Acute Central Nervous System Toxicity Research Articles

Working with cattle slurry on farms: emission and dispersion of hydrogen sulfide gas during stirring.

Over the past 15 years, there have been numerous fatalities related to working with animal slurry. Working with cattle slurry releases toxic gases, in particular, hydrogen sulphide (H2S), which can cause acute central nervous system toxicity, breathing difficulties, and death if exposed to high concentrations. Real-time measurements of H2S gas were taken over distance and time, during the stirring of cattle slurry on farms. Gas was measured at eight slurry stores with differing typical configurations of indoor or outdoor stores and with or without slatted flooring. Highest H2S gas levels were measured from indoor stores under slatted floors, and generally at positions closest to the stirrer or the point of maximum stirring, with levels decreasing with distance from source. Most of the data indicate H2S gas levels increase very rapidly after stirring starts, and mostly decline to baseline levels within 30 min post start of stirring. There were, however, circumstances where gas levels remained high and only started to decline once the stirrer had stopped. H2S gas levels at all farms, at all positions measured were consistently below 10 ppm within 30 min of the stirrer being stopped. The current data highlight areas of the farm and ways of working that have the potential for workers and others to be at risk of exposure to toxic slurry gases. The area should be left to ventilate naturally for at least 30 min after the stirrer has been stopped before re-entering buildings. Influencing the design of stirring equipment and future slurry stores would likely reduce the risk of worker exposure to slurry gases.

Favorable efficacy and reduced acute neurotoxicity by antisense oligonucleotides with 2′,4′-BNA/LNA with 9-(aminoethoxy)phenoxazine

An increasing number of antisense oligonucleotides (ASOs) have been approved for clinical use. However, improvements of both efficacy and safety in the central nervous system (CNS) are crucial for the treatment with CNS diseases. We aimed to overcome the crucial issues by our development of various gapmer ASOs with anovel nucleoside derivative including a 2',4'-BNA/LNA with9-(aminoethoxy)phenoxazine (BNAP-AEO). The various gapmer ASOs with BNAP-AEO were evaluated for thermal stability, invitro and invivo efficacy, and acute CNS toxicity. Thermal stability analysis of the duplexes with their complementary RNAs showed that ASOs with BNAP-AEO had a higher binding affinity than those without BNAP-AEO. Invitro assays, when transfected into neuroblastoma cell lines, demonstrated that ASOs with BNAP-AEO, had a more efficient gene silencing effect than those without BNAP-AEO. Invivo assays, involving intracerebroventricular injections into mice, revealed ASOs with BNAP-AEO potently suppressed gene expression in the brain. Surprisingly, the acute CNS toxicity in mice, as assessed through open field tests and scoring systems, was significantly lower for ASOs with BNAP-AEO than for those without BNAP-AEO. This study underscores the efficient gene-silencing effect and low acute CNS toxicity of ASOs incorporating BNAP-AEO, indicating the potential for future therapeutic applications.

Transient Mutism Related to Capecitabine-Induced Acute Toxic Leukoencephalopathy

Capecitabine, a precursor of 5-fluorouracil (5-FU), is a well-tolerated and safe chemotherapy that has been used to treat breast, pancreatic, and colorectal cancers. Albeit rare, both 5-FU and capecitbine have been reported to be associated with acute central nervous system toxicity, including cerebellar dysfunction, posterior reversible encephalopathy syndrome, and transient leukoencephalopathies. Here we present a case of 32-year-old female, demonstrating transient mutism related to capecitabine induced acute toxic leukoencephalopathy.

Acute central nervous system toxicity during treatment of pediatric acute lymphoblastic leukemia: phenotypes, risk factors and genotypes

