Preliminary evaluation of novel Bodily Attention Task to assess the role of the brain in chemotherapy-induced peripheral neurotoxicity (CIPN).

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common, sometimes dose-limiting side effect of neurotoxic chemotherapy. Treatment is limited because its pathophysiology is poorly understood. Compared to research on peripheral mechanisms, the role of the brain in CIPN is understudied and it may be important to develop better treatments. We propose a novel task that assesses brain activation associated with attention to bodily sensations (interoception), without the use of painful stimulation, to understand how CIPN symptoms may be processed in the brain. The goals of this preliminary study were to assess, 1) feasibility of the task, 2) sensitivity to changes in brain activity, and 3) suitability for assessing relationships between brain activation and CIPN severity. Eleven participants with varying types of cancer completed a brain fMRI scan and rated CIPN severity (CIPN-20) before and/or 12 weeks after starting neurotoxic chemotherapy. The Bodily Attention Task is a 7.5-min long fMRI task involving attentional focus on the left fingertips, the heart, or a flashing word "target" for visual attention (reference condition). Feasibility was confirmed, as 73% of all data collected were usable and participants reported feeling or focus during 75% of the trials. Regarding brain activity, finger attention increased activation in somatosensory regions (primary sensory cortex, insula) and sensory integration regions (precuneus, dorsolateral prefrontal cortex). Exploratory analyses suggested that brain activation may be associated with CIPN severity. A larger sample size and accounting of confounding factors is needed to test for replication and to identify brain and interoceptive biomarkers to help improve the prediction, prevention, and treatment of CIPN.

MRI brain findings of Abamectin toxic encephalopathy: a case report with review of literature.

Abamectin is an insecticidal/miticidal compound derived from the soil bacterium "Streptomyces avermitilis". Abamectin toxicity in humans is very rare. We present a case of acute neurotoxicity induced by Abamectin, showcasing distinctive MRI brain findings in a 33-year-old female who exhibited a favourable recovery with the aid of supportive care. In a patient with known exposure to toxins, even with a lack of knowledge of the specific type or class of toxin, recognition of anatomical distribution of lesions on brain MRI and their characteristic appearance can help exclude other causes of neurologic impairment and aid in timely management.

Performance of the prospective T2 MRI biomarker of neurotoxicity in a trimethyltin model in rats at 7 T.

The assessment of the sensitivity and specificity of any potential biomarker against the gold standard is an important step in the process of its qualification by regulatory authorities. Such qualification is an important step towards incorporating the biomarker into the panel of tools available for drug development. In the current study we analyzed the sensitivity and specificity of T2 MRI relaxometry to detect trimethyltin-induced neurotoxicity in rats. Seventy-five male Sprague-Dawley rats were injected with a single intraperitoneal dose of either TMT (8, 10, 11, or 12 mg/kg) or saline (2 ml/kg) and imaged with 7 T MRI before and 3, 7, 14, and 21 days after injection using a quantitative T2 mapping. Neurohistopathology (the gold standard in the case of neurotoxicity) was performed at the end of the observation and used as an outcome qualifier in receiver-operator characteristic (ROC) curve analysis of T2 changes as a predictor of neurotoxicity. TMT treatment led to a significant increase in T2 values in many brain areas. The biggest changes in T2 values were seen around the lateral ventricles, which was interpreted as ventricular dilation. The area under the ROC curve for the volume of the lateral ventricles was 0.878 with the optimal sensitivity/specificity of 0.805/0.933, respectively. T2 MRI is a promising method for generating a non-invasive biomarkers of neurotoxicity, which shows the dose-response behavior with substantial sensitivity and specificity. While its performance was strong in the TMT model, further characterization of the sensitivity and specificity of T2 MRI with other neurotoxicants is warranted.

Current knowledge and perspectives of contrast-induced neurotoxicity: A survey of Australian clinicians.

