Late-onset vascular complications of radiotherapy for primary brain tumors: a case-control and cross-sectional analysis.

PURPOSE: Radiotherapy (RT) is a recognized risk factor for cerebrovascular (CV) disease in children and in adults with head and neck cancer. We aimed to investigate whether cerebral RT increases the risk of CV disease in adults with primary brain tumors (PBT). METHODS: We retrospectively identified adults with a supratentorial PBT diagnosed between 1975 and 2006 and with at least 10 years follow-up after treatment. We analyzed demographic, clinical, and radiological features with special attention to CV events. We also described CV events, vascular risk factors, and intracranial artery modifications in a cross-sectional study of irradiated patients alive at the time of the study. RESULTS: A total of 116 patients, treated with RT (exposed group), and 85 non-irradiated patients (unexposed group) were enrolled. Stroke was more frequent in irradiated PBT patients than in the unexposed group (42/116 (36%) vs 7/85 (8%); p < 0.001), with higher prevalence of both ischemic (27/116 (23%) vs 6/85 (7%); p = 0.004) and hemorrhagic (12/116 (10%) vs 1/85 (1%); p = 0.02) stroke. In the irradiated group, patients with tumors near the Willis Polygon were more likely to experience stroke (p < 0.016). Fourty-four alive irradiated patients were included in the cross-sectional study. In this subgroup, intracranial arterial stenosis was more prevalent (11/45, 24%) compared to general population (9%). CONCLUSIONS: Stroke prevalence is increased in long-surviving PBT patients treated with cranial RT. IMPLICATIONS FOR CANCER SURVIVORS: CV events are frequent in long survivors of PBT treated with cerebral RT. We propose a check list to guide management of late CV complications in adults treated with RT for PBT.

White matter tracts and executive functions: a review of causal and correlation evidence.

Executive functions are high-level cognitive processes involving abilities such as working memory/updating, set-shifting and inhibition. These complex cognitive functions are enabled by interactions among widely distributed cognitive networks, supported by white matter tracts. Executive impairment is frequent in neurological conditions affecting white matter; however, whether specific tracts are crucial for normal executive functions is unclear. We review causal and correlation evidence from studies that used direct electrical stimulation during awake surgery for gliomas, voxel-based and tract-based lesion-symptom mapping, and diffusion tensor imaging to explore associations between the integrity of white matter tracts and executive functions in healthy and impaired adults. The corpus callosum was consistently associated with all executive processes, notably its anterior segments. Both causal and correlation evidence showed prominent support of the superior longitudinal fasciculus to executive functions, notably to working memory. More specifically, strong evidence suggested that the second branch of the superior longitudinal fasciculus is crucial for all executive functions, especially for flexibility. Global results showed left lateralization for verbal tasks and right lateralization for executive tasks with visual demands. The frontal aslant tract potentially supports executive functions, however, additional evidence is needed to clarify whether its involvement in executive tasks goes beyond the control of language. Converging evidence indicates that a right-lateralized network of tracts connecting cortical and subcortical grey matter regions supports the performance of tasks assessing response inhibition, some suggesting a role for the right anterior thalamic radiation. Finally, correlation evidence suggests a role for the cingulum bundle in executive functions, especially in tasks assessing inhibition. We discuss these findings in light of current knowledge about the functional role of these tracts, descriptions of the brain networks supporting executive functions and clinical implications for individuals with brain tumours.

Innovative multidimensional gait evaluation using IMU in multiple sclerosis: introducing the semiogram.

