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Cureus May 2024Immune effector cell-associated neurotoxicity syndrome (ICANS) is a well-known side effect of chimeric antigen receptor (CAR) T-cell therapy but has occasionally been...
Glofitamab-Associated Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) Presenting as Serial Seizures and Responding Positively to Antiseizure Drugs and Anakinra: A Case Report.
Immune effector cell-associated neurotoxicity syndrome (ICANS) is a well-known side effect of chimeric antigen receptor (CAR) T-cell therapy but has occasionally been described with immune checkpoint inhibitors as well. Glofitamab-associated ICANS with a bispecific monoclonal antibody has rarely been reported. The patient is a 63-year-old male with a history of mantle cell lymphoma, diagnosed at age 37, and aggressive large-cell B-cell lymphoma, diagnosed at age 50. Despite adequate chemotherapy, immunotherapy, autologous stem cell transplantation, and CAR T-cell therapy, there were several relapses, including meningeal carcinomatosis at age 61 and intracerebral lymphoma at age 62. For this reason, glofitamab was started. One week after the ninth cycle, the patient developed drowsiness, behavioral changes, word-finding difficulties, aphasia, focal to bilateral tonic-clonic seizures, and focal onset seizures, which resolved after 16 days with levetiracetam, valproic acid, lorazepam, and midazolam. Since there was no infectious disease, electrolyte disturbance, metabolic disorder, cardiovascular disease, or relapse of lymphoma, glofitamab-associated ICANS was suspected, and anakinra was administered. The case shows that ICANS with drowsiness, behavioral changes, aphasia, and seizures can develop with glofitamab and that patients with structural brain abnormalities may be prone to this.
PubMed: 38910651
DOI: 10.7759/cureus.60833 -
Frontiers in Pharmacology 2024Brain histamine is considered an endogenous anticonvulsant and histamine H1 receptor. H1R antagonists have, in earlier studies, been found to induce convulsions....
Brain histamine is considered an endogenous anticonvulsant and histamine H1 receptor. H1R antagonists have, in earlier studies, been found to induce convulsions. Moreover, research during the last two decades has provided more information concerning the anticonvulsant activities of histamine H3R (H3R) antagonists investigated in a variety of animal epilepsy models. Therefore, the anticonvulsant effect of the H3R antagonist DL76, with proven high affinity, selectivity profile, and high antagonist potency in mice against maximal electroshock (MES)-induced seizures in mice, was assessed. Valproic acid (VPA) was used as a reference antiepileptic drug (AED). In addition, DL76 was tested for its reproductive and fetal toxicity in the same animal species. Our observations showed that acute systemic administration (intraperitoneal; i.p.) of DL76 (7.5 mg/kg, 15 mg/kg, 30 mg/kg, and 60 mg/kg, i.p.) provided significant and dose-dependent protection against MES-induced seizures in female and male mice. Moreover, the DL76-provided protective effects were comparable to those offered by the VPA and were reversed when animals were co-administered the CNS-penetrant selective H3R agonist -(α)-methylhistamine (RAM, 10 mg/kg, i.p.). Furthermore, the administration of single (7.5 mg/kg, 15 mg/kg, 30 mg/kg, or 60 mg/kg, i.p.) or multiple doses (3 × 15 mg/kg, i.p.) of H3R antagonist DL76 on gestation days (GD) 8 or 13 failed to affect the maternal body weight of mice when compared with the control mice group. No significant alterations were detected in the average number of implantations and resorptions between the control and DL76-treated groups at the early stages of gestation and the organogenesis period. In addition, no significant differences in the occurrence of skeletal abnormalities, urogenital abnormalities, exencephaly, exomphalos, facial clefts, and caudal malformations were observed. The only significant abnormalities witnessed in the treated groups of mice were in the length of long bones and body length. In conclusion, the novel H3R antagonist DL76 protected test animals against MES-induced seizures and had a low incidence of reproductive and fetal malformation with decreased long bone lengths , signifying the potential therapeutic value of H3R antagonist DL76 for future preclinical as well as clinical development for use in the management of epilepsy.
PubMed: 38903994
DOI: 10.3389/fphar.2024.1364353 -
Revista Do Colegio Brasileiro de... 2024valproic acid (VPA), an epigenetic drug, has potential for the treatment of neoplasms. Its effects on the healing of the peritoneal-musculo-aponeurotic plane (PMA) of...