BACKGROUND: Contrast-induced Neurotoxicity (CIN) is an increasingly recognised complication following endovascular procedures. It remains a relatively unexplored clinical entity, and we sought to characterise clinician perspectives towards CIN, as well as identify gaps in knowledge and provide directions for future research. METHODS: An online survey was distributed to members of the Australian and New Zealand Society of Neuroradiology, as well as several Australian tertiary hospitals. Questions related to clinical exposure to CIN, diagnosis, management and pathophysiology were explored. Descriptive analysis was conducted on survey responses, and statistical analysis was performed using Chi-square and Fisher's exact test as appropriate. RESULTS: A total of 95 survey responses were recorded (26.8% response rate). Only 28.4% of respondents were comfortable in diagnosing CIN, and even fewer (24.2%) were comfortable in independently managing CIN patients. Based on clinician opinion, symptoms including impaired consciousness and cortical blindness were thought to be most associated with CIN, whilst the radiological findings of parenchymal oedema and cortical enhancement were considered to be most indicative of CIN. Most clinicians agreed that further investigation is required related to pathophysiology (86.3%), diagnosis (83.2%), and treatment (82.1%). CONCLUSION: CIN is a poorly understood complication following endovascular procedures. Significant gaps in clinical understanding are evident, and further investigation is vital to improve diagnosis and management.

Capecitabine related neurotoxicity: Clinical and radiologic features.

AIM: To study the clinical and radiologic features of patients with capecitabine neurotoxicity. METHODS: We performed a retrospective analysis and systematic review on the clinical and radiologic characteristics of all patients with capecitabine neurotoxicity reported in literature between 2003 and 2020. RESULTS: 24 cases including our patient were retrospectively analysed, with their clinical and radiologic features summarized. Their median age was 59 years old (ranges from 31 to 82 years old). Encephalopathy was the predominant clinical symptom affecting more than half (15/24, 63%) of the patients. This was followed by cerebellar ataxia (10/24, 42%). Amongst the patients who had magnetic resonance imaging(MRI) brain imaging performed, majority of them (18/23, 78%) had acute radiologic abnormalities. Leukoencephalopathy was the commonest radiologic abnormality seen in more than half of the patients (15/23,65%). Despite the preponderance of female patients in our study, there were no significant statistical differences in the clinical and radiologic features. Short term prognosis was excellent with complete resolution of neurologic symptoms observed in nearly all of the patients (22/23, 96%). CONCLUSION: Capecitabine-related neurotoxicity is an uncommon cause of toxic encephalopathy, with a predilection for females. Clinical features are non-specific, with encephalopathy being the commonest. Prognosis remains good with timely recognition, and cessation of capecitabine. Future research looking into other pathogenic pharmacogenetic processes should be conducted for further elucidation of these associations.

MRI Spectrum of Toxic Encephalopathy-An Institutional Experience.

Background: There are numerous toxins that affect our nervous system, both central and peripheral. Innumerable differentials exist in patients of acute encephalopathy and the list can be narrowed down with appropriate imaging. Specific neuroradiological features point to a particular diagnosis in a substantial number of cases. Objective: Through this study, we aimed to demonstrate the varied imaging findings of toxic encephalopathy on MRI encountered at our institute. Material and Methods: A retrospective analysis of the patients clinically diagnosed as toxic encephalopathy and referred for imaging between March 2015 and December 2019 was done. A total of 25 patients were included. Patient records were reviewed for clinical details, laboratory investigations, and treatment; the institute Picture Archiving and Communication System provided the imaging findings. Results: Patients presenting were aged between 22 and 55 years (mean-34.3 years). Four patients (16%) presented with imaging findings characteristic of Marchiafava-Bignami disease and six patients (24%) had MRI findings of Wernicke encephalopathy. Three patients (12%) had methanol poisoning sequelae while imaging findings of nitroimidazole drug toxicity were observed in another three patients (12%). Two patients (8%) each of carbon monoxide poisoning and lead toxicity were seen. We had one patient (4%) each of isoniazid, methyl iodide, dextropropoxyphene toxicity, chronic toluene abuse, and hyperglycemia-induced hemiballismus-hemichorea. Conclusion: Our study illustrates the amalgamated spectrum of MRI appearances in various subgroups of toxic encephalopathies. Imaging substantiated by relevant history and clinical manifestations can accurately diagnose the possible causative agent in the majority of the cases.

[Amphetamine-induced toxic encephalopathy].

In this case report, a 40-year-old woman presented with altered mentation, central facial palsy and hemiparesis. Acute CT scan showed several hypodense, rounded areas in both hemispheres. Urine toxicology tested positive for amphetamine. Subsequent cerebral MRI had hyperintense T2-weighted fluid-attenuated inverse recovery (FLAIR) lesions in both hemispheres, indicating demyelinating disease. A biopsy was made from one of the lesions. The final diagnosis was toxic encephalopathy.

[Imaging features of 10 patients with toxic encephalopathy caused by diquat].