Background: Quantifying gait using inertial measurement units has gained increasing interest in recent years. Highly degraded gaits, especially in neurological impaired patients, challenge gait detection algorithms and require specific segmentation and analysis tools. Thus, the outcomes of these devices must be rigorously tested for both robustness and relevancy in order to recommend their routine use. In this study, we propose a multidimensional score to quantify and visualize gait, which can be used in neurological routine follow-up. We assessed the reliability and clinical coherence of this method in a group of severely disabled patients with progressive multiple sclerosis (pMS), who display highly degraded gait patterns, as well as in an age-matched healthy subjects (HS) group. Methods: Twenty-two participants with pMS and nineteen HS were included in this 18-month longitudinal follow-up study. During the follow-up period, all participants completed a 10-meter walk test with a U-turn and back, twice at M0, M6, M12, and M18. Average speed and seven clinical criteria (sturdiness, springiness, steadiness, stability, smoothness, synchronization, and symmetry) were evaluated using 17 gait parameters selected from the literature. The variation of these parameters from HS values was combined to generate a multidimensional visual tool, referred to as a semiogram. Results: For both cohorts, all criteria showed moderate to very high test-retest reliability for intra-session measurements. Inter-session quantification was also moderate to highly reliable for all criteria except smoothness, which was not reliable for HS participants. All partial scores, except for the stability score, differed between the two populations. All partial scores were correlated with an objective but not subjective quantification of gait severity in the pMS population. A deficit in the pyramidal tract was associated with altered scores in all criteria, whereas deficits in cerebellar, sensitive, bulbar, and cognitive deficits were associated with decreased scores in only a subset of gait criteria. Conclusions: The proposed multidimensional gait quantification represents an innovative approach to monitoring gait disorders. It provides a reliable and informative biomarker for assessing the severity of gait impairments in individuals with pMS. Additionally, it holds the potential for discriminating between various underlying causes of gait alterations in pMS.

Neurological outcomes in immune checkpoint inhibitor-related neurotoxicity.

While the spectrum of neurological immune checkpoint inhibitor-related adverse events is expanding, patients' outcomes are not well documented. This study aimed to assess outcomes of neurological immune-related adverse events and to identify prognostic factors. All patients experiencing grade ≥2 neurological immune-related adverse events identified at two clinical networks (French Reference Center for Paraneoplastic Neurological Syndromes, Lyon; and OncoNeuroTox, Paris) over five years were included. Modified Rankin scores were assessed at onset, 6, 12, 18 months, and last visit. A multi-state Markov model was used to estimate the transition rates between minor disability (mRS <3), severe disability (mRS 3-5), and death (mRS 6), over the study period. The state-to-state transition rates were estimated using maximum likelihood and variables were introduced into the different transitions to study their effects. A total of 147 patients were included out of 205 patients with a suspicion of neurological immune-related adverse events. The median age was 65 years (range 20-87) and 87/147 patients (59.2%) were male. Neurological immune-related adverse events involved the peripheral nervous system in 87/147 patients (59.2%), the central nervous system in 51/147 (34.7%), and both systems in 9/147 (6.1%). Paraneoplastic-like syndromes were observed in 30/147 patients (20.4%). Cancers included lung cancers (36.1%), melanoma (30.6%), urological cancers (15.6%), and others (17.8%). Patients were treated with programmed cell death protein (ligan) 1 (PD(L)1) inhibitors (70.1%), CTLA4 inhibitors (3.4%) or both (25.9%). Severe disability was reported in 108/144 patients (75.0%) at onset and in 33/146 patients (22.6%) at last visit (median follow-up duration: 12 months, range 0.5-50); 48/147 (32.7%) patients died, from cancer progression (17/48, 35.4%), neurological toxicity (15/48, 31.2%), other causes (10/48, 20.8%) or unknown causes (6/48, 12.5%). The rate of transition from severe to minor disability independently increased with melanoma [compared to lung cancer, hazard ratio = 3.26, 95%CI (1.27; 8.41)] and myositis/neuromuscular junction disorders [hazard ratio = 8.26, 95%CI (2.90; 23.58)], and decreased with older age [hazard ratio = 0.68, 95%CI (0.47; 0.99)] and paraneoplastic-like syndromes [hazard ratio = 0.29, 95%CI (0.09; 0.98)]. In patients with neurological immune-related adverse events, myositis/neuromuscular junction disorders and melanoma increase the transition rate from severe to minor disability, while older age and paraneoplastic-like syndromes result in poorer neurological outcomes; future studies are needed to optimize the management of such patients.

A Machine Learning Pipeline for Gait Analysis in a Semi Free-Living Environment.

