewer neurological deficits at 3 months (26 [22%] of 120 vs 107 [33%] of 323; p=0·019) and 6 months (30 [26%] of 115 vs 125 [41%] of 305; p=0·0048) postoperatively, longer overall survival (median 17·0 months [95% CI 15·0-24·0] vs 14·0 months [13·0-16·0]; p=0·00054), and longer progression-free survival (median 9·0 months [8·0-11·0] vs 7·3 months [6·0-8·8]; p=0·0060). In subgroup analyses, fewer postoperative neurological deficits occurred at 3 months and at 6 months with awake craniotomy versus asleep resection in patients younger than 70 years (3 months: 22 [21%] of 103 vs 93 [34%] of 272; p=0·016; 6 months: 24 [24%] of 101 vs 108 [42%] of 258; p=0·0014), those with an NIHSS score of 0-1 (3 months: 22 [23%] of 96 vs 97 [38%] of 254; p=0·0071; 6 months: 27 [28%] of 95 vs 115 [48%] of 239; p=0·0010), and those with a KPS of 90-100 (3 months: 17 [19%] of 88 vs 74 [35%] of 237; p=0·034; 6 months: 24 [28%] of 87 vs 101 [45%] of 223, p=0·0043). Additionally, fewer postoperative neurological deficits were seen in the awake group versus the asleep group at 3 months in patients aged 70 years and older (two [13%] of 16 vs 15 [43%] of 35; p=0·033; no difference seen at 6 months), with a NIHSS score of 2 or higher (3 months: three [13%] of 23 vs 21 [36%] of 58; p=0·040) and at 6 months in those with a KPS of 80 or lower (five [18%] of 28 vs 34 [39%] of 88; p=0·043; no difference seen at 3 months). Median overall survival was longer for the awake group than the asleep group in the subgroups younger than 70 years (19·5 months [95% CI 16·0-31·0] vs 15·0 months [13·0-17·0]; p<0·0001), an NIHSS score of 0-1 (18·0 months [16·0-31·0] vs 14·0 months [13·0-16·5]; p=0·00047), and KPS of 90-100 (19·0 months [16·0-31·0] vs 14·5 months [13·0-16·5]; p=0·00058). Median progression-free survival was also longer in the awake group than in the asleep group in patients younger than 70 years (9·3 months [95% CI 8·0-12·0] vs 7·5 months [6·5-9·0]; p=0·0061), in those with an NIHSS score of 0-1 (9·5 months [9·0-12·0] vs 8·0 months [6·5-9·0]; p=0·0035), and in those with a KPS of 90-100 (10·0 months [9·0-13·0] vs 8·0 months [7·0-9·0]; p=0·0010). No difference was seen in overall survival or progression-free survival between the awake group and the asleep group for those aged 70 years and older, with NIHSS scores of 2 or higher, or with a KPS of 80 or lower. INTERPRETATION: These data might aid neurosurgeons with the assessment of their surgical strategy in individual glioblastoma patients. These findings will be validated and further explored in the SAFE trial (NCT03861299) and the PROGRAM study (NCT04708171). FUNDING: None.

The feasibility and added value of mapping music during awake craniotomy: A systematic review.

The value of mapping musical function during awake craniotomy is unclear. Hence, this systematic review was conducted to examine the feasibility and added value of music mapping in patients undergoing awake craniotomy. An extensive search, on 26 March 2021, in four electronic databases (Medline, Embase, Web of Science and Cochrane CENTRAL register of trials), using synonyms of the words "Awake Craniotomy" and "Music Performance," was conducted. Patients performing music while undergoing awake craniotomy were independently included by two reviewers. This search resulted in 10 studies and 14 patients. Intra-operative mapping of musical function was successful in 13 out of 14 patients. Isolated music disruption, defined as disruption during music tasks with intact language/speech and/or motor functions, was identified in two patients in the right superior temporal gyrus, one patient in the right and one patient in the left middle frontal gyrus and one patient in the left medial temporal gyrus. Pre-operative functional MRI confirmed these localizations in three patients. Assessment of post-operative musical function, only conducted in seven patients by means of standardized (57%) and non-standardized (43%) tools, report no loss of musical function. With these results, we conclude that mapping music is feasible during awake craniotomy. Moreover, we identified certain brain regions relevant for music production and detected no decline during follow-up, suggesting an added value of mapping musicality during awake craniotomy. A systematic approach to map musicality should be implemented, to improve current knowledge on the added value of mapping musicality during awake craniotomy.