Objective: To explore the CT and MRI imaging findings of diquat toxic encephalopathy. Methods: CT and MRI imaging features of 10 patients with diquat poisoning encephalopathy who had been clinically diagnosed were retrospectively reviewed. Results: CT was performed in all 10 patients, and MRI was performed in 8 patients. In 10 patients, 7 had positive signs on CT, and 8 patients with MRI examination had abnormal changes in the images. The main CT findings were symmetrical hypodensity in bilateral cerebellar hemisphere, brainstem, thalamus and basal ganglia, and swelling of brain tissue. The main MRI findings were symmetrical lesions and brain edema in the deep nuclei of cerebellar hemisphere, brainstem, thalamus and basal ganglia, low signal on T1WI, high signal on T2WI and T2-FLAIR, and cytotoxic edema on diffusion weighted imaging (DWI) . On review after treatment, both CT and MRI showed resorption of the lesion, which narrowed in size. Conclusion: The imaging findings of diquat poisoning encephalopathy are characteristic and the location of the lesion is characteristic, and CT and MRI have a certain diagnostic value in diquat poisoning encephalopathy, which is important for clinical treatment.

Neuroimaging findings in immune effector cell associated neurotoxicity syndrome after chimeric antigen receptor T-cell therapy.

Chimeric antigen receptor T-cell (CAR-T) therapy is a promising immunotherapy approved for hematological malignancies. Despite its effectiveness, clinically significant rates of toxicity, including immune effector cell associated neurotoxicity syndrome (ICANS), limit its widespread use. In certain contexts, ICANS may occur in up to one-third of patients using commercially available CAR-T therapies. The syndrome presents with a range of neurological signs and symptoms, as well as a variety of neuroimaging manifestations reported in the literature. A systematic review of the literature was performed. The systematic search strategy identified 24 studies discussing the neuroimaging appearances associated with ICANS. Imaging findings are more common in patients with higher grade neurotoxicity. The neuroimaging findings are heterogeneous, but can be grouped either anatomically (white matter, gray matter, brainstem, or leptomeninges) or pathologically (ischemic changes, hemorrhages, or cerebral edema). An understanding of the imaging manifestations of ICANS has the potential to impact the management of patients.

Reversible Toxic Encephalopathy Involving the Cerebellum and Subcortical White Matter Attributed to Capecitabine.

Capecitabine is an anticancer drug related to 5-fluorouracil (5-FU) that is used to treat multiple cancers. Little is known about the central nervous system toxicity of capecitabine owing to the low frequency of occurrence. In this report we describe a rare case of capecitabine-related toxic encephalopathy involving the cerebellum and subcortical white matter. A review of the literature showed that most reported cases have shown excellent recovery within a few days of capecitabine termination. Whether uridine triacetate is a reasonable treatment choice for patients with life-threatening toxic encephalopathy depends on the availability of reliable clinical data. Prescreening for dihydropyrimidine dehydrogenase genotype variants and detection of 5-FU degradation rate prior to capecitabine treatment may become an effective way to avoid toxic reactions by regulating the therapeutic dose for each patient, which remains to be investigated and needs more clinical data to support.

Imaging-based Toxicity and Response Pattern Assessment Following CAR T-Cell Therapy.

Background Chimeric antigen receptor (CAR) T-cell immunotherapy is increasingly used for refractory lymphoma but may lead to cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Imaging may assist in clinical management. Associations between CRS or ICANS grade and imaging findings remain not fully established. Purpose To determine associations between imaging findings and clinical grade of CRS or ICANS, evaluate response patterns, and assess imaging use following CAR T-cell treatment. Materials and Methods Patients with refractory B-cell lymphoma who received CAR T-cell infusion between 2018 and 2020 at a single center were analyzed retrospectively. Clinical CRS or ICANS toxicity grade was assessed using American Society for Transplantation and Cellular Therapy, or ASTCT, consensus grading. Thoracic and head images (radiographs, CT scans, MRI scans) were evaluated. Associations between imaging findings and clinical CRS or ICANS grade were analyzed. Wilcoxon signed-rank and χ2 tests were used to assess associations between thoracic imaging findings, clinical CRS toxicity grade, and imaging-based response. Response to therapy was evaluated according to Deauville five-point scale criteria. Results A total of 38 patients (mean age ± standard deviation, 59 years ± 10; 23 men) who received CAR T-cell infusion were included. Of these, 24 (63% [95% CI: 48, 79]) and 11 (29% [95% CI: 14, 44]) experienced clinical grade 1 or higher CRS and ICANS, respectively. Patients with grade 2 or higher CRS were more likely to have thoracic images with abnormal findings (10 of 14 patients [71%; 95% CI: 47, 96] vs five of 24 patients [21%; 95% CI: 4, 37]; P = .002) and more likely to have imaging evidence of pleural effusions (five of 14 [36%; 95% CI: 10, 62] vs two of 24 [8.3%; 95% CI: 0, 20]; P = .04) and atelectasis (eight of 14 [57%; 95% CI: 30, 84] vs six of 24 [25%; 95% CI: 7, 43]; P = .048). Positive imaging findings were identified in three of seven patients (43%) with grade 2 or higher ICANS who underwent neuroimaging. The best treatment response included 20 of 36 patients (56% [95% CI: 39, 72]) with complete response, seven of 36 (19% [95% CI: 6, 33]) with partial response, one of 36 (2.8% [95% CI: 0, 8]) with stable disease, and eight of 36 (22% [95% CI: 8, 36]) with progressive disease. Conclusion Thoracic imaging findings, including pleural effusions and atelectasis, correlated with cytokine release syndrome grade following chimeric antigen receptor (CAR) T-cell infusion. CAR T-cell therapy yielded high response rates. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Langer in this issue.