This paper presents a novel approach to creating a graphical summary of a subject's activity during a protocol in a Semi Free-Living Environment. Thanks to this new visualization, human behavior, in particular locomotion, can now be condensed into an easy-to-read and user-friendly output. As time series collected while monitoring patients in Semi Free-Living Environments are often long and complex, our contribution relies on an innovative pipeline of signal processing methods and machine learning algorithms. Once learned, the graphical representation is able to sum up all activities present in the data and can quickly be applied to newly acquired time series. In a nutshell, raw data from inertial measurement units are first segmented into homogeneous regimes with an adaptive change-point detection procedure, then each segment is automatically labeled. Then, features are extracted from each regime, and lastly, a score is computed using these features. The final visual summary is constructed from the scores of the activities and their comparisons to healthy models. This graphical output is a detailed, adaptive, and structured visualization that helps better understand the salient events in a complex gait protocol.

Long-term systemic and mucosal SARS-CoV-2 IgA response and its association with persistent smell and taste disorders.

Introduction: Current approved COVID-19 vaccines, notably mRNA and adenoviral vectored technologies, still fail to fully protect against infection and transmission of various SARS-CoV-2 variants. The mucosal immunity at the upper respiratory tract represents the first line of defense against respiratory viruses such as SARS-CoV-2 and is thus critical to develop vaccine blocking human-to-human transmission. Methods: We measured systemic and mucosal Immunoglobulin A (IgA) response in serum and saliva from 133 healthcare workers from Percy teaching military hospital following a mild infection (SARS-CoV-2 Wuhan strain, n=58) or not infected (n=75), and after SARS-CoV-2 vaccination (Vaxzevria®/Astrazeneca and/or Comirnaty®/Pfizer). Results: While serum anti-SARS-CoV-2 Spike IgA response lasted up to 16 months post-infection, IgA response in saliva had mostly fallen to baseline level at 6 months post-infection. Vaccination could reactivate the mucosal response generated by prior infection, but failed to induce a significant mucosal IgA response by itself. Early post-COVID-19 serum anti-Spike-NTD IgA titer correlated with seroneutralization titers. Interestingly, its saliva counterpart positively correlated with persistent smell and taste disorders more than one year after mild COVID-19. Discussion: As breakthrough infections have been correlated with IgA levels, other vaccine platforms inducing a better mucosal immunity are needed to control COVID-19 infection in the future. Our results encourage further studies to explore the prognosis potential of anti-Spike-NTD IgA in saliva at predicting persistent smell and taste disorders.

Real-World Effectiveness of Natalizumab Extended Interval Dosing in a French Cohort.

INTRODUCTION: Natalizumab, a therapy for relapsing-remitting multiple sclerosis (RRMS), is associated with a risk of progressive multifocal leukoencephalopathy (PML). Over the last several years, practitioners have used off-label extended interval dosing (EID) of natalizumab to reduce PML risk, despite the absence of a large-scale efficacy evaluation. METHODS: We conducted a retrospective, multicenter cohort study among adults with RRMS receiving stable standard interval dosing (SID), defined as a ≥ 12-month consecutive period of ≥ 11 natalizumab infusions/year in France. We compared the 12-month risk difference of remaining relapse-free (primary endpoint) between patients who switched to EID (≤ 9 natalizumab infusions) and those who remained on SID, with a noninferiority margin of - 11%. We used propensity score methods such as inverse probability treatment weighting (IPTW) and 1:1 propensity score matching (PSM). Secondary endpoints were annualized relapse rate, disease progression, and safety. RESULTS: Baseline characteristics were similar between patients receiving EID (n = 147) and SID (n = 156). The proportion of relapse-free patients 12 months postbaseline was 142/147 in the EID (96.6%) and 144/156 in the SID group (92.3%); risk difference (95% CI) 4.3% (- 1.3 to 9.8%); p < 0.001 for non-inferiority. There were no significant differences between relapse rates (0.043 vs. 0.083 per year, respectively; p = 0.14) or Expanded Disability Status Scale mean scores (2.43 vs. 2.72, respectively; p = 0.18); anti-JC virus index values were similar (p = 0.23); and no instances of PML were reported. The comparisons using IPTW (n = 306) and PSM (n = 204) were consistent. CONCLUSION: These results support the pertinence of using an EID strategy for RRMS patients treated with natalizumab. CLINICAL TRIALS: gov identifier (NCT04580381).

