Clinical implementation of standardized neurocognitive assessment before and after radiation to the brain.

Background: Radiotherapy induced impairment of cognitive function can lead to a reduced quality of life. The aim of this study was to describe the implementation and compliance of standardized neurocognitive assessment. In addition, the first results of cognitive changes for patients receiving a radiation dose to the brain are described. Materials and methods: Patients that received radiation dose to the brain (neuro, head and neck and prophylactic cranial irradiation between April-2019 and Dec-2021 were included. Three neuro cognitive tests were performed a verbal learning and memory test, the Hopkins Verbal Learning Test; a verbal fluency test, the Controlled Oral Word Association Test and a speed and cognitive flexibility test, the Trail Making Test A&B. Tests were performed before the start of radiation, 6 months (6 m) and 1 year (1y) after irradiation. The Reliable Change Index (RCI) between baseline and follow-up was calculated using reference data from literature. Results: 644 patients performed the neurocognitive tests at baseline, 346 at 6 months and 205 at 1y after RT, with compliance rates of 90.4%, 85.6%, and 75.3%, respectively. Reasons for non-compliance were: 1. Patient did not attend appointment (49%), 2. Patient was unable to perform the test due to illness (12%), 3. Patient refused the test (8 %), 4. Various causes, (31%). A semi-automated analysis was developed to evaluate the test results. In total, 26% of patients showed a significant decline in at least one of variables at 1y and 11% on at least 2 variables at 1y. However, an increase in cognitive performance was observed in 49% (≥1 variable) and 22% (≥2 variables). Conclusion: Standardized neurocognitive testing within the radiotherapy clinic was successfully implemented, with a high patient compliance. A semi-automatic method to evaluate cognitive changes after treatment was defined. Data collection is ongoing, long term follow-up (up to 5 years after treatment) and dose-effect analysis will be performed.

Incidence of clinically relevant psychiatric symptoms during glioblastoma treatment: an exploratory study.

PURPOSE: In addition to neurological symptoms glioblastoma (GBM) patients can experience psychiatric complaints, which are often hard to recognize and difficult to treat. Research on psychiatric symptoms during glioblastoma treatment is limited, but can have significant impact on quality of life, treatment processes and even survival. The aim of this study is to explore the incidence of clinically relevant psychiatric symptoms, during glioblastoma treatment and active surveillance. METHODS: Medical records of 302 GBM patients were reviewed from diagnostic surgery until discontinuation of treatment or active surveillance. Clinical relevance was defined as psychiatric symptoms that interfered with the oncological treatment and required referral to a psychiatrist. "Referred" versus "non-referred" GBM patients were compared using the Pearson Chi-Square test, Fisher's Exact Test or Mann Whitney-U test. RESULTS: Psychiatric symptoms occurred in 11.5% of patients during glioblastoma treatment or active surveillance, most often mood or behavioral symptoms, followed by psychotic symptoms. Referral occurred mainly during concomitant chemoradiation or adjuvant chemotherapy (64.3%). In 28.6% of patients psychiatric symptoms were thought to be attributive to medication. Treatment was discontinued in 17.9% of patients and temporarily interrupted in 3.6%. Possible risk factors included male gender, history of psychiatric disorder, postoperative delirium, non-frontal tumor location, anti-epileptic drug use at baseline and corticosteroid initiation during treatment. CONCLUSION: The found incidence of 11.5% and the high number of patients discontinuing treatment due to psychiatric symptoms justify more research in this, to date, understudied topic in scientific literature. Further prospective studies are needed to identify risk factors and unravel possible effects on survival.

Myasthenia gravis after glioblastoma resection: paraneoplastic syndrome or coincidence? A unique case report and review of the literature.

Paraneoplastic neurological syndromes (PNS) can manifest with every type of malignancy. A well-known syndrome is myasthenia gravis (MG) in combination with thymomas. No association between primary brain tumors and neuromuscular disorders has been described. Here, we present a case of a 65-year-old patient who developed MG, following an uncomplicated, gross-total resection of a glioblastoma. To our knowledge, this is the first case describing the onset of MG during the early postoperative phase after glioblastoma resection. Current criteria of PNS are insufficient when the neurological syndrome is diagnosed at the time of a malignancy or shortly thereafter and should be revisited.