Intravenous methadone causes acute toxic and delayed inflammatory encephalopathy with persistent neurocognitive impairments.

BACKGROUND: The mu-opioid agonist methadone is administered orally and used in opioid detoxification and in the treatment of moderate-to-severe pain. Acute oral methadone-use and -abuse have been associated with inflammatory and toxic central nervous system (CNS) damage in some cases and cognitive deficits can develop in long-term methadone users. In contrast, reports of intravenous methadone adverse effects are rare. CASE PRESENTATION: Here, we report a patient who developed acute bilateral hearing loss, ataxia and paraparesis subsequently to intravenous methadone-abuse. While the patient gradually recovered from these deficits, widespread magnetic resonance imaging changes progressed and delayed-onset encephalopathy with signs of cortical dysfunction persisted. This was associated with changes in the composition of monocyte and natural killer cell subsets in the cerebrospinal fluid. CONCLUSION: This case suggests a potential bi-phasic primary toxic and secondary inflammatory CNS damage induced by intravenous methadone.

Metronidazole-induced reversible cerebellar dysfunction.

A 73-year-old man who presented with fever and abdominal discomfort was diagnosed to have a liver abscess. He was treated with antimicrobials which included metronidazole. One month into treatment, he developed neurological symptoms and signs that were suggestive of cerebellar pathology. MRI of the brain showed T2/fluid attenuated inversion recovery hyperintensities involving bilateral dentate, fastigial and interpositus nuclei. After excluding common aetiologies, the possibility of metronidazole-induced neurotoxicity was considered. After stopping metronidazole, his symptoms and signs resolved. A subsequent MRI scan of the brain showed reversal of changes. Neurotoxicity caused by metronidazole is an uncommon adverse effect of a commonly used antimicrobial drug and should be considered in the appropriate clinical scenario.

Beyond the storm - subacute toxicities and late effects in children receiving CAR T cells.

As clinical advances with chimeric antigen receptor (CAR) T cells are increasingly described and the potential for extending their therapeutic benefit grows, optimizing the implementation of this therapeutic modality is imperative. The recognition and management of cytokine release syndrome (CRS) marked a milestone in this field; however, beyond the understanding gained in treating CRS, a host of additional toxicities and/or potential late effects of CAR T cell therapy warrant further investigation. A multicentre initiative involving experts in paediatric cell therapy, supportive care and/or study of late effects from cancer and haematopoietic stem cell transplantation was convened to facilitate the comprehensive study of extended CAR T cell-mediated toxicities and establish a framework for new systematic investigations of CAR T cell-related adverse events. Together, this group identified six key focus areas: extended monitoring of neurotoxicity and neurocognitive function, psychosocial considerations, infection and immune reconstitution, other end organ toxicities, evaluation of subsequent neoplasms, and strategies to optimize remission durability. Herein, we present the current understanding, gaps in knowledge and future directions of research addressing these CAR T cell-related outcomes. This systematic framework to study extended toxicities and optimization strategies will facilitate the translation of acquired experience and knowledge for optimal application of CAR T cell therapies.

Neurotoxicidad inducida por metronidazol / Neurotoxicity induced by metronidazole

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CAR-T Cell Therapy-Related Neurotoxicity in Pediatric Acute Lymphoblastic Leukemia: Spectrum of Imaging Findings.