Central nervous system (CNS) toxicity is common at diagnosis and during treatment of pediatric acute lymphoblastic leukemia (ALL). We studied CNS toxicity in 1,464 children aged 1.0–17.9 years, diagnosed with ALL and treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol. Genome-wide association studies, and a candidate single-nucleotide polymorphism (SNP; n=19) study were performed in 1,166 patients. Findings were validated in an independent Australian cohort of children with ALL (n=797) in whom two phenotypes were evaluated: diverse CNS toxicities (n=103) and methotrexate-related CNS toxicity (n=48). In total, 135/1,464 (9.2%) patients experienced CNS toxicity for a cumulative incidence of 8.7% (95% confidence interval: 7.31–10.20) at 12 months from diagnosis. Patients aged ≥10 years had a higher risk of CNS toxicity than had younger patients (16.3% vs. 7.4%; P<0.001). The most common CNS toxicities were posterior reversible encephalopathy syndrome (n=52, 43 with seizures), sinus venous thrombosis (n=28, 9 with seizures), and isolated seizures (n=16). The most significant SNP identified by the genome-wide association studies did not reach genomic significance (lowest P-value: 1.11x10-6), but several were annotated in genes regulating neuronal functions. In candidate SNP analysis, ATXN1 rs68082256, related to epilepsy, was associated with seizures in patients <10 years (P=0.01). ATXN1 rs68082256 was validated in the Australian cohort with diverse CNS toxicities (P=0.04). The role of ATXN1 as well as the novel SNP in neurotoxicity in pediatric ALL should be further explored.

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

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. 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. Our research in the FPDB identified six patients who, within 3days 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 8.5days 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. 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.

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.

Use of Stereotactic Radiosurgery in Elderly and Very Elderly Patients With Brain Metastases to Limit Toxicity Associated With Whole Brain Radiation Therapy

We evaluated the toxicity associated with stereotactic radiosurgery (SRS) and whole brain radiation therapy (WBRT) in elderly and very elderly patients with brain metastases, as the role of SRS in geriatric patients who would traditionally receive WBRT is unclear. We conducted a retrospective review of elderly patients (aged 70-79years) and very elderly patients (aged ≥80years) with brain metastases who underwent RT from 2010 to 2015 at Johns Hopkins Hospital. Patients received either upfront WBRT or SRS for metastatic solid malignancies, excluding small cell lung cancer. Acute central nervous system toxicity within 3months of RT was graded using the Radiation Therapy Oncology Group acute radiation central nervous system morbidity scale. The toxicity data between age groups and treatment modalities were analyzed using Fisher's exact test and multivariate logistic regression analysis. Kaplan-Meier curves were used to estimate the median overall survival, and the Cox proportion hazard model was used for multivariate analysis. A total of 811 brain metastases received RT in 119 geriatric patients. The median overall survival from the diagnosis of brain metastases was 4.3months for the patients undergoing WBRT and 14.4months for the patients undergoing SRS. On multivariate analysis, WBRT was associated with worse overall survival in this cohort of geriatric patients (odds ratio [OR] 3.7, 95% confidence interval [CI] 1.9-7.0, P<.0001) and age ≥80years was not. WBRT was associated with significantly greater rates of any grade 1 to 4 toxicity (OR 7.5, 95% CI 1.6-33.3, P=.009) and grade 2 to 4 toxicity (OR 2.8, 95% CI 1.0-8.1, P=.047) on multivariate analysis. Elderly and very elderly patients did not have significantly different statistically acute toxicity rates when stratified by age. WBRT was associated with increased toxicity compared with SRS in elderly and very elderly patients with brain metastases. SRS, rather than WBRT, should be prospectively evaluated in geriatric patients with the goal of minimizing treatment-related toxicity.

Electrophysiological Monitoring in Patients With Tumors of the Skull Base Treated by Carbon-12 Radiation Therapy

To report the results of short-term electrophysiologic monitoring of patients undergoing (12)C therapy for the treatment of skull chordomas and chondrosarcomas unsuitable for radical surgery. Conventional electroencephalogram (EEG) and retinal and cortical electrophysiologic responses to contrast stimuli were recorded from 30 patients undergoing carbon ion radiation therapy, within a few hours before the first treatment and after completion of therapy. Methodologies and procedures were compliant with the guidelines of the International Federation for Clinical Neurophysiology and International Society for Clinical Electrophysiology of Vision. At baseline, clinical signs were reported in 56.6% of subjects. Electrophysiologic test results were abnormal in 76.7% (EEG), 78.6% (cortical evoked potentials), and 92.8% (electroretinogram) of cases, without correlation with neurologic signs, tumor location, or therapy plan. Results on EEG, but not electroretinograms and cortical responses, were more often abnormal in patients with reported clinical signs. Abnormal EEG results and retinal/cortical responses improved after therapy in 40% (EEG), 62.5% (cortical potentials), and 70% (electroretinogram) of cases. Results on EEG worsened after therapy in one-third of patients whose recordings were normal at baseline. The percentages of subjects whose EEG results improved or worsened after therapy and the improvement of retinal/cortical responses in the majority of patients are indicative of a limited or negligible (and possibly transient) acute central nervous system toxicity of carbon ion therapy, with a significant beneficial effect on the visual pathways. Research on large samples would validate electrophysiologic procedures as a possible independent test for central nervous system toxicity and allow investigation of the correlation with clinical signs; repeated testing overtime after therapy would demonstrate, and may help predict, possible late toxicity.

