Chimeric antigen receptor T-cell therapy-induced nervous system toxicity: a real-world study based on the FDA Adverse Event Reporting System database.

BACKGROUND: Nervous system toxicity (NST) is one of the most frequent and dangerous side effects of chimeric antigen receptor T-cell (CAR-T) therapy, which is an effective treatment for related tumors in most relapsed/refractory (r/r) hematologic malignancies. Current clinical trial data do not fully reflect the real-world situation. Therefore, this study evaluated the NST of CAR-T therapy using the FDA Adverse Event Reporting System (FAERS). METHODS: Data were retrieved from FAERS for the period from January 1, 2017 to March 31, 2023. Disproportionality analysis and Bayesian analysis were used for data mining. The reporting odds ratio (ROR) for NST with 95% confidence interval (CI) was calculated for each CAR-T product. The time to onset (TTO) and clinical outcomes due to CAR-T therapy-associated NST were assessed. RESULTS: Overall, 6946 cases of NST associated with CAR-T therapy were identified. The patients had a median age of 61 years (interquartile range [IQR]: 47-69 years). Significant signals were observed for all CAR-T products (ROR: 2.19, 95% CI: 2.13-2.44). Anti-CD19 CAR-T products showed a higher NST signal than anti-B cell maturation antigen (BCMA) CAR-T products (ROR025 2.13 vs. 1.98). Brexucabtagene autoleucel (ROR: 3.17, 95% CI: 2.90-3.47) and axicabtagene ciloleucel (ROR: 2.92, 95% CI: 2.81-3.03) had the two highest NST signals. For the preferred term "brain edema," the highest signals were obtained for CD28 CAR-T products. The median TTO of NST for all CAR-T products was 7 days (IQR: 3-17 days). The proportion of death, life-threatening and hospitalization adverse events associated with NST was 20.06%, 7.21%, and 32.70%, respectively. The proportion of death outcomes was higher in patients treated with tisagenlecleucel (30.36%) than in those treated with other CAR-T products, except ciltacabtagene autoleucel (P < 0.001). The proportion of hospitalizations was significantly higher for lisocabtagene maraleucel-associated NST (53.85%) than for other drugs, except for ciltacabtagene autoleucel (P < 0.001). CONCLUSIONS: NST is more closely associated with anti-CD19 CAR-Ts and CAR-Ts containing CD28. Serious NST (brain oedema) is likely to occur with CAR-Ts that contain CD28. CAR-T-related NST warrants greater attention owing to the high proportion of serious adverse events and delayed NST.

Mid-to-late stage diquat accumulation in the central nervous system: A severe case of oral poisoning.

A 54-year-old woman in good health was admitted to our hospital with diquat poisoning. The patient drank an unknown dose of diquat, and acute kidney injury developed early. However, there were no obvious pulmonary abnormalities and no signs of central nervous system toxicity in the early stage. The woman underwent active treatment, which resulted in a significant decrease in blood diquat levels, but her lung condition progressively worsened and neurological symptoms developed. Fortunately, the patient survived after intensive hemoperfusion combined with continuous renal replacement therapy (CRRT), intracranial pressure reduction, and anti-infective treatment. This case report highlights the importance of being aware of the development of delayed pulmonary symptoms and neurologic complications when caring for patients poisoned with diquat, even in those with low diquat blood concentrations. Interestingly, we also detected the concentration of diquat in the cerebrospinal fluid (CSF) of patients with diquat poisoning, and found that the rate of decrease of diquat concentration in the CSF was considerably slower than that in the blood.Notably, a specific correlation was observed between the concentration of diquat in the CSF, rather than in the blood, and both the intracranial pressure (ICP) and the severity of cerebral edema in this patient.

Intravenous lipid emulsion modifies synaptic transmission in hippocampal CA1 pyramidal neurons after bupivacaine-induced central nervous system toxicity.