DIMA-fr: a French adaptation and standardization of the Dutch Diagnostic Instrument for Mild Aphasia (DIMA-nl).

The Dutch Diagnostic Instrument for Mild Aphasia (DIMA-nl) is a standardized battery recently created for evaluating the language performance of patients during the perioperative period of glioma surgery. Our aim was to establish normative data for the DIMA-fr, a French version of the DIMA-nl. The DIMA-nl was first adapted to French. The 14 subtasks of the DIMA-fr were then administered to 391 participants recruited from the general French population. The effects of sex, age and level of education were determined by analysis of variance (ANOVA). Normative data were computed as means, medians, standard deviations and percentiles. Our results demonstrated that age and level of education had an effect on the performance of all subtests but not sex. We thus stratified the norms into four different groups: (i) 18-69 years-old with Baccalauréat (Bac, the French High School Diploma) (n = 246); (ii) 18-69 years-old without Bac (n = 70); (iii) >70 years-old with Bac (n = 48); (iv) >70 years-old without Bac (n = 27). The DIMA-fr is thus the first standardized French battery of tests to specifically assess language during the perioperative period of awake glioma surgery. However, to be used in the clinic, the DIMA-fr must now be validated in patients. The DIMA, which is currently standardized in several languages, could become a reference tool for international studies.

Dutch Diagnostic Instrument for Mild Aphasia (DIMA): standardisation and a first clinical application in two brain tumour patients.

Brain tumour patients with mild language disturbances are typically underdiagnosed due to lack of sensitive tests leading to negative effects in daily communicative and social life. We aim to develop a Dutch standardised test-battery, the Diagnostic Instrument for Mild Aphasia (DIMA) to detect characteristics of mild aphasia at the main linguistic levels phonology, semantics and (morpho-)syntax in production and comprehension. We designed 4 DIMA subtests: 1) repetition (words, non-words, compounds and sentences), 2) semantic odd-picture-out (objects and actions), 3) sentence completion and 4) sentence judgment (accuracy and reaction time). A normative study was carried out in a healthy Dutch-speaking population (N = 211) divided into groups of gender, age and education. Clinical application of DIMA was demonstrated in two brain tumour patients (glioma and meningioma). Standard language tests were also administered: object naming, verbal fluency (category and letter), and Token Test. Performance was at ceiling on all sub-tests, except semantic odd-picture-out actions, with an effect of age and education on most subtests. Clinical application DIMA: repetition was impaired in both cases. Reaction time in the sentence judgment test (phonology and syntax) was impaired (not accuracy) in one patient. Standard language tests: category fluency was impaired in both cases and object naming in one patient. The Token Test was not able to detect language disturbances in both cases. DIMA seems to be sensitive to capture mild aphasic deficits. DIMA is expected to be of great potential for standard assessment of language functions in patients with also other neurological diseases than brain tumours.

eHealth cognitive rehabilitation for brain tumor patients: results of a randomized controlled trial.

BACKGROUND: Evidence-based cognitive rehabilitation programs for brain tumor patients are not widely available, despite the high need. We aimed to evaluate the effects of a tablet-based cognitive rehabilitation program on cognitive performance, cognitive complaints, fatigue, and psychological distress in primary brain tumor patients following neurosurgery. Also, attrition, adherence and patient satisfaction with the program were evaluated. METHODS: Adults with presumed low-grade glioma and meningioma were recruited before surgery. Three months thereafter, participants were allocated to the intervention group or waiting-list control group using minimization. The 10-week eHealth app ReMind, based on the effective face-to-face intervention, consisted of psychoeducation, strategy-training and attention retraining. Performance-based cognitive outcomes and patient-reported outcomes were assessed before surgery and 3, 6 and 12 months thereafter. Mean scores, percentages of cognitively impaired individuals and reliable change indices (RCIs) were compared between groups. RESULTS: Sixty-two out of 183 eligible patients were randomized. Of the people who declined, 56% reported that participation would to be too burdensome. All participants found a tablet-app suitable for delivery of cognitive rehabilitation and 90% rated the program as "good" or "excellent". Performance-based cognitive outcomes and patient-reported outcomes did not significantly differ in group means over time nor RCIs between the intervention (final n = 20) and control group (final n = 25). CONCLUSIONS: Recruitment at this early stage was difficult, resulting in limited statistical power. No significant effects were demonstrated, while adherence and satisfaction with the eHealth program were good. In clinical practice, ReMind may be helpful, if timing would be adapted to patients' needs.

