Ropivacaine: An Unusual Cause of Neuroleptic Malignant-Like Syndrome

Ropivacaine is commonly used for post-operative pain management. We describe a case of neuroleptic malignant-like syndrome in a woman administered ropivacaine delivered using a drug infusion balloon. The presenting symptoms were confusion, agitation and fever. Blood analysis showed elevated C-reactive protein, leucocytosis and increased creatine phosphokinase. As intoxication was suspected, ropivacaine was suspended and the patient gradually improved. Possible leakage of ropivacaine into the intrathecal space may have resulted in central nervous system toxicity.

Intracerebral administration of CTLA-4 and PD-1 immune checkpoint blocking monoclonal antibodies in patients with recurrent glioblastoma: a phase I clinical trial

BackgroundPatients with recurrent glioblastoma (rGB) have a poor prognosis with a median overall survival (OS) of 30–39 weeks in prospective clinical trials. Intravenous administration of programmed cell death protein 1 and cytotoxic T-lymphocyte-associated antigen 4 inhibitors has low activity in patients with rGB. In this phase I clinical trial, intracerebral (IC) administration of ipilimumab (IPI) and nivolumab (NIVO) in combination with intravenous administration of NIVO was investigated.MethodsWithin 24 hours following the intravenous administration of a fixed dose (10 mg) of NIVO, patients underwent a maximal safe resection, followed by injection of IPI (10 mg; cohort-1), or IPI (5 mg) plus NIVO (10 mg; cohort-2) in the brain tissue lining the resection cavity. Intravenous administration of NIVO (10 mg) was repeated every 2 weeks (max. five administrations). Next generation sequencing and RNA gene expression profiling was performed on resected tumor tissue.ResultsTwenty-seven patients were enrolled (cohort-1: n=3; cohort-2: n=24). All patients underwent maximal safe resection and planned IC administrations and preoperative NIVO. Thirteen patients (cohort-1: n=3; cohort-2: n=10) received all five postoperative intravenous doses of NIVO. In cohort-2, 14 patients received a median of 3 (range 1–4) intravenous doses. Subacute postoperative neurological deterioration (n=2) was reversible on steroid treatment; no other central nervous system toxicity was observed. Immune-related adverse events were infrequent and mild. GB recurrence was diagnosed in 26 patients (median progression-free survival (PFS) is 11.7 weeks (range 2–152)); 21 patients have died due to progression. Median OS is 38 weeks (95% CI: 27 to 49) with a 6-month, 1-year, and 2-year OS-rate of, respectively, 74.1% (95% CI: 57 to 90), 40.7% (95% CI: 22 to 59), and 27% (95% CI: 9 to 44). OS compares favorable against a historical cohort (descriptive Log-Rank p>0.003). No significant difference was found with respect to PFS (descriptive Log-Rank test p>0.05). A higher tumor mRNA expression level of B7-H3 was associated with a significantly worse survival (multivariate Cox logistic regression, p>0.029).ConclusionIC administration of NIVO and IPI following maximal safe resection of rGB was feasible, safe, and associated with encouraging OS.Trial registrationNCT03233152.

CAR T Cell-Based Immunotherapy for the Treatment of Glioblastoma

Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor in adults. Current treatment options typically consist of surgery followed by chemotherapy or more frequently radiotherapy, however, median patient survival remains at just over 1 year. Therefore, the need for novel curative therapies for GBM is vital. Characterization of GBM cells has contributed to identify several molecules as targets for immunotherapy-based treatments such as EGFR/EGFRvIII, IL13Rα2, B7-H3, and CSPG4. Cytotoxic T lymphocytes collected from a patient can be genetically modified to express a chimeric antigen receptor (CAR) specific for an identified tumor antigen (TA). These CAR T cells can then be re-administered to the patient to identify and eliminate cancer cells. The impressive clinical responses to TA-specific CAR T cell-based therapies in patients with hematological malignancies have generated a lot of interest in the application of this strategy with solid tumors including GBM. Several clinical trials are evaluating TA-specific CAR T cells to treat GBM. Unfortunately, the efficacy of CAR T cells against solid tumors has been limited due to several factors. These include the immunosuppressive tumor microenvironment, inadequate trafficking and infiltration of CAR T cells and their lack of persistence and activity. In particular, GBM has specific limitations to overcome including acquired resistance to therapy, limited diffusion across the blood brain barrier and risks of central nervous system toxicity. Here we review current CAR T cell-based approaches for the treatment of GBM and summarize the mechanisms being explored in pre-clinical, as well as clinical studies to improve their anti-tumor activity.

Pharmacogenetics of the Central Nervous System—Toxicity and Relapse Affecting the CNS in Pediatric Acute Lymphoblastic Leukemia

Despite improving cure rates in childhood acute lymphoblastic leukemia (ALL), therapeutic side effects and relapse are ongoing challenges. These can also affect the central nervous system (CNS). Our aim was to identify germline gene polymorphisms that influence the risk of CNS events. Sixty single nucleotide polymorphisms (SNPs) in 20 genes were genotyped in a Hungarian non-matched ALL cohort of 36 cases with chemotherapy related acute toxic encephalopathy (ATE) and 544 controls. Five significant SNPs were further analyzed in an extended Austrian-Czech-NOPHO cohort (n = 107 cases, n = 211 controls) but none of the associations could be validated. Overall populations including all nations’ matched cohorts for ATE (n = 426) with seizure subgroup (n = 133) and posterior reversible encephalopathy syndrome (PRES, n = 251) were analyzed, as well. We found that patients with ABCB1 rs1045642, rs1128503 or rs2032582 TT genotypes were more prone to have seizures but those with rs1045642 TT developed PRES less frequently. The same SNPs were also examined in relation to ALL relapse on a case-control matched cohort of 320 patients from all groups. Those with rs1128503 CC or rs2032582 GG genotypes showed higher incidence of CNS relapse. Our results suggest that blood-brain-barrier drug transporter gene-polymorphisms might have an inverse association with seizures and CNS relapse.