Local anesthetics can cause severe toxicity when absorbed systemically. Rapid intravenous administration of lipid emulsion (LE) is the standard of care for severe local anesthetic systemic toxicity which can cause cardiovascular and central nervous system (CNS) injury. The biological mechanism by which LE alleviates CNS toxicity remains unknown and understudied. Previous research has suggested that local anesthetics cause an imbalance of excitatory and inhibitory transmission in the brain. Therefore, this study aimed to observe the effect of LE on glutamate- and GABA-induced currents in CA1 pyramidal neurons after bupivacaine-induced CNS toxicity. We further characterized post-synaptic modifications in these cells to try to elucidate the mechanism by which LE mediates bupivacaine-induced CNS toxicity. Sprague-Dawley rats received intravenous bupivacaine (1 mg kg-1  min-1 ) in either normal saline or LE (or LE without bupivacaine) for 5 min. An acute brain slice preparation and a combination of whole-cell patch clamp techniques and whole-cell recordings were used to characterize action potential properties, miniature excitatory, and inhibitory post-synaptic currents, and post-synaptic modifications of excitatory and inhibitory transmission in CA1 hippocampal pyramidal neurons. The expression level of GABAA receptors were assessed with western blotting, whereas H&E and TUNEL staining were used to assess cytoarchitecture and apoptosis levels respectively. Bupivacaine treatment significantly increased the number of observed action potentials, whereas significantly decreasing rheobase, the first interspike interval (ISI), and hyperpolarization-activated cation currents (Ih) in CA1 pyramidal neurons. LE treatment significantly reduced the frequency of miniature inhibitory post-synaptic currents and enhanced GABA-induced paired pulse ratio with 50 ms interval stimulation in bupivacaine-treated rats. Regulation of GABAA levels is a promising mechanism by which LE may ameliorate CNS toxicity after systemic absorption of bupivacaine.

Neuropathology changed by 3- and 6-months low-level PM2.5 inhalation exposure in spontaneously hypertensive rats.

BACKGROUND: Epidemiological evidence has linked fine particulate matter (PM2.5) to neurodegenerative diseases; however, the toxicological evidence remains unclear. The objective of this study was to investigate the effects of PM2.5 on neuropathophysiology in a hypertensive animal model. We examined behavioral alterations (Morris water maze), lipid peroxidation (malondialdehyde (MDA)), tau and autophagy expressions, neuron death, and caspase-3 levels after 3 and 6 months of whole-body exposure to urban PM2.5 in spontaneously hypertensive (SH) rats. RESULTS: SH rats were exposed to S-, K-, Si-, and Fe-dominated PM2.5 at 8.6 ± 2.5 and 10.8 ± 3.8 µg/m3 for 3 and 6 months, respectively. We observed no significant alterations in the escape latency, distance moved, mean area crossing, mean time spent, or mean swimming velocity after PM2.5 exposure. Notably, levels of MDA had significantly increased in the olfactory bulb, hippocampus, and cortex after 6 months of PM2.5 exposure (p < 0.05). We observed that 3 months of exposure to PM2.5 caused significantly higher expressions of t-tau and p-tau in the olfactory bulb (p < 0.05) but not in other brain regions. Beclin 1 was overexpressed in the hippocampus with 3 months of PM2.5 exposure, but significantly decreased in the cortex with 6 months exposure to PM2.5. Neuron numbers had decreased with caspase-3 activation in the cerebellum, hippocampus, and cortex after 6 months of PM2.5 exposure. CONCLUSIONS: Chronic exposure to low-level PM2.5 could accelerate the development of neurodegenerative pathologies in subjects with hypertension.

Changes in AmotL2 Expression in Cells of the Human Enteral Nervous System in Oxaliplatin-Induced Enteric Neuropathy.