Augmented reality for the virtual dissection of white matter pathways.

BACKGROUND: The human white matter pathway network is complex and of critical importance for functionality. Thus, learning and understanding white matter tract anatomy is important for the training of neuroscientists and neurosurgeons. The study aims to test and evaluate a new method for fiber dissection using augmented reality (AR) in a group which is experienced in cadaver white matter dissection courses and in vivo tractography. METHODS: Fifteen neurosurgeons, neurolinguists, and neuroscientists participated in this questionnaire-based study. We presented five cases of patients with left-sided perisylvian gliomas who underwent awake craniotomy. Diffusion tensor imaging fiber tracking (DTI FT) was performed and the language-related networks were visualized separated in different tracts by color. Participants were able to virtually dissect the prepared DTI FTs using a spatial computer and AR goggles. The application was evaluated through a questionnaire with answers from 0 (minimum) to 10 (maximum). RESULTS: Participants rated the overall experience of AR fiber dissection with a median of 8 points (mean ± standard deviation 8.5 ± 1.4). Usefulness for fiber dissection courses and education in general was rated with 8 (8.3 ± 1.4) and 8 (8.1 ± 1.5) points, respectively. Educational value was expected to be high for several target audiences (student: median 9, 8.6 ± 1.4; resident: 9, 8.5 ± 1.8; surgeon: 9, 8.2 ± 2.4; scientist: 8.5, 8.0 ± 2.4). Even clinical application of AR fiber dissection was expected to be of value with a median of 7 points (7.0 ± 2.5). CONCLUSION: The present evaluation of this first application of AR for fiber dissection shows a throughout positive evaluation for educational purposes.

Language assessment in awake brain surgery: the Portuguese adaptation of the Dutch linguistic intraoperative protocol (DuLIP).

Awake brain surgery, combined with neurophysiological evaluation and intraoperative mapping, is one of the preferential lines of treatment when approaching low-grade gliomas. Speech and language assessment is used while applying Direct Electrical Stimulation (DES) and during the resection of a lesion/tumour, as it allows to establish related eloquent areas and optimise the extent of the resection and avoid impairments. Patients need to be assessed pre, intra and post-surgery, but in under resourced countries such as Portugal, there are still no standardised and validated tools to conduct this type of evaluation. To address this need, the tasks of the Dutch Linguistic Intraoperative Protocol (DuLIP) were adapted to European Portuguese, and the resulting materials were standardised for a group of 144 Portuguese participants. For each task, the impact of age, gender and schooling were measured. The resulting Portuguese version of the DuLIP (DuLIP-EP) consists of 17 tasks, including phonological, syntactic, semantic, naming and articulatory tests. No significant differences were found between male and female participants. However, schooling influenced phonological and syntactic fluency, object naming and verb generation. Schooling and age had a significant impact on semantic fluency and reading with semantic odd word out tasks. This is the first contribution to the standardisation of a tool that can be used during an awake brain surgery in Portugal, which includes a new phonological odd word out task that is not currently available in the Dutch version.

Survey on current cognitive practices within the European Low-Grade Glioma Network: towards a European assessment protocol.

BACKGROUND: The European Low-Grade Glioma network indicated a need to better understand common practices regarding the managing of diffuse low-grade gliomas. This area has experienced great advances in recent years. METHOD: A general survey on the managing of diffuse low-grade gliomas was answered by 21 centres in 11 European countries. Here we focused on specific questions regarding perioperative and intraoperative cognitive assessments. RESULTS: More centres referred to the same speech and language therapist and/or neuropsychologist across all assessments; a core of assessment tools was routinely used across centres; fluency tasks were commonly used in the perioperative stages, and object naming during surgery; tasks that tapped on attention, executive functions, visuospatial awareness, calculation and emotions were sparsely administered; preoperative assessments were performed 1 month or 1 week before surgery; timing for postoperative assessments varied; finally, more centres recommended early rehabilitation, whenever needed. CONCLUSIONS: There is an emerging trend towards following similar practices for the management of low-grade gliomas in Europe. Our results are descriptive and formalise current discussions in our group. Also, they contribute towards the development of a European assessment protocol.