INTRODUCTION
valproic acid (VPA), an epigenetic drug, has potential for the treatment of neoplasms. Its effects on the healing of the peritoneal-musculo-aponeurotic plane (PMA) of the abdominal wall are studied.
METHOD
sixty Wistar rats were allocated into two groups: experimental (VPA) and control (0.9% sodium chloride), treated daily, starting three days before the intervention and until euthanasia. Under anesthesia, a median laparotomy was performed and repaired with two synthetic layers. Assessments took place 3, 7 and 14 days after surgery. The integrity of the wounds, the quality of the inflammatory reaction, the intensity of the leukocyte infiltrate, collagen synthesis, the intensity of angiogenesis and the presence of myofibroblasts were studied.
RESULTS
there was dehiscence of the PMA plane in 11 of the 30 animals (p=0.001) in the experimental group. There was no difference in the quality and intensity of the inflammatory reaction. Immunohistochemistry revealed, in the experimental group, less collagen I (p3=0.003, p7=0.013 and p14=0.001) and more collagen III (p3=0.003, p7=0.013 and p14= 0.001). Collagen evaluated by Sirus Supra Red F3BA showed, in the experimental group, less collagen at all three times (p<0.001) with less collagen I and collagen III (p<0.001). A lower number of vessels was found on the 3rd day (p<0.001) and on the 7th day (p=0.001) and did not affect the number of myofibroblasts.
CONCLUSION
VPA showed dehiscence of the PMA plane, with less deposition of total collagen and collagen I, less angiogenic activity, without interfering with the number of myofibroblasts.
Topics: Animals; Rats, Wistar; Wound Healing; Rats; Abdominal Wall; Valproic Acid; Male; Abdominal Muscles
PubMed: 38896636
DOI: 10.1590/0100-6991e-20243676-en -
Molecules (Basel, Switzerland) May 2024Epilepsy is a prevalent neurological disorder characterized by recurrent seizures. Validamycin A (VA) is an antibiotic fungicide that inhibits trehalase activity and is...
Epilepsy is a prevalent neurological disorder characterized by recurrent seizures. Validamycin A (VA) is an antibiotic fungicide that inhibits trehalase activity and is widely used for crop protection in agriculture. In this study, we identified a novel function of VA as a potential anti-seizure medication in a zebrafish epilepsy model. Electroencephalogram (EEG) analysis demonstrated that VA reduced pentylenetetrazol (PTZ)-induced seizures in the brains of larval and adult zebrafish. Moreover, VA reduced PTZ-induced irregular movement in a behavioral assessment of adult zebrafish. The developmental toxicity test showed no observable anatomical alteration when the zebrafish larvae were treated with VA up to 10 µM within the effective range. The median lethal dose of VA in adult zebrafish was > 14,000 mg/kg. These results imply that VA does not demonstrate observable toxicity in zebrafish at concentrations effective for generating anti-seizure activity in the EEG and alleviating abnormal behavior in the PTZ-induced epileptic model. Furthermore, the effectiveness of VA was comparable to that of valproic acid. These results indicate that VA may have a potentially safer anti-seizure profile than valproic acid, thus offering promising prospects for its application in agriculture and medicine.
Topics: Animals; Zebrafish; Anticonvulsants; Disease Models, Animal; Pentylenetetrazole; Epilepsy; Seizures; Electroencephalography; Valproic Acid; Larva; Brain; Inositol
PubMed: 38893448
DOI: 10.3390/molecules29112572 -
Epilepsia Open Jun 2024To describe the sociodemographic and clinical characteristics of imprisoned patients with epilepsy seen at Samaritana University Hospital (HUS) in Bogotá D.C., between...
OBJECTIVE
To describe the sociodemographic and clinical characteristics of imprisoned patients with epilepsy seen at Samaritana University Hospital (HUS) in Bogotá D.C., between January 2017 and November 2020.
METHODS
Cross-sectional cohort study of inmate patients over 18 years of age seen at HUS between January 2017 and November 2020, with a discharge diagnosis of epilepsy. A descriptive univariate analysis of patient sociodemographic and clinical characteristics was carried out.