Gastrointestinal (GI) toxicity is a common side effect in patients undergoing oxaliplatin (OxPt)-based chemotherapy for colorectal cancer (CRC). Frequently, this complication persists in the long term and could affect the efficacy of the treatment and the patient's life quality. This long-term GI toxicity is thought to be related to OxPt-induced enteral neuropathy. AmotL2 is a member of the Angiomotin family of proteins, which play a role in cell survival, neurite outgrowth, synaptic maturation, oxidative stress protection, and inflammation. In order to assess the role of AmotL2 in OxPt-induced enteral neuropathy, we studied the expression of AmotL2 in cells of the enteric nervous system (ENS) of untreated and OxPt-treated CRC patients and its relationship with inflammation, using immunofluorescence confocal microscopy. Our results in human samples show that the total number of neurons and glial cells decreased in OxPt-treated patients, and TNF-α and AmotL2 expression was increased and colocalized in both neurons and glia. AmotL2 differential expression between OxPt-treated and untreated CRC patients shows the involvement of this scaffold protein in the inflammatory component and toxicity by OxPt in the ENS.

[Central nervous system toxicity caused by bortezomib: five case reports and a review of literature].

Objective: To investigate the clinical features, diagnosis, and treatment of the central nervous system (CNS) toxicity caused by bortezomib. Methods: This study reports five new cases of CNS toxicity caused by bortezomib to elucidate its characteristics along with a review of the literature. Results: CNS toxicity caused by bortezomib presents in three clinical forms: syndrome of inappropriate antidiuresis (SIAD) , posterior reversible encephalopathy syndrome (PRES) , and central fever, which is the most common clinical manifestation. Four of our five patients developed central fever after the administration of bortezomib, manifested as persistent high fever, anhidrosis, and absence of infective foci; the symptom could be improved by discontinuance of bortezomib. Of these patients, three concurrently presented with refractory hyponatremia and one was clearly diagnosed with SIAD. The bortezomib could have caused damages to the hypothalamus and induced both central fever and SIAD. In addition, one patient was diagnosed with PRES due to disturbance of consciousness and epilepsy after taking bortezomib. After discontinuation of bortezomib, the symptoms disappeared and did not recur. We also found that thrombocytopenia may be related to the severity of the CNS toxicity of bortezomib. Conclusion: Cases of CNS toxicity of bortezomib are extremely rare and present as SIAD, PRES and central fever. Early detection and treatment of bortezomib are very important to prevent irreversible neurological complications.

Prediction of overt hepatic encephalopathy after transjugular intrahepatic portosystemic shunt treatment: a cohort study.

BACKGROUND/PURPOSE: Overt hepatic encephalopathy (HE) risk should be preoperatively predicted to identify patients suitable for curative transjugular intrahepatic portosystemic shunt (TIPS) instead of palliative treatments. METHODS: A total of 185 patients who underwent TIPS procedure were randomised (130 in the training dataset and 55 in the validation dataset). Clinical factors and imaging characteristics were assessed. Three different models were established by logistic regression analyses based on clinical factors (ModelC), imaging characteristics (ModelI), and a combination of both (ModelCI). Their discrimination, calibration, and decision curves were compared, to identify the best model. Subgroup analysis was performed for the best model. RESULTS: ModelCI, which contained two clinical factors and two imaging characteristics, was identified as the best model. The areas under the curve of ModelC, ModelI, and ModelCI were 0.870, 0.963, and 0.978 for the training dataset and 0.831, 0.971, and 0.969 for the validation dataset. The combined model outperformed the clinical and imaging models in terms of calibration and decision curves. The performance of ModelCI was not influenced by total bilirubin, Child-Pugh stages, model of end-stage liver disease score, or ammonia. The subgroup with a risk score ≥ 0.88 exhibited a higher proportion of overt HE (training dataset: 13.3% vs. 97.4%, p < 0.001; validation dataset: 0.0% vs. 87.5%, p < 0.001). CONCLUSION: Our combination model can successfully predict the risk of overt HE post-TIPS. For the low-risk subgroup, TIPS can be performed safely; however, for the high-risk subgroup, it should be considered more carefully.

A cautionary note on the selectivity of oncolytic poxviruses.