Narcolepsy secondary to anti-Ma2 encephalitis: two case reports.

Recent studies suggest that sleep disorders are present in two-thirds of patients with autoimmune encephalitis. In anti-Ma2 encephalitis, hypersomnia appears to be frequent. However, only few cases of type 1 narcolepsy have been reported to date with anti-Ma2 encephalitis. We report 2 new cases of patients with narcolepsy secondary to anti-Ma2 encephalitis. Patient 1, a 68-year-old man, had narcolepsy type 1, including sleep attacks, cataplexy, abnormal Multiple Sleep Latency Tests and hypocretin-1 deficiency (< 50 ng/L) in the cerebrospinal fluid (CSF), associated with a cerebellar syndrome. Anti-Ma2 antibodies were present in the serum and CSF and antivoltage-gated potassium channel antibodies in the serum. He benefited from a treatment with pitolisant. Patient 2, a 42-year-old man, had narcolepsy type 2, including hypersomnolence, no cataplexy, intermediate CSF levels of hypocretin-1 (138 ng/L), abnormal Multiple Sleep Latency Tests, and a limbic encephalitis presentation. Anti-Ma2 antibodies were present in the serum and CSF, and anti-Ma1 antibodies were in the CSF. For both, repeated polysomnographies were necessary to establish the precise diagnosis of central hypersomnia, emphasizing the importance of carrying out sleep investigations in a tertiary neurology center with sleep medicine expertise in patients with anti-Ma2 encephalitis. CITATION: Brunet de Courssou J-B, Testard P, Sallansonnet-Froment M, et al. Narcolepsy secondary to anti-Ma2 encephalitis: two case reports. J Clin Sleep Med. 2023;19(4):837-841.

Preventing falls: the use of machine learning for the prediction of future falls in individuals without history of fall.

Nowadays, it becomes of paramount societal importance to support many frail-prone groups in our society (elderly, patients with neurodegenerative diseases, etc.) to remain socially and physically active, maintain their quality of life, and avoid their loss of autonomy. Once older people enter the prefrail stage, they are already likely to experience falls whose consequences may accelerate the deterioration of their quality of life (injuries, fear of falling, reduction of physical activity). In that context, detecting frailty and high risk of fall at an early stage is the first line of defense against the detrimental consequences of fall. The second line of defense would be to develop original protocols to detect future fallers before any fall occur. This paper briefly summarizes the current advancements and perspectives that may arise from the combination of affordable and easy-to-use non-wearable systems (force platforms, 3D tracking motion systems), wearable systems (accelerometers, gyroscopes, inertial measurement units-IMUs) with appropriate machine learning analytics, as well as the efforts to address these challenges.

Symptoms of Depression and Anxiety in Adults with High-Grade Glioma: A Literature Review and Findings in a Group of Patients before Chemoradiotherapy and One Year Later.

High-grade glioma (HGG) is associated with several external and internal stressors that may induce mood alterations at all stages of the disease. Symptoms of depression and anxiety in persons with glioma have multifactorial etiology and require active follow-up. We reviewed the literature data on the prevalence, mechanisms likely involved in the etiology of mood alterations in persons with HGG and psychosocial interventions found beneficial in treating these symptoms. We also investigated the prevalence and clinical variables that could increase the risk of depression and anxiety symptoms in a group of patients with HGG at two disease time-points: after surgery, before and 1 year after chemoradiotherapy. Literature findings revealed complex mechanisms underlying these symptoms and highlighted the importance of providing early access to palliative care. Our results show a high rate of anxiety and depression symptoms in the first stage of the disease and increased concomitance of these symptoms at the 1-year follow-up. Depression and anxiety symptoms at 1 year after the end of chemoradiotherapy were associated with the presence of symptoms at the first stage of the disease and tumor progression. Antiepileptic drugs and corticosteroid intake did not increase the risk of depressive and anxious symptoms among patients. Active management of mood alterations is an essential part of the care and contributes to patients' well-being and quality of life.