The emergence of CD19-targeted chimeric antigen receptor-T (CAR-T) cell therapy has created a new era in the management of pediatric patients with refractory B-cell malignancies such as B-cell acute lymphoblastic leukemia. Immune effector cell-associated neurotoxicity syndrome (ICANS) is frequently encountered in the postinfusion period of CD19-targeted chimeric antigen receptor-T cell therapy and in some cases may be fatal. Knowledge related to the spectrum of imaging findings of CD19-targeted CAR-T cell therapy-related ICANS is, however, still very much lacking, underscoring the need for continued research in this area. In this review, we hope to provide an overview of current knowledge and provide an in-depth literature review related to this topic. A brief discussion of possible imaging differential diagnoses, specifically in children with acute lymphoblastic leukemia, will also be included. Illustrative cases for each imaging phenotype will be provided to facilitate a better understanding. A greater level of insight of the spectrum of imaging findings related to ICANS will improve patients' management and enhance efforts to safely deliver CAR-T cell immunotherapy. It will also facilitate further studies to derive mechanistic insights of ICANS and potentially assist in the testing and monitoring of therapeutic interventions.

Clinical and radiologic correlates of neurotoxicity after axicabtagene ciloleucel in large B-cell lymphoma.

Neurotoxicity or immune effector cell-associated neurotoxicity syndrome (ICANS) is the second most common acute toxicity after chimeric antigen receptor (CAR) T-cell therapy. However, there are limited data on the clinical and radiologic correlates of ICANS. We conducted a cohort analysis of 100 consecutive patients with relapsed or refractory large B-cell lymphoma (LBCL) treated with standard of care axicabtagene ciloleucel (axi-cel). ICANS was graded according to an objective grading system. Neuroimaging studies and electroencephalograms (EEGs) were reviewed by an expert neuroradiologist and neurologist. Of 100 patients included in the study, 68 (68%) developed ICANS of any grade and 41 (41%) had grade ≥3. Median time to ICANS onset was 5 days, and median duration was 6 days. ICANS grade ≥3 was associated with high peak ferritin (P = .03) and C-reactive protein (P = .001) levels and a low peak monocyte count (P = .001) within the 30 days after axi-cel infusion. Magnetic resonance imaging was performed in 38 patients with ICANS and revealed 4 imaging patterns with features of encephalitis (n = 7), stroke (n = 3), leptomeningeal disease (n = 2), and posterior reversible encephalopathy syndrome (n = 2). Abnormalities noted on EEG included diffuse slowing (n = 49), epileptiform discharges (n = 6), and nonconvulsive status epilepticus (n = 8). Although reversible, grade ≥3 ICANS was associated with significantly shorter progression-free (P = .02) and overall survival (progression being the most common cause of death; P = .001). Our results suggest that imaging and EEG abnormalities are common in patients with ICANS, and high-grade ICANS is associated with worse outcome after CAR T-cell therapy in LBCL patients.

CAR T-cell therapy-related neurotoxicity in paediatric acute lymphocytic leukaemia.

BACKGROUND: The advent of chimeric antigen receptor (CAR) T-cell therapy has created a paradigm shift in the management of patients with refractory B-cell acute lymphocytic leukaemia (ALL). The aim of this study is to correlate imaging findings of CAR T-cell therapy related neurotoxicity with clinical course and eventual clinical outcome, with the hope that it will bring us a step closer to the identification of potential imaging biomarkers that may allow more accurate prognostication and risk stratification of patients. PROCEDURE: Our imaging database was queried from January 2018 to April 2020 to identify paediatric patients who fulfil the following criteria: (a) diagnosed with ALL, (b) underwent CAR T-cell therapy, and (c) had magnetic resonance imaging (MRI) brain studies performed before and after CAR T-cell therapy. A total of seven patients were included and all MRI studies were analysed by a paediatric neuroradiologist for the presence of acute neuroimaging findings post CAR T-cell infusion. Acute neuroimaging findings are defined as new imaging findings detected within 28 days of CAR T-cell infusion. RESULTS: Three out of four patients with acute neuroimaging findings had sustained complete remission for more than 6 months, while all three patients without acute neuroimaging findings had positive minimal residual disease (MRD) within 1 month. Both patients with acute diffuse leptomeningeal enhancement showed clinical improvement within 1-2 days. CONCLUSIONS: Acute neuroimaging findings may be a potential imaging biomarker for peak neurotoxicity and treatment response, and it is not necessarily associated with poor outcome, as previously reported.