RESULTS
Overall, 92 patients were included, 95.7% were males with a median age of 32 years (IQR: 26-44); 65% were assessed in the outpatient clinic; median hospital length of stay was 2 days (IQR: 0) and 7.6% required admission to the intensive care unit; 75% had focal onset epilepsy, 63.04% with undetermined etiology 31.52% with structural causes. Polytherapy was found in 53.3%, valproic acid being the most frequently used antiseizure medication in 59.78%; lack of adherence was reported in 15.22% and inadequate seizure control in 81.52%; status epilepticus occurred in 5.34%. A total of 31 EEG recordings and 53 brain images were performed, of which, 29% and 39.62%, respectively, were abnormal. Non-epileptic paroxysmal events were diagnosed in 5.34%, while organic or psychiatric comorbidities were found in 25%, and the use of psychoactive substances was documented in 17.39%. Upon discharge, 93.47% had no disability, and only 45.65% returned for outpatient follow-up.
SIGNIFICANCE
The clinical profile was of men in the fourth decade of life with focal onset epilepsy characterized by high seizure frequency, most of whom were receiving antiseizure medication, with a high proportion of polytherapy. The results are a point of departure for prospective studies designed to identify points to intervene and improve healthcare for inmates with epilepsy.
PLAIN LANGUAGE SUMMARY
Inmates are a vulnerable proportion of persons with epilepsy. In this group there are significant differences compared to the general population, especially with greater psychiatric comorbidity and worse control of epileptic seizures due to difficulties in accessing medical care, antiseizure medication and diagnostic tests. We found that the most characteristic population is made up of men in the fourth decade of life with a high frequency of seizures, most of whom were receiving multiple antiseizure medication This study is the first of its kind in Latin America and it is an initial approach to epilepsy in inmates.
PubMed: 38877877
DOI: 10.1002/epi4.12995 -
Scientific Reports Jun 2024Autism spectrum disorder (ASD) is a pervasive neurodevelopmental condition characterized by social interaction deficits, communication impairments, repetitive behaviors,...
Effects of (S)-3,4-DCPG, an mGlu8 receptor agonist, on hippocampal long-term potentiation at perforant pathway-dentate gyrus synapses in prenatal valproic acid-induced rat model of autism.
Autism spectrum disorder (ASD) is a pervasive neurodevelopmental condition characterized by social interaction deficits, communication impairments, repetitive behaviors, and sensory sensitivities. While the etiology of ASD is multifaceted, abnormalities in glutamatergic neurotransmission and synaptic plasticity have been implicated. This study investigated the role of metabotropic glutamate receptor 8 (mGlu8) in modulating long-term potentiation (LTP) in a rat model of ASD induced by prenatal valproic acid (VPA) exposure. To induce an animal model with autism-like characteristics, pregnant rats received an intraperitoneal injection of 500 mg/kg of sodium valproate (NaVPA) on embryonic day 12.5. High-frequency stimulation was applied to the perforant path-dentate gyrus (PP-DG) synapse to induce LTP, while the mGlu8 receptor agonist (S)-3,4-dicarboxyphenylglycine (DCPG) was administered into the DG. The results revealed that VPA-exposed rats exhibited reduced LTP compared to controls. DCPG had contrasting effects, inhibiting LTP in controls and enhancing it in VPA-exposed rats. Moreover, reduced social novelty preference index (SNPI) in VPA-exposed rats was reversed by intra-DG administration of S-3,4-DCPG. In conclusion, our study advances our understanding of the complex relationship between glutamatergic neurotransmission, synaptic plasticity, and VPA-induced autism model. The findings suggest that mGlu8 receptor dysfunction plays a role in the impaired synaptic plasticity seen in ASD.
Topics: Animals; Valproic Acid; Long-Term Potentiation; Female; Pregnancy; Rats; Disease Models, Animal; Dentate Gyrus; Synapses; Receptors, Metabotropic Glutamate; Prenatal Exposure Delayed Effects; Perforant Pathway; Autistic Disorder; Glycine; Hippocampus; Rats, Sprague-Dawley; Autism Spectrum Disorder; Male
PubMed: 38849397
DOI: 10.1038/s41598-024-63728-y -
Gut Microbes 2024Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting over 1% of the global population. Individuals with ASD often exhibit complex behavioral...
Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting over 1% of the global population. Individuals with ASD often exhibit complex behavioral conditions, including significant social difficulties and repetitive behaviors. Moreover, ASD often co-occurs with several other conditions, including intellectual disabilities and anxiety disorders. The etiology of ASD remains largely unknown owing to its complex genetic variations and associated environmental risks. Ultimately, this poses a fundamental challenge for the development of effective ASD treatment strategies. Previously, we demonstrated that daily supplementation with the probiotic PS128 (PS128) alleviates ASD symptoms in children. However, the mechanism underlying this improvement in ASD-associated behaviors remains unclear. Here, we used a well-established ASD mouse model, induced by prenatal exposure to valproic acid (VPA), to study the physiological roles of PS128 . Overall, we showed that PS128 selectively ameliorates behavioral abnormalities in social and spatial memory in VPA-induced ASD mice. Morphological examination of dendritic architecture further revealed that PS128 facilitated the restoration of dendritic arborization and spine density in the hippocampus and prefrontal cortex of ASD mice. Notably, PS128 was crucial for restoring oxytocin levels in the paraventricular nucleus and oxytocin receptor signaling in the hippocampus. Moreover, PS128 alters the gut microbiota composition and increases the abundance of spp. and PS128-induced changes in abundance positively correlated with PS128-induced behavioral improvements. Together, our results show that PS128 treatment can effectively ameliorate ASD-associated behaviors and reinstate oxytocin levels in VPA-induced mice, thereby providing a promising strategy for the future development of ASD therapeutics.
Topics: Animals; Autism Spectrum Disorder; Mice; Probiotics; Disease Models, Animal; Social Behavior; Female; Male; Valproic Acid; Gastrointestinal Microbiome; Behavior, Animal; Mice, Inbred C57BL; Hippocampus; Pregnancy; Oxytocin; Prefrontal Cortex; Lactobacillus plantarum; Humans
PubMed: 38841895
DOI: 10.1080/19490976.2024.2359501 -
PloS One 2024Epilepsy patients exhibit considerable differences in their response to sodium valproate (VPA) therapy, a phenomenon that might be attributed to individual genetic...
OBJECTIVE
Epilepsy patients exhibit considerable differences in their response to sodium valproate (VPA) therapy, a phenomenon that might be attributed to individual genetic variances. The role of genetic variations, specifically in sodium channels encoded by SCN1A and SCN2A genes, in influencing the effectiveness of VPA in treating epilepsy is still debated. This research focuses on examining the impact of these genetic polymorphisms on the efficacy of VPA therapy among pediatric epilepsy patients in China.
METHODS
Five single nucleotide polymorphisms (SNPs), including SCN1A (rs10188577, rs2298771, rs3812718) and SCN2A (rs2304016, rs17183814), were genotyped in 233 epilepsy patients undergoing VPA therapy. The associations between genotypes and the antiepileptic effects of VPA were assessed, with 128 patients categorized as VPA responders and 105 as VPA non-responders.
RESULTS
In the context of VPA monotherapy, SCN1A rs2298771 and SCN2A rs17183814 were found to be significantly associated with VPA response (P< 0.05).
CONCLUSION
Our study suggests the findings of this investigation indicate that the polymorphisms SCN1A rs2298771 and SCN2A rs17183814 could potentially act as predictive biomarkers for the responsiveness to VPA among Chinese epilepsy patients.
Topics: Humans; NAV1.1 Voltage-Gated Sodium Channel; Valproic Acid; NAV1.2 Voltage-Gated Sodium Channel; Child; Polymorphism, Single Nucleotide; Male; Female; Epilepsy; Anticonvulsants; Child, Preschool; China; Asian People; Adolescent; Treatment Outcome; Genotype; Infant; East Asian People
PubMed: 38837984
DOI: 10.1371/journal.pone.0304869 -
Frontiers in Psychiatry 2024This case report describes an exceptionally rare case in which a prior diagnosis of schizophrenia was later determined to be early-onset Fahr's disease, linked to a...