Evaluation methods to assess the efficacy of equinovarus foot surgery on the gait of post-stroke hemiplegic patients: A literature review.

Introduction: The aim of this study was to realize a systematic review of the different ways, both clinical and instrumental, used to evaluate the effects of the surgical correction of an equinovarus foot (EVF) deformity in post-stroke patients. Methods: A systematic search of full-length articles published from 1965 to June 2021 was performed in PubMed, Embase, CINAHL, Cochrane, and CIRRIE. The identified studies were analyzed to determine and to evaluate the outcomes, the clinical criteria, and the ways used to analyze the impact of surgery on gait pattern, instrumental, or not. Results: A total of 33 studies were included. The lack of methodological quality of the studies and their heterogeneity did not allow for a valid meta-analysis. In all, 17 of the 33 studies involved exclusively stroke patients. Ten of the 33 studies (30%) evaluated only neurotomies, one study (3%) evaluated only tendon lengthening procedures, 19 studies (58%) evaluated tendon transfer procedures, and only two studies (6%) evaluated the combination of tendon and neurological procedures. Instrumental gait analysis was performed in only 11 studies (33%), and only six studies (18%) combined it with clinical and functional analyses. Clinical results show that surgical procedures are safe and effective. A wide variety of different scales have been used, most of which have already been validated in other indications. Discussion: Neuro-orthopedic surgery for post-stroke EVF is becoming better defined. However, the method of outcome assessment is not yet well established. The complexity in the evaluation of the gait of patients with EVF, and therefore the analysis of the effectiveness of the surgical management performed, requires the integration of a patient-centered functional dimension, and a reliable and reproducible quantified gait analysis, which is routinely usable clinically if possible.

Impact of Sensory Afferences in Postural Control Quantified by Force Platform: A Protocol for Systematic Review.

Older adults' postural balance is a critical domain of research as balance deficit is an important risk factor for falls that can lead to severe injuries and death. Considering the effects of ageing on sensory systems, we propose that posturographic evaluation with a force platform exploring the effect of sensory deprivation or perturbation on balance could help understand postural control alterations in the elderly. The aim of the future systematic review and meta-analysis described in this protocol is to explore the capacity of older adults to maintain their balance during sensory perturbations, and compare the effect of perturbation between the sensory channels contributing to balance. Seven databases will be searched for studies evaluating older adults' balance under various sensory conditions. After evaluating the studies' risk of bias, results from similar studies (i.e., similar experimental conditions and posturographic markers) will be aggregated. This protocol describes a future review that is expected to provide a better understanding of changes in sensory systems of balance due to ageing, and therefore perspectives on fall assessment, prevention, and rehabilitation.

Peripheral neuropathies after BRAF and/or MEK inhibitor treatment: A pharmacovigilance study.

Reports suggested the potential occurrence of peripheral neuropathies (PN) in patients treated with BRAF (BRAFi) and/or MEK inhibitors (MEKi) for BRAF-activated tumours. We aimed to better characterize these PN. We queried the French pharmacovigilance database for all cases of PN attributed to BRAFi and/or MEKi. Fifteen patients were identified. Two main clinical PN phenotypes were seen. Six patients presented a length-dependent, axonal polyneuropathy: symptoms were mostly sensory and affecting the lower limbs; management and outcome were variable. Nine patients developed a demyelinating polyradiculoneuropathy: symptoms affected the four limbs and included hypoesthesia, weakness and ataxia; cranial nerves were involved in four cases; most patients received intravenous immunoglobulins or glucocorticoids, with variable outcome; one patient was rechallenged with a different BRAFi/MEKi combination with a rapid relapse in symptoms. In conclusion, patients under BRAFi/MEKi therapy may develop treatment-induced PN. Two main phenotypes can occur: a symmetric, axonal, length-dependent polyneuropathy and a demyelinating polyradiculoneuropathy.