Pathogenic neurofibromatosis type 1 (NF1) RNA splicing resolved by targeted RNAseq.

Neurofibromatosis type 1 (NF1) is caused by loss-of-function variants in the NF1 gene. Approximately 10% of these variants affect RNA splicing and are either missed by conventional DNA diagnostics or are misinterpreted by in silico splicing predictions. Therefore, a targeted RNAseq-based approach was designed to detect pathogenic RNA splicing and associated pathogenic DNA variants. For this method RNA was extracted from lymphocytes, followed by targeted RNAseq. Next, an in-house developed tool (QURNAs) was used to calculate the enrichment score (ERS) for each splicing event. This method was thoroughly tested using two different patient cohorts with known pathogenic splice-variants in NF1. In both cohorts all 56 normal reference transcript exon splice junctions, 24 previously described and 45 novel non-reference splicing events were detected. Additionally, all expected pathogenic splice-variants were detected. Eleven patients with NF1 symptoms were subsequently tested, three of which have a known NF1 DNA variant with a putative effect on RNA splicing. This effect could be confirmed for all 3. The other eight patients were previously without any molecular confirmation of their NF1-diagnosis. A deep-intronic pathogenic splice variant could now be identified for two of them (25%). These results suggest that targeted RNAseq can be successfully used to detect pathogenic RNA splicing variants in NF1.

Trajectories of recovery in depressed Parkinson's disease patients treated with paroxetine or venlafaxine.

INTRODUCTION: Depression is considered a syndrome with a constellation of symptoms that are frequently categorized into 3 domains including affective, somatic and cognitive. There has been limited research into the domain specific magnitude or relative timing of treatment response in patients with Parkinson's disease (PD). In addition, antidepressant trials involving patients with PD have demonstrated a similar robust placebo response to that seen in other populations. However, the timing of the placebo response has not been carefully studied. METHODS: We studied differential responses to antidepressant treatment in affective, somatic and cognitive domains of depression. Patients were treated for twelve weeks with placebo, venlafaxine or paroxetine as part of the Study of Antidepressants in Parkinson's Disease (SAD-PD) randomized controlled trial. Depressive symptoms were evaluated with three commonly used rating scales. RESULTS: All symptom domains improved during the study period, There was a significant placebo effect, especially in the first two weeks that had diminished by week 12. Compared to placebo, the affective symptoms significantly improved during treatment as early as week 4, followed by the somatic symptoms of depression in week 6 and cognitive symptoms in week 8. The largest response was seen in the affective domain. CONCLUSION: In depressed PD patients treated with venlafaxine or paroxetine, affective symptoms improved first, followed by somatic symptoms and cognitive symptoms. These findings could guide patient counselling and increase patient compliance by informing about the expected treatment responses. The substantial placebo effect underlines the importance of a sufficiently long study period in future studies.

Factor analysis of the Hamilton Depression Rating Scale in Parkinson's disease.

INTRODUCTION: Several studies have validated the Hamilton Depression Rating Scale (HAMD) in patients with Parkinson's disease (PD), and reported adequate reliability and construct validity. However, the factorial validity of the HAMD has not yet been investigated. The aim of our analysis was to explore the factor structure of the HAMD in a large sample of PD patients. METHODS: A principal component analysis of the 17-item HAMD was performed on data of 341 PD patients, available from a previous cross sectional study on anxiety. An eigenvalue ≥1 was used to determine the number of factors. Factor loadings ≥0.4 in combination with oblique rotations were used to identify which variables made up the factors. Kaiser-Meyer-Olkin measure (KMO), Cronbach's alpha, Bartlett's test, communality, percentage of non-redundant residuals and the component correlation matrix were computed to assess factor validity. RESULTS: KMO verified the sample's adequacy for factor analysis and Cronbach's alpha indicated a good internal consistency of the total scale. Six factors had eigenvalues ≥1 and together explained 59.19% of the variance. The number of items per factor varied from 1 to 6. Inter-item correlations within each component were low. There was a high percentage of non-redundant residuals and low communality. CONCLUSION: This analysis demonstrates that the factorial validity of the HAMD in PD is unsatisfactory. This implies that the scale is not appropriate for studying specific symptom domains of depression based on factorial structure in a PD population.