Glioma surgery in eloquent areas: can we preserve cognition?

BACKGROUND: Cognitive preservation is crucial in glioma surgery, as it is an important aspect of daily life functioning. Several studies claimed that surgery in eloquent areas is possible without causing severe cognitive damage. However, this conclusion was relatively ungrounded due to the lack of extensive neuropsychological testing in homogenous patient groups. In this study, we aimed to elucidate the short-term and long-term effects of glioma surgery on cognition by identifying all studies who conducted neuropsychological tests preoperatively and postoperatively in glioma patients. METHODS: We systematically searched the electronical databases Embase, Medline OvidSP, Web of Science, PsychINFO OvidSP, PubMed, Cochrane, Google Scholar, Scirius and Proquest aimed at cognitive performance in glioma patients preoperatively and postoperatively. RESULTS: We included 17 studies with tests assessing the cognitive domains: language, memory, attention, executive functions and/or visuospatial abilities. Language was the domain most frequently examined. Immediately postoperatively, all studies except one, found deterioration in one or more cognitive domains. In the longer term (3-6/6-12 months postoperatively), the following tests showed both recovery and deterioration compared with the preoperative level: naming and verbal fluency (language), verbal word learning (memory) and Trailmaking B (executive functions). CONCLUSIONS: Cognitive recovery to the preoperative level after surgery is possible to a certain extent; however, the results are too arbitrary to draw definite conclusions and not all studies investigated all cognitive domains. More studies with longer postoperative follow-up with tests for cognitive change are necessary for a better understanding of the conclusive effects of glioma surgery on cognition.

Long-term evaluation of cognition after glioma surgery in eloquent areas.

Preservation of cognition is an important outcome measure in eloquent area glioma surgery. Glioma patients may have pre-operative deficits in one or more cognitive domains which could deteriorate post-operatively. It is assumed that these impairments recover within 3 months; some studies however, still detected cognitive decline. Longer follow-up is necessary to elucidate the conclusive effects of surgery. 45 patients with gliomas (low- and high-grade, but without contrast enhancement at diagnosis) in eloquent areas were assessed pre-operatively, 3 months and 1 year post-operatively with a neuropsychological test-protocol. Patients' performance was compared to normal population and between test-moments. Univariate analyses were performed between cognitive change and tumor-characteristics (localization, grade, volume, extent of resection [EOR]) and treatment-related factors (radio-/chemotherapy). Pre- and post-operatively, impairments were found in all cognitive domains; language, memory, attention and executive functions (p < 0.05). Post-operatively, permanent improvement was observed on a memory test (verbal recall: t = -1.931, p = 0.034), whereas deterioration was found on a language test (category fluency: t = 2.517, p = 0.030). Between 3 months and 1 year, patients improved on 2 language tests (naming: t = -2.781, p = 0.026 and letter fluency: t = -1.975, p = 0.047). There was no influence of tumor- or treatment-related factors on cognitive change. The findings underline the importance of cognitive testing at longer term post-operatively, as cognitive recovery took longer than 3 months, especially within the language domain. However, this longitudinal follow-up study showed that glioma surgery is possible without major long-term damage of cognitive functions. Tumor characteristics and EOR are no additional risk factors for cognitive outcome.

Dynamic aphasia following low-grade glioma surgery near the supplementary motor area: a selective spontaneous speech deficit.

We describe a patient (KO) with reduced spontaneous speech, resembling dynamic aphasia, after awake glioma surgery in the proximity of the supplementary motor area. Naming, repetition, and comprehension were intact. He was tested with an extensive neuropsychological test-battery and a protocol for dynamic aphasia at 1 year. He presented with postoperative reduced spontaneous speech and selective executive function deficits. Most language recovery took place at 3 months postoperatively, whereas the executive functions improved between 3 months and 1 year. Results suggest that resection near the supplementary motor area could increase the risk of cognitive disturbances at long term, especially language.

Differential contribution of language and executive functioning to verbal fluency performance in glioma patients.