This case report describes an exceptionally rare case in which a prior diagnosis of schizophrenia was later determined to be early-onset Fahr's disease, linked to a genetic mutation in the SLC20A2 gene. Initially, the patient exhibited symptoms resembling schizophrenia, including aggression and hostility, and was highly susceptible to medication side effects such as restlessness and Parkinsonism. Despite maintaining independent activities of daily living, his neurological examinations revealed hidden weakness on the left side. Following adjustments to the medication regimen, stability was achieved with residual psychotic symptoms under treatment with Risperidone 1.5mg/day, Valproic acid 1500mg/day, and Quetiapine 37.5mg/day. This case underscores the importance of conducting comprehensive imaging studies at the time of initial psychiatric diagnosis, regardless of the apparent typicality of the presentation. Additionally, it emphasizes the need for patience and adherence to the "Start Low and Go Slow" approach in medication management to minimize the risk of exacerbating psychiatric symptoms and aggression.
PubMed: 38835553
DOI: 10.3389/fpsyt.2024.1391607 -
JAMA Network Open Jun 2024Concerns exist about teratogenic and long-term neurodevelopmental outcomes of paternal use of valproate during spermatogenesis.
IMPORTANCE
Concerns exist about teratogenic and long-term neurodevelopmental outcomes of paternal use of valproate during spermatogenesis.
OBJECTIVE
To evaluate the association between paternal use of valproate during spermatogenesis and offspring risk of congenital malformations and neurodevelopmental disorders.
DESIGN, SETTING, AND PARTICIPANTS
This nationwide cohort study included 1 235 353 singletons born in Denmark between January 1, 1997, and December 31, 2017, identified in the Medical Birth Register; 1336 children had fathers who had filled prescriptions for valproate during spermatogenesis. Congenital malformations were identified in the first year of life and neurodevelopmental disorders were identified from 1 year of age until December 31, 2018. Statistical analysis was performed March 2024.
EXPOSURES
Paternal valproate exposure was defined as fathers who filled 1 or more prescriptions for valproate immediately before or during the time of spermatogenesis (ie, 3 months prior to conception).
MAIN OUTCOMES AND MEASURES
Children with major congenital malformations in the first year of life and with neurodevelopmental disorders before death or end of follow-up were identified in Danish health registers. Log-binomial regression was used to estimate adjusted relative risks (ARRs) of congenital malformations, and Cox proportional hazards regression was used to estimate adjusted hazards ratios (AHRs) of neurodevelopmental disorders, adjusted for relevant confounders.
RESULTS
Among 1 235 353 live births (634 415 boys [51.4%] and 600 938 girls [48.6%]), 1336 children (0.1%) had fathers who filled prescriptions for valproate during spermatogenesis. The median follow-up was 10.1 years (IQR, 5.1-14.8 years) for valproate-exposed children and 10.3 years (IQR, 5.2-15.6 years) for valproate-unexposed children. A total of 43 903 children (3.6%) received a diagnosis of major congenital malformations in the first year of life, and 51 633 children (4.2%) received a diagnosis of neurodevelopmental disorders during follow-up. When comparing the risk among valproate-exposed children with that among unexposed children, the ARR of major congenital malformations was 0.89 (95% CI, 0.67-1.18), the AHR of neurodevelopmental disorders was 1.10 (95% CI, 0.88-1.37), and the AHR of autism spectrum disorder was 0.92 (95% CI, 0.65-1.30). In analyses addressing the robustness of the findings (ie, dose-response analyses, sibling analyses, analyses restricted to children of fathers with epilepsy, analyses that used children with paternal lamotrigine exposure as active comparator, and analyses that used children with paternal exposure to valproate only before spermatogenesis as a negative control exposure), there still was no increased risk of any of the included end points.
CONCLUSIONS AND RELEVANCE
In all analyses based on this large Danish cohort study, results suggest that exposure to valproate during spermatogenesis was not associated with offspring risk of congenital malformations or neurodevelopmental disorders, including autism spectrum disorder.
Topics: Humans; Valproic Acid; Male; Denmark; Spermatogenesis; Female; Neurodevelopmental Disorders; Infant; Adult; Cohort Studies; Child, Preschool; Child; Paternal Exposure; Anticonvulsants; Registries; Infant, Newborn; Abnormalities, Drug-Induced; Risk Factors; Congenital Abnormalities; Prenatal Exposure Delayed Effects
PubMed: 38833248
DOI: 10.1001/jamanetworkopen.2024.14709