Local Anesthetic-Induced Central Nervous System Toxicity during Interscalene Brachial Plexus Block: A Case Series Study of Three Patients

Local anesthetics are commonly administered by nuchal infiltration to provide a temporary interscalene brachial plexus block (ISB) in a surgical setting. Although less commonly reported, local anesthetics can induce central nervous system toxicity. In this case study, we present three patients with acute central nervous system toxicity induced by local anesthetics applied during ISB with emphasis on neurological symptoms, key neuroradiological findings and functional outcome. Medical history, clinical and imaging findings, and outcome of three patients with local anesthetic-induced toxic left hemisphere syndrome during left ISB were analyzed. All patients were admitted to our neurological intensive care unit between November 2016 and September 2019. All three patients presented in poor clinical condition with impaired consciousness and left hemisphere syndrome. Electroencephalography revealed slow wave activity in the affected hemisphere of all patients. Seizure activity with progression to status epilepticus was observed in one patient. In two out of three patients, cortical FLAIR hyperintensities and restricted diffusion in the territory of the left internal carotid artery were observed in magnetic resonance imaging. Assessment of neurological severity scores revealed spontaneous partial reversibility of neurological symptoms. Local anesthetic-induced CNS toxicity during ISB can lead to severe neurological impairment and anatomically variable cerebral lesions.

Long-term Implication of Metronidazole Induced Reversible Cerebellar Toxicity and Peripheral Neuropathy- A Case Report

Metronidazole Induced Encephalopathy (MIE) is rare and serious central nervous system toxicity. A 40-year-old male, on long-term self treatment with metronidazole (cumulative dose: 102 gm) presented with dysarthria, nystagmus, unsteadiness, and numbness in both legs. A Magnetic Resonance Imaging (MRI) scan of the brain revealed a symmetric hyperintensity in both the dentate nuclei of cerebellum on both T2 weighted and Fluid-Attenuated Inversion-Recovery (FLAIR) imaging. Discontinuation of metronidazole resulted in resolution of the imaging findings and clinical improvement occurred within one month. Metronidazole-induced neurotoxicity should be considered in patient who present with cerebellar symptoms and characteristic lesion on MRI in close temporal relation with metronidazole intake and drug should be discontinued to prevent permanent neurological deficit.

Long-term Implication of Metronidazole Induced Reversible Cerebellar Toxicity and Peripheral Neuropathy- A Case Report

Metronidazole Induced Encephalopathy (MIE) is rare and serious central nervous system toxicity. A 40-year-old male, on long-term self treatment with metronidazole (cumulative dose: 102 gm) presented with dysarthria, nystagmus, unsteadiness, and numbness in both legs. A Magnetic Resonance Imaging (MRI) scan of the brain revealed a symmetric hyperintensity in both the dentate nuclei of cerebellum on both T2 weighted and Fluid-Attenuated Inversion-Recovery (FLAIR) imaging. Discontinuation of metronidazole resulted in resolution of the imaging findings and clinical improvement occurred within one month. Metronidazole-induced neurotoxicity should be considered in patient who present with cerebellar symptoms and characteristic lesion on MRI in close temporal relation with metronidazole intake and drug should be discontinued to prevent permanent neurological deficit.

Possible protection against cisplatin induced behavioral changes by dietary antioxidants in adult albino mice.

Cisplatin (Cis) has been proved to be successful in treating cancers but it has several toxicities. Central nervous system toxicity is considered as one of its most common toxic effects. Vitamin E and Green tea are antioxidant with proven results on prevention of life threatening diseases. Objectives: To assess the preventive role of two antioxidants vitamin E and green tea against cisplatin induced neurobehavioral abnormalities in albino mice. Study Design: Experimental Study. Setting: Department of Anatomy, Liaquat University of Medical and Health Sciences (LUMHS) Jamshoro, in collaboration with Sindh Agriculture University TandoJam. Material & Methods: A total of 60 mice were grouped in to Group A, (control), Group B (Cisplatin), Group C (Cisplatin plus vitamin E) and Group D (cisplatin plus green tea). The weight, gross features and behavior of the animals was monitored before and in between drug administration. Behavioral studies were performed in quiet atmosphere, and included Pain stimulation test, heat Stimulation test, cold Stimulation test, Hearing, Object Recognition test. Results: A significant decrease in weight and body hair of the Cis treated animals was noticed as compared to control animals. Paw edema, mental orientation, object recognition, noise stimulation, heat and cold stimulation, time to move away from the stimulus were also significantly different to control. All features were improved with the addition of vitamin E and green tea. Conclusion: Toxic effects of cisplatin, on morphology and behavior of adult albino mice partially abrogated with antioxidant supplementation.