Radiotherapy or Autologous Stem-Cell Transplantation for Primary CNS Lymphoma in Patients Age 60 Years and Younger: Long-Term Results of the Randomized Phase II PRECIS Study.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We previously reported the results of a randomized phase II study in patients with newly diagnosed primary CNS lymphoma (age 18-60 years). Patients were treated with high-dose methotrexate-based induction chemotherapy followed by whole-brain radiotherapy (WBRT) or high-dose chemotherapy (thiotepa-busulfan-cyclophosphamide) with autologous stem-cell transplantation (ASCT). The median follow-up was 33 months. In this report, we provide long-term data (median follow-up, 8 years) regarding the outcomes and toxicities. Fifty-three and 44 patients received induction chemotherapy followed by WBRT or ASCT, respectively. Their 8-year event-free survival from random assignment was 67% and 39% in the ASCT and WBRT arms, respectively (P = .03), with a significantly lower risk of relapse after ASCT (hazard ratio, 0.13; P < .001). One third of patients who relapsed after WBRT were alive after salvage treatment. Five and four patients died of ASCT and WBRT-related toxicities, respectively. The 8-year overall survival was 69% and 65% in the ASCT and WBRT arms, respectively (not significant). Balance (52% v 10%, P ≤ 0.001) and neurocognition (64% v 13%, P < .001) significantly deteriorated after WBRT compared with ASCT during the follow-up. This study shows that 40 Gy WBRT should be avoided in first-line treatment because of its neurotoxicity and suboptimal efficacy in reducing relapses while ASCT appears to be highly efficient in preventing relapses.

A topological data analysis-based method for gait signals with an application to the study of multiple sclerosis.

In the past few years, light, affordable wearable inertial measurement units have been providing to clinicians and researchers the possibility to quantitatively study motor degeneracy by comparing gait trials from patients and/or healthy subjects. To do so, standard gait features can be used but they fail to detect subtle changes in several pathologies including multiple sclerosis. Multiple sclerosis is a demyelinating disease of the central nervous system whose symptoms include lower limb impairment, which is why gait trials are commonly used by clinicians for their patients' follow-up. This article describes a method to compare pairs of gait signals, visualize the results and interpret them, based on topological data analysis techniques. Our method is non-parametric and requires no data other than gait signals acquired with inertial measurement units. We introduce tools from topological data analysis (sublevel sets, persistence barcodes) in a practical way to make it as accessible as possible in order to encourage its use by clinicians. We apply our method to study a cohort of patients suffering from progressive multiple sclerosis and healthy subjects. We show that it can help estimate the severity of the disease and also be used for longitudinal follow-up to detect an evolution of the disease or other phenomena such as asymmetry or outliers.

Adaptive Change-Point Detection for Studying Human Locomotion.

This paper presents an innovative method to analyze inertial signals recorded in a semi-controlled environment. It uses an adaptive and supervised change point detection procedure to decompose the signals into homogeneous segments, allowing a refined analysis of the successive phases within a gait protocol. Thanks to a training procedure, the algorithm can be applied to a wide range of protocols and handles different levels of granularity. The method is tested on a cohort of 15 healthy subjects performing a complex protocol composed of different activities and shows promising results for the automated and adaptive study of human gait and activity.Clinical relevance- A new approach to study human activity and locomotion in Free-Living Environments FLEs through an adaptive change-point detection which isolates homogeneous phases.

A review of center of pressure (COP) variables to quantify standing balance in elderly people: Algorithms and open-access code.