Sodium nitrite induces acute central nervous system toxicity in guinea pigs exposed to systemic cell-free hemoglobin

Systemic cell-free hemoglobin (Hb) released via hemolysis disrupts vascular homeostasis, in part, through the scavenging of nitric oxide (NO). Sodium nitrite (NaNO2) therapy can attenuate the hypertensive effects of Hb. However, the chemical reactivity of NaNO2 with Hb may enhance heme- or iron-mediated toxicities. Here, we investigate the effect of NaNO2 on the central nervous system (CNS) in guinea pigs exposed to systemic cell-free Hb. Intravascular infusion of NaNO2, at doses sufficient to alleviate Hb-mediated blood pressure changes, reduced the expression of occludin, but not zona occludens-1 (ZO-1) or claudin-5, in cerebral tight junctions 4h after Hb infusion. This was accompanied by increased perivascular heme oxygenase-1 expression, neuronal iron deposition, increased astrocyte and microglial activation, and reduced expression of neuron-specific nuclear protein (NeuN). These CNS changes were not observed in animals treated with Hb or NaNO2 alone. Taken together, these findings suggest that the use of nitrite salts to treat systemic Hb exposure may promote acute CNS toxicity.

Semicontinuous Low-Dose-Rate Teletherapy for the Treatment of Recurrent Glial Brain Tumors: Final Report of a Phase I/II Study

Semicontinuous low-dose-rate teletherapy (SLDR) is a novel irradiation strategy that exploits the increased radiosensitivity of glial cells in a narrow range of reduced dose rate. We present the final report of a prospective Phase I/II study testing the feasibility of SLDR for the treatment of recurrent gliomas. Patients with previously irradiated recurrent gliomas were enrolled from November 1993 to March 1998. Patients received SLDR, delivered 6 to 8 hours/day at a dose rate of 40 to 50 cGy/hour for a total dose of 30 to 35 Gy given over 12 days using a modified cobalt-60 treatment unit. Acute central nervous system toxicity after SLDR treatment was the primary endpoint. Overall survival was a secondary endpoint. Twenty patients were enrolled (14 World Health Organization Grade 4 glioma, 5 Grade 2 glioma, 1 ependymoma). No patients developed ≥ Grade 3 central nervous system toxicity at 3 months without radiographic evidence of tumor progression. Overall survival after SLDR was 56% at 6 months, 28% at 12 months, and 17% at 24 months. One patient survived >48 months, and 1 patient survived >60 months after SLDR treatment. Re-resection before SLDR treatment significantly improved 1-year overall survival for all patients and patients with Grade 4 glioma. The delivery of SLDR is feasible in patients with recurrent gliomas and resulted in improved outcomes for patients who underwent re-resection. There were 2 long-term survivors (>48 months). This pilot study supports the notion that reduced dose rate influences the efficacy and tolerance of reirradiation in the treatment of recurrent gliomas.

Glyphosate–surfactant herbicide-induced reversible encephalopathy

Glyphosate–surfactant (GlySH) is a commonly used herbicide that has been used in attempted suicide. Most reports of GlySH toxicity in patients have followed ingestion of the commercial product “Round-up” (Monsanto Ltd; Melbourne, Victoria, Australia), which consists of a mixture of glyphosate (as a isopropylanine salt) and a surfactant (polyoxyethyleneamine). Ingestion of Round-up is reported to cause significant toxicity including nausea, vomiting, oral and abdominal pain. Renal and hepatic impairment and pulmonary oedema may also occur. Impaired consciousness and encephalopathy have been reported as sequelae but there are limited data on the central nervous system (CNS) effects of Round-up toxicity. We report a 71-year-old male who attempted suicide with GlySH and developed a prolonged but reversible encephalopathy suggestive of acute CNS toxicity.