Glioma patients often suffer from deficits in language and executive functioning. Performance in verbal fluency (generating words within one minute according to a semantic category-category fluency, or given letter-letter fluency) is typically impaired in this patient group. While both language and executive functioning play a role in verbal fluency, the relative contribution of both domains remains unclear. We aim to retrospectively investigate glioma patients' performance on verbal and nonverbal fluency and to explore the influence of language and executive functioning on verbal fluency. Sixty-nine adults with gliomas in eloquent areas underwent a neuropsychological test battery (verbal fluency, nonverbal fluency, language, and executive functioning tests) before surgery (T1) and a subgroup of 31 patients also at three (T2) and twelve months (T3) after surgery. Preoperatively, patients were impaired in all verbal fluency tasks and dissociations were found based on tumour location. In contrast, nonverbal fluency was intact. Different language and executive functioning tests predicted performance on category fluency animals and letter fluency, while no significant predictors for category fluency professions were found. The longitudinal results indicated that category fluency professions deteriorated after surgery (T1-T2, T1-T3) and that nonverbal fluency improved after surgery (T1-T3, T2-T3). Verbal fluency performance can provide information on different possible underlying deficits in language and executive functioning in glioma patients, depending on verbal fluency task selection. Efficient task (order) selection can be based on complexity. Category fluency professions can be selected to detect more permanent long-term deficits.

SUPRAMAX-study: supramaximal resection versus maximal resection for glioblastoma patients: study protocol for an international multicentre prospective cohort study (ENCRAM 2201).

INTRODUCTION: A greater extent of resection of the contrast-enhancing (CE) tumour part has been associated with improved outcomes in glioblastoma. Recent results suggest that resection of the non-contrast-enhancing (NCE) part might yield even better survival outcomes (supramaximal resection, SMR). Therefore, this study evaluates the efficacy and safety of SMR with and without mapping techniques in high-grade glioma (HGG) patients in terms of survival, functional, neurological, cognitive and quality of life outcomes. Furthermore, it evaluates which patients benefit the most from SMR, and how they could be identified preoperatively. METHODS AND ANALYSIS: This study is an international, multicentre, prospective, two-arm cohort study of observational nature. Consecutive glioblastoma patients will be operated with SMR or maximal resection at a 1:1 ratio. Primary endpoints are (1) overall survival and (2) proportion of patients with National Institute of Health Stroke Scale deterioration at 6 weeks, 3 months and 6 months postoperatively. Secondary endpoints are (1) residual CE and NCE tumour volume on postoperative T1-contrast and FLAIR (Fluid-attenuated inversion recovery) MRI scans; (2) progression-free survival; (3) receipt of adjuvant therapy with chemotherapy and radiotherapy; and (4) quality of life at 6 weeks, 3 months and 6 months postoperatively. The total duration of the study is 5 years. Patient inclusion is 4 years, follow-up is 1 year. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethics Committee (METC Zuid-West Holland/Erasmus Medical Center; MEC-2020-0812). The results will be published in peer-reviewed academic journals and disseminated to patient organisations and media.

Spontaneous speech of patients with gliomas in eloquent areas before and early after surgery.

BACKGROUND: Glioma patients often complain about problems in daily conversation. A detailed spontaneous speech analysis could provide more insight in these communicative problems; no previous studies are reported. OBJECTIVE: To select sensitive parameters in spontaneous speech pre- and post-operatively in patients with gliomas in eloquent areas. METHODS: We included 27 patients and 21 healthy controls. In addition to a naming and category fluency test, spontaneous speech was collected 1 month pre-operatively and 3 months post-operatively, and analysed with the variables: Self-corrections, Repetitions, Lexical Diversity, Incomplete Sentences and Mean Length of Utterance (MLUw). A correlation analysis was performed between the linguistic variables and tumour characteristics (grade, localisation and volume), treatment related factors, and between the linguistic variables and the language tasks. RESULTS: Pre-operatively, patients produced more Incomplete Sentences than the controls (p < 0.001). Post-operatively, patients' utterance length (MLUw) (p < 0.05) was also deviant. The quality of the spontaneous speech was influenced by tumour grade and localisation. There was no influence of tumour volume or treatment-related factors. Pre- and post-operatively, patients' performance on the naming and the fluency task deviated from normal (p < 0.001). The majority of the linguistic variables did not correlate with the language tasks, pointing to a measurement of distinct linguistic aspects. CONCLUSION: Pre- and post-operatively there was a disorder in naming, category fluency and spontaneous speech, partly influenced by tumour characteristics. A spontaneous speech analysis appeared to be a valuable addition to standardised language tasks. Both measurements are important tools to obtain a complete linguistic profile.

Longitudinal changes in qualitative aspects of semantic fluency in presymptomatic and prodromal genetic frontotemporal dementia.