BACKGROUND: Oncolytic viruses selectively infect cancer cells while avoiding infection of normal cells. Usually, selectivity is demonstrated by injecting a virus into tumor-bearing mice and observing infection and lysis of tumor cells without infection of other tissues. The general view is that this selectivity is due to tropisms of the virus. However, apparent selectivity could be due to accessibility. For example, intravenously injected virus may not gain access to cells within the central nervous system (CNS) because of the blood-brain barrier. PURPOSE: We tested the CNS safety of two oncolytic poxviruses that have been demonstrated to be safe for treatment of peripheral tumors (vaccinia virus vvDD-IL15-Rα and myxoma virus vMyx-IL15Rα-tdTr). METHODS: Two poxviruses were tested for selectivity in vitro and in vivo. RESULTS: Both viruses infected glioma cells in vitro. In vivo, both viruses infected glioma cells and did not infect neurons when injected into a tumor or into the normal striatum. However, viral gene expression was observed in ependymal cells lining the ventricles, implying that these poxviruses were not as selective as originally predicted. For vvDD-IL15-Rα, some tumor-bearing mice died soon after virus treatment. If the same titer of vvDD-IL15-Rα was injected directly into the lateral cerebral ventricle of nontumor-bearing mice, it was uniformly fatal. Infection of ependymal cells, subventricular cells, and meninges was widespread. On the other hand, vMyx-IL15Rα-tdTr only transiently infected ependymal cells and was safe even when injected directly into the lateral cerebral ventricles. The two poxviruses also differed in their infection of dendritic cells; vvDD-IL15-Rα infected dendritic cells and lysed them but vMyx-IL15Rα-tdTr did not. CONCLUSION: Vaccinia virus vvDD-IL15-Rα is very promising for treating cancer types outside of the brain. However, for cancers located within the brain, myxoma virus vMyx-IL15Rα-tdTr offers a safer alternative.

Levofloxacin-associated Encephalopathy with Severe Hyperventilation.

A 64-year-old woman with no previous mental illness took a single 500 mg tablet of levofloxacin for cystitis. Two hours later, she developed psychosis with involuntary movement and severe hyperventilation with respiratory alkalosis. Cranial magnetic resonance imaging findings were unremarkable, and an electroencephalogram revealed no epileptiform discharge. Her symptoms improved on the third day after levofloxacin was discontinued. Levofloxacin-associated encephalopathy with psychotic features is a rare adverse event. Disturbance of gamma-aminobutyric acid-ergic (GABAergic) interneurons by levofloxacin may lead to hyperventilation via dysfunction of the brainstem respiratory network. Physicians should be aware of hyperventilation as an additional serious symptom of levofloxacin-associated encephalopathy in acute settings.

Meperidine-induced reversible retrograde amnesia.

INTRODUCTION: Meperidine is a synthetic opioid analog that is frequently prescribed for acute pain management. Normeperidine, the only active metabolite of meperidine, is neurotoxic and can cause significant central nervous system adverse events. CASE SUMMARY: A 29-year-old woman (height, 170 cm; weight, 85 kg) presented to Marmara University Hospital Emergency Department, Istanbul, Turkey, complaining of low back pain she described as "stabbing." Physical examination revealed impaired lower-extremity mobility and normal vital-sign findings. There was no evidence of foot drop, head or other trauma, and systemic physical examination was unremarkable. Other common causes (eg, pyelonephritis, nephrolithiasis, pancreatitis, trauma) of lower back pain were excluded. To achieve analgesia, meperidine 80 mg was administered intravenously in 100 mL of isotonic saline solution for 20 minutes. Within 20 minutes,analgesia was achieved,but the patient developed retrograde amnesia, becoming disoriented to time, location, and persons. Her speech slowed and perceptional changes developed. After the onset of amnesia, a complete physical examination was conducted.It failed to reveal focal neurologic deficit,and laboratory (sodium, potassium, magnesium, phosphorus, serum creatinine, blood urea nitrogen, albumin, bilirubin, hemoglobin,and platelet count) and subsequent vital-sign findings (blood pressure, 150/100 mm Hg; heart rate, 100 beats per minute; respiratory rate, 18 breaths per minute; body temperature, 37 ଌ and pulse oximetry,99%) were within the normal range. Noncontrast computed tomography did not reveal any abnormality. Initially, the patient's condition was attributed to medication error due to incorrect dosage or infusion rate. Despite a review of medication logs, equipment, and the vital-sign record, the etiology for the phenomenon could not be identified. Meperidine was discontinued and oxygen and intravenous isotonic saline solution were initiated as supportive treatment. Three hours after meperidine administration was discontinued, the amnesia and disorientation spontaneously resolved. CONCLUSION: Meperidine was probably associated with reversible amnesia in this healthy patient after a single therapeutic dose.