High-dose radiotherapy to 78 Gy with or without temozolomide for high grade gliomas

To describe outcomes associated with high-dose radiotherapy with and without temozolomide for high grade central nervous system (CNS) neoplasms. Retrospective chart review of 60 patients diagnosed with malignant glioma treated with > or =70 Gy radiotherapy. Median age at diagnosis was 52 years, and 52 patients had astrocytomas (38 glioblastomas). Median prescribed radiotherapy dose was 78 Gy (range 70-80), and 29 patients received concurrent temozolomide. Eighty-six percent completed the planned course treatment. Three patients experienced RTOG grade 3 acute CNS toxicity; late brain necrosis was suspected in four patients. Overall median survival was 13 months (range 2-83). Within glioblastoma patients, temozolomide provided a statistically significant survival improvement over no chemotherapy (median survival 12.7 vs. 7.5 months; P = 0.0058). High dose conformal radiotherapy to > or =70 Gy with chemotherapy for high-grade CNS neoplasms appears safe but survival remains suboptimal. Within glioblastoma patients, temozolomide provided statistically significant survival improvement over no chemotherapy.

Intractable Epilepsy Secondary to Cyclosporine Toxicity in Children Undergoing Allogeneic Hematopoietic Bone Marrow Transplantation

The long-term evolution to intractable epilepsy in children treated with cyclosporine administered for graft-versus-host-disease after hematopoietic stem cell transplantation was evaluated. In a group of 185 children treated with cyclosporine after bone marrow transplantation, 15 (8%) presented with acute seizures that were generalized in 7 and focal in 7 and had absence status in 1. Electroencephalography (EEG) and neuroimaging showed predominant abnormalities in the occipital regions. One patient died shortly after the seizure; in seven cases, seizures remitted, whereas relapses were observed in seven others. After the first year, seizures persisted chronically in four cases and evolved to intractable epilepsy. Focal temporal epilepsy was diagnosed in three cases, whereas in the fourth case, a multifocal epilepsy was observed. Magnetic resonance imaging (MRI) detected mesial temporal sclerosis in all of these cases. The risk factors associated with evolution to epilepsy included lower age at transplantation (3-5 years), more than one relapsing seizure in the first year after transplantation, and longer treatment with cyclosporine. Not only can cyclosporine cause acute central nervous system toxicity, it can also determine intractable epilepsy associated with mesial temporal sclerosis.

Intensity-modulated radiation therapy (IMRT) for meningioma

Purpose: To assess the safety and efficacy of intensity-modulated radiation therapy (IMRT) in the treatment of intracranial meningioma. Methods and Materials: Forty patients with intracranial meningioma (excluding optic nerve sheath meningiomas) were treated using IMRT with the NOMOS Peacock system between 1994 and 1999. Twenty-five patients received IMRT after surgery either as adjuvant therapy for incomplete resection or for recurrence, and 15 patients received definitive IMRT after presumptive diagnosis based on imaging. Thirty-two patients had skull base lesions, and 8 had nonskull base lesions. The prescribed dose ranged from 40 to 56 Gy (median 50.4 Gy) at 1.71 to 2 Gy per fraction, and the volume of the primary target ranged from 1.55 to 324.57 cc (median 20.22 cc). The mean dose to the target ranged from 44 to 60 Gy (median 53 Gy). Follow-up ranged from 6 to 71 months (median 30 months). Acute and chronic toxicity were assessed using Radiation Therapy Oncology Group (RTOG) morbidity criteria and tumor response was assessed by patient report, examination, and imaging. Overall survival, progression-free survival, and local control were calculated using the Kaplan-Meier method. Results: Cumulative 5-year local control, progression-free survival, and overall survival were 93%, 88%, and 89%, respectively. Two patients progressed after IMRT, one locally and one distantly. Each was treated with IMRT after multiple recurrences of benign meningioma over many years. Both were found to have malignant meningioma at the time of relapse after IMRT, and it is likely their tumors had already undergone malignant change by the time IMRT was given. Defined normal structures generally received a significantly lower dose than the target. The most common acute central nervous system (CNS) toxicity was mild headache, usually relieved with steroids. One patient experienced RTOG Grade 3 acute CNS toxicity, and 2 experienced Grade 3 or higher late CNS toxicity, with one possible treatment-related death. No toxicity was observed with mean doses to the optic nerve/chiasm up to 47 Gy and maximum doses up to 55 Gy. Conclusion: IMRT is a promising new technology that is safe and efficacious in the primary and adjuvant treatment of intracranial meningiomas. A history of local aggression may indicate malignant degeneration and predict a poorer outcome. Toxicity data are encouraging, but the potential for serious side effects exists, as demonstrated by one possible treatment-related death. Larger cohort and longer follow-up are needed to better define efficacy and late toxicity of IMRT.