Postural control is often quantified by recording the trajectory of the center of pressure (COP)-also called stabilogram-during human quiet standing. This quantification has many important applications, such as the early detection of balance degradation to prevent falls, a crucial task whose relevance increases with the aging of the population. Due to the complexity of the quantification process, the analyses of sway patterns have been performed empirically using a number of variables, such as ellipse confidence area or mean velocity. This study reviews and compares a wide range of state-of-the-art variables that are used to assess the risk of fall in elderly from a stabilogram. When appropriate, we discuss the hypothesis and mathematical assumptions that underlie these variables, and we propose a reproducible method to compute each of them. Additionally, we provide a statistical description of their behavior on two datasets recorded in two elderly populations and with different protocols, to hint at typical values of these variables. First, the balance of 133 elderly individuals, including 32 fallers, was measured on a relatively inexpensive, portable force platform (Wii Balance Board, Nintendo) with a 25-s open-eyes protocol. Second, the recordings of 76 elderly individuals, from an open access database commonly used to test static balance analyses, were used to compute the values of the variables on 60-s eyes-open recordings with a research laboratory standard force platform.

Cumulative incidence and risk factors for radiation induced leukoencephalopathy in high grade glioma long term survivors.

The incidence and risk factors associated with radiation-induced leukoencephalopathy (RIL) in long-term survivors of high-grade glioma (HGG) are still poorly investigated. We performed a retrospective research in our institutional database for patients with supratentorial HGG treated with focal radiotherapy, having a progression-free overall survival > 30 months and available germline DNA. We reviewed MRI scans for signs of leukoencephalopathy on T2/FLAIR sequences, and medical records for information on cerebrovascular risk factors and neurological symptoms. We investigated a panel of candidate single nucleotide polymorphisms (SNPs) to assess genetic risk. Eighty-one HGG patients (18 grade IV and 63 grade III, 50M/31F) were included in the study. The median age at the time of radiotherapy was 48 years old (range 18-69). The median follow-up after the completion of radiotherapy was 79 months. A total of 44 patients (44/81, 54.3%) developed RIL during follow-up. Twenty-nine of the 44 patients developed consistent symptoms such as subcortical dementia (n = 28), gait disturbances (n = 12), and urinary incontinence (n = 9). The cumulative incidence of RIL was 21% at 12 months, 42% at 36 months, and 48% at 60 months. Age > 60 years, smoking, and the germline SNP rs2120825 (PPARg locus) were associated with an increased risk of RIL. Our study identified potential risk factors for the development of RIL (age, smoking, and the germline SNP rs2120825) and established the rationale for testing PPARg agonists in the prevention and management of late-delayed radiation-induced neurotoxicity.

Leukoencephalopathy with transient splenial lesions related to 5-fluorouracil or capecitabine.

BACKGROUND: 5-Fluorouracil (5-FU) and its oral prodrug capecitabine have been rarely but consistently associated with acute central nervous system toxicity, including transient leukoencephalopathies involving the splenium of the corpus callosum. METHODS: We performed a retrospective search in the French Pharmacovigilance database (FPDB) (January 1985-July 2020) for adult patients affected by solid cancers who developed acute toxic leukoencephalopathies with splenial lesions following treatment with 5-FU or capecitabine. A comprehensive review of the literature helped to circumstantiate our findings. RESULTS: Our research in the FPDB identified six patients who, within 3 days from their first cycle of 5-FU or capecitabine, developed acute neurological symptoms, including gait ataxia (n = 4), dysarthria (n = 3), dysmetria (n = 2), headache (n = 2), and confusion (n = 2). Brain magnetic resonance imaging (MRI) showed T2/FLAIR (fluid-attenuated inversion recovery) hyperintensities in the corpus callosum, with diffusion restriction and no contrast enhancement, generally accompanied by additional alterations in the bilateral supratentorial white matter (n = 5). All patients discontinued the agent supposedly responsible for the toxicity and experienced full recovery after a median of 8.5 days from symptom onset. Control MRI showed a progressive normalization of acute MRI abnormalities. Literature review identified 26 cases with similar clinical and paraclinical characteristics. A single patient from the literature resumed 5-FU at a lower dose, with no recurrent toxicity. CONCLUSIONS: 5-FU and capecitabine might be responsible for acute leukoencephalopathies with transient splenial lesions that are generally reversible upon drug discontinuation. Resuming the agent responsible for toxicity might be feasible in selected cases, after having excluded dihydropyrimidine dehydrogenase deficiency, if expected benefits outweigh the risks.