Central Nervous System Complications in Children Receiving Chemotherapy or Hematopoietic Stem Cell Transplantation.

Therapy-related neurotoxicity greatly affects possibility of survival and quality of life of pediatric patients treated for cancer. Central nervous system (CNS) involvement is heterogeneous, varying from very mild and transient symptoms to extremely severe and debilitating, or even lethal syndromes. In this review, we will discuss the broad scenario of CNS complications and toxicities occurring during the treatment of pediatric patients receiving both chemotherapies and hematopoietic stem cell transplantation. Different types of complications are reviewed ranging from therapy related to cerebrovascular with a specific focus on neuroradiologic and clinical features.

A Case Report of Toxic Brain Syndrome Caused by Methyl Bromide.

Methyl bromide (CH3Br) is a halogenated aliphatic hydrocarbon that may cause acute and chronic toxicities. We describe a case of a 44-year-old male patient who developed toxic brain syndrome (TBS) and central nervous system (CNS) toxicity after exposure to CH3Br by inhalation. Toxicity began with progressive nervousness, dysarthria and coordination disorder. The complaints on admission to the hospital were speech defect, balance disorder, consciousness disorder and involuntary movements. The patient was treated symptomatically in the intensive care unit (ICU), and organic reasons were excluded. Findings in the magnetic resonance imaging were considered secondary demyelination related to systemic intoxication. Because of the CH3Br, alkylates the crucial sulfhydryl-containing enzymes, N-acetylcysteine was used as a source of sulfhydryl groups for the treatment of the patient. He was hospitalised for nearly 1.5 months in the ICU.

Lipid emulsion mitigates local anesthesia-induced central nervous system toxicity in rats.

The aim of the present study was to investigate the effect of intravenously administered lipid emulsion on local anesthetic (LA)-induced central nervous system (CNS) toxicity. A total of 100 male Sprague Dawley rats were allocated at random into the following groups: Sham (A), lidocaine (B), levobupivacaine (C) and ropivacaine (D). Groups B-D were each subdivided into three subgroups: Toxic, post-conditioning and pre-conditioning. Intracerebroventricular injections of 0.9% normal saline (sham group) or LA were administered via microsyringe; in addition, a 20% lipid emulsion was injected into tail vein prior to the LA injection (pre-conditioning subgroups) or following rat respiratory arrest (post-conditioning subgroups). The heart rate, blood pressure, neurological behavior scores, neuronal density and time from LA injection to respiratory arrest, apnea and start of arrhythmia were measured. Rats in the toxic groups died due to respiratory arrest following the injection of LA into the lateral ventricle. Rats in the post-conditioning subgroups were resuscitated from the LA-induced respiratory arrest, while the pre-conditioning subgroup rats exhibited no respiratory arrest. No significant differences in heart rate were observed between the toxic and post-conditioning subgroups in the levobupivacaine and ropivacaine groups (P>0.05); however, a significant difference was observed between these treatment groups and the rats treated with lidocaine (P<0.01). A significant difference was also observed in the time from the LA injection to the onset of arrhythmia among the rats in groups B, C and D (P<0.01). No significant differences in the neurological behavior scores and neuronal density were observed in the hippocampal CA1 zone among group C and D rats in the post- and pre-conditioning subgroups at various time-points following treatment. Beyond that, the same phenomena regarding neurological behavior scores was observed in post- and pre-conditioning subgroups of group B at 12 and 24 h treatment, contrasting with the statistically significant difference between post- and pre-conditioning subgroups at 6 h treatment (P<0.01). The results of the present study therefore indicate that pre- and post-conditioning with lipid emulsion effectively mitigates LA-induced CNS toxicity in rats.