BACKGROUND: The semantic fluency test is one of the most widely used neuropsychological tests in dementia diagnosis. Research utilizing the qualitative, psycholinguistic information embedded in its output is currently underexplored in presymptomatic and prodromal genetic FTD. METHODS: Presymptomatic MAPT (n = 20) and GRN (n = 43) mutation carriers, and controls (n = 55) underwent up to 6 years of neuropsychological assessment, including the semantic fluency test. Ten mutation carriers became symptomatic (phenoconverters). Total score and five qualitative fluency measures (lexical frequency, age of acquisition, number of clusters, cluster size, number of switches) were calculated. We used multilevel linear regression modeling to investigate longitudinal decline. We assessed the co-correlation of the qualitative measures at each time point with principal component analysis. We explored associations with cognitive decline and grey matter atrophy using partial correlations, and investigated classification abilities using binary logistic regression. RESULTS: The interrater reliability of the qualitative measures was good (ICC = 0.75-0.90). There was strong co-correlation between lexical frequency and age of acquisition, and between clustering and switching. At least 4 years pre-phenoconversion, GRN phenoconverters had fewer but larger clusters (p < 0.001), and fewer switches (p = 0.004), correlating with lower executive function (r = 0.87-0.98). Fewer switches was predictive of phenoconversion, correctly classifying 90.3%. Starting at least 4 years pre-phenoconversion, MAPT phenoconverters demonstrated an increase in lexical frequency (p = 0.009) and a decline in age of acquisition (p = 0.034), correlating with lower semantic processing (r = 0.90). Smaller cluster size was predictive of phenoconversion, correctly classifying 89.3%. Increase in lexical frequency and decline in age of acquisition were associated with grey matter volume loss of predominantly temporal areas, while decline in the number of clusters, cluster size, and switches correlated with grey matter volume loss of predominantly frontal areas. CONCLUSIONS: Qualitative aspects of semantic fluency could give insight into the underlying mechanisms as to why the "traditional" total score declines in the different FTD mutations. However, the qualitative measures currently demonstrate more fluctuation than the total score, the measure that seems to most reliably deteriorate with time. Replication in a larger sample of FTD phenoconverters is warranted to identify if qualitative measures could be sensitive cognitive biomarkers to identify and track mutation carriers converting to the symptomatic stage of FTD.

Neuropsychiatric adverse effects of synthetic glucocorticoids: A systematic review and meta-analysis.

BACKGROUND: Synthetic glucocorticoids are widely used among patients suffering from a wide range of diseases. Glucocorticoids are very efficacious, but can be accompanied by neuropsychiatric adverse effects. This systematic review and meta-analysis assesses and quantifies the proportion of different neuropsychiatric adverse effects in patients using synthetic glucocorticoids. METHODS: Six electronic databases were searched to identify potentially relevant studies. Randomized controlled trials, cohort and cross-sectional studies assessing psychiatric side effects of glucocorticoids measured with validated questionnaires were eligible. Risk of bias was assessed with RoB 2, ROBINS-I, and AXIS appraisal tool. For proportions of neuropsychiatric outcomes, we pooled proportions, and when possible, differences in questionnaire scores between glucocorticoid users and non-users were expressed as standardized mean differences (SMD). Data were pooled in a random-effects logistic regression model. RESULTS: We included 49 studies with heterogeneity in study populations, type, dose, and duration of glucocorticoids. For glucocorticoid users, meta-analysis showed a proportion of 22% for depression (95%CI 14%-33%), 11% for mania (95%CI 2%-46%), 8% for anxiety (95%CI 2%-25%), 16% for delirium (95%CI 6%-36%), and 52% for behavioural changes (95%CI 42%-61%). Questionnaire scores for depression (SMD of 0.80 (95%CI 0.35-1.26)), and mania (0.78 (95%CI 0.14-1.42)) were higher than in controls, indicating more depressive and manic symptoms following glucocorticoid use. CONCLUSIONS: The heterogeneity of glucocorticoid use is reflected in the available studies. Despite this heterogeneity, the proportion of neuropsychiatric adverse effects in glucocorticoid users is high. The most substantial associations with glucocorticoid use were found for depression and mania. Upon starting glucocorticoid treatment, awareness of possible psychiatric side effects is essential. More structured studies on incidence and potential pathways of neuropsychiatric side effects of prescribed glucocorticoids are clearly needed.