A phase I study of the combination of two hypoxic cell radiosensitizers, Ro 03-8799 and SR-2508: Toxicity and pharmacokinetics

The hypoxic cell radiosensitizer Ro 03-8799 produces acute central nervous system toxicity which limits repeated doses of the drug to 0.75 g/m 2, but peripheral neuropathy does not occur. SR-2508 causes no acute effects at doses > 3.0 g/m 2, but causes peripheral neuropathy at cumulative doses of 30 g/M 2. By combining maximum tolerated doses of each agent, it may be possible to increase efficacy, but not toxicity. Escalating single doses of Ro 03-8799 and SR-2508 were administered to 10 patients. The drugs were infused together in 50 ml of 0.9% saline over 10 min, beginning at 0.5 g/m 2 of each agent, and proceeding to a fixed dose of 0.75 g/m 2 Ro 03-8799 with 0.5, 1.0, 2.0, and 3.0 g/m 2 SR-2508. Four patients experienced the expected acute syndrome related to Ro 03-8799, but the incidence was not increased by escalating doses of SR-2508, and no peripheral neuropathy was seen. Plasma and urine pharmacokinetic studies showed that no drug interaction occurred. Six patients have been given a 9-dose regime over a 3 week period, using 0.75 g/m 2 Ro 03-8799 and escalating doses of 0.5, 1.0, and 1.5 g/m 2 SR-2508. All exhibited the expected acute side effects related to Ro 03-8799, but with no increase at the higher doses of SR-2508. No other toxicity was seen. Plasma pharmacokinetics performed at the beginning and end of the schedule were similar. Biopsies were taken from six superficial tumors following combined radiosensitizer administration. Mean tumor concentrations over the 30 min following the end of infusion were 30 and 72 μg/g for Ro 03-8799 and SR-2508, respectively. These values would be expected to translate into an approximate single dose sensitizer enhancement ratio of 1.5 to 1.6, offering a significant gain over the enhancement possible with the drugs given alone. The overall advantage will be determined by the maximum dose levels and number of doses possible; the escalation of both parameters is now in progress.

A clinical phase I toxicity study of Ro 03-8799: plasma, urine, tumour and normal brain pharmacokinetics.

Ro 03-8799 is a lipophilic, basic 2-nitroimidazole of greater potency than misonidazole, which we have administered to 52 patients. The dose-limiting toxicity is an acute central nervous system toxicity with symptoms which include nausea, disorientation, sweating, a feeling of heat and, in one extreme case, coma. Pharmacokinetic analysis was carried out in 31 patients. The mean distribution phase half-life was 44 min and the mean elimination half-life was 6.1 h. Peak concentration was linearly related to dose over the range 0.25 g/m2 to 3 g/m2 with a mean at 1 g/m2 of 15.7 micrograms/ml. Area under the curve was also linearly related to dose and the average whole body clearance was 20.1 l/h. Urinary recovery at 24 h was 31% for the parent compound and 28% for the N-oxide metabolite. The drug is concentrated in normal brain, brain tumour and non-brain tumour to a similar extent, the respective mean tissue/plasma ratios being 381%, 329% and 355%. For a dose of 1 g/m2, tumour concentrations were 1.5 times as high as for misonidazole, and the available in vivo and in vitro sensitisation data predict as improvement of 1.8 and 3.3 times respectively.