Adrenocorticotropic Hormone-Secreting Pituitary Microadenoma Presenting with Acute Psychosis, Delirium and Paroxysmal Sympathetic Hyperactivity.

Adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas are known to be associated with behavioural changes but acute presentation including psychosis and delirium are less common. We report the case of a 42-year-old female patient with a known medical history of hypertension and diabetes mellitus, presenting with acute onset behavioural changes suggestive of psychosis to a tertiary care centre in Muscat, Oman in 2022. Further evaluation revealed an ACTH dependent Cushing's disease with a pituitary microadenoma. The patient was admitted for endoscopic resection of the adenoma. During the peri-operative period, she experienced worsening of psychosis in addition to delirium. She also developed episodes of unresponsiveness, posturing, severe diaphoresis and dyspnoea accompanied by tachycardia and hypertension which were managed with midazolam and levetiracetam. A seizure work-up and computed tomography brain scan were unremarkable. At follow-up, she showed full resolution of symptoms with good blood pressure and glycaemic control.

Perfil de prescripción de levetiracetam en niños menores de cuatro años atendidos en un hospital de alta complejidad de Chile / Levetiracetam prescription profile in children younger than 4 years treated at a tertiary care hospital in Chile

Introducción. El levetiracetam (LEV) es un antiepiléptico aprobado por el Instituto de Salud Pública de Chile como terapia concomitante en crisis epilépticas en niños mayores de cuatro años. Sin embargo, es ampliamente indicado desde el periodo neonatal, lo que hace necesario evaluar su utilización fuera de ficha técnica. Objetivo. Determinar el perfil de prescripción-indicación de LEV en el tratamiento de las crisis epilépticas en menores de cuatro años en un hospital de alta complejidad del sur de Chile. Población y método. Estudio observacional, descriptivo y retrospectivo. Se revisaron las historias clínicas de quienes iniciaron tratamiento con LEV entre 2014 y 2019, y se recopilaron datos sobre variables sociodemográficas, farmacológicas y clínicas. El análisis se basó en la descripción del perfil de los pacientes, prescripción, seguimiento y seguridad. Resultados. Se incluyeron 68 pacientes: 40 (58,8 %) de sexo masculino, 49 (72,1 %) con edad gestacional ≥ 37 semanas. La etiología principal de la epilepsia fue de tipo estructural (35,3 %); el LEV se utilizó principalmente en niños diagnosticados con malformación del sistema nervioso central (17,6 %) y predominó la monoterapia (55,9 %). En el 50 % se usó LEV para crisis focales. Cinco niños (7,3 %) presentaron trastornos de tipo psiquiátrico clasificados como probables reacciones adversas al medicamento. Conclusión. El LEV se utilizó en niños con diferentes diagnósticos con baja frecuencia de eventos adversos. El perfil de utilización varió en los diferentes grupos etarios. Es necesario identificar en futuros estudios la efectividad especialmente en el recién nacido y en epilepsias refractarias.

Introduction. Levetiracetam (LEV) is an antiepileptic drug approved by the Chilean Institute of Public Health as concomitant therapy for epileptic seizures in children older than 4 years of age. However, it is widely prescribed from the neonatal period, which makes it necessary to evaluate its off-label use. Objective. To determine the prescription-indication profile of LEV in the treatment of epileptic seizures in children younger than 4 years in a tertiary care hospital in southern Chile. Population and method. Observational, descriptive, and retrospective study. The medical records of patients who started treatment with LEV between 2014 and 2019 were reviewed, and data on sociodemographic, pharmacological, and clinical variables were collected. The analysis was based on the description of the profile of patients, prescriptions, follow-up, and safety. Results. A total of 68 patients were included: 40 (58.8%) were males, 49 (72.1%) were born at a gestational age ≥ 37 weeks. The main etiology of epilepsy was structural (35.3%); LEV was mostly used in children diagnosed with central nervous system malformation (17.6%), and monotherapy was the prevailing dosage (55.9%). LEV was used for focal seizures in 50% of cases. Five children (7.3%) had psychiatric disorders, classified as probable adverse drug reactions. Conclusion. LEV was used in children with various diagnoses, with a low rate of adverse events. The profile of drug use varied in the different age groups. Future studies are needed to identify effectiveness, especially in newborn infants and patients with refractory epilepsy.

Efficacy and tolerability of levetiracetam in people with and without intellectual disabilities: A naturalistic case control study.

INTRODUCTION: People with Intellectual Disabilities (PwID) are twenty times more likely than general population to have epilepsy. Guidance for prescribing antiseizure medication (ASM) to PwID is driven by trials excluding them. Levetiracetam (LEV) is a first-line ASM in the UK. Concerns exist regarding LEV's behavioural and psychological adverse effects, particularly in PwID. There is no high-quality evidence comparing effectiveness and adverse effects in PwID to those without, prescribed LEV. METHODS: Pooled casenote data for patients prescribed LEV (2000-2020) at 18 UK NHS Trusts were analysed. Demographics, starting and maximum dose, adverse effects, dropouts and seizure frequency between ID (mild vs. moderate-profound (M/P)) and general population for a 12-month period were compared. Descriptive analysis, Mann-Whitney, Fisher's exact and logistic regression methods were employed. RESULTS: 173 PwID (mild 53 M/P 120) were compared to 200 without ID. Mean start and maximum dose were similar across all groups. PwID (Mild & M/P) were less likely to withdraw from treatment (P = 0.036). No difference was found between ID and non-ID or between ID groups (Mild vs M/P) in LEV's efficacy i.e. >50 % seizure reduction. Significant association emerged between ID severity and psychiatric adverse effects (P = 0.035). More irritability (14.2 %) and aggression (10.8 %) were reported in M/P PwID. CONCLUSION: PwID and epilepsy have high rates of premature mortality, comorbidities, treatment resistance and polypharmacy but remain poorly researched for ASM use. This is the largest studied cohort of PwID trialled on LEV compared to general population controls. Findings support prescribing of LEV for PwID as a first-line ASM.

The course of tumor-related epilepsy in glioblastoma patients: A retrospective analysis.

PURPOSE: Many patients with glioblastoma suffer from tumor-related seizures. However, there is limited data on the characteristics of tumor-related epilepsy achieving seizure freedom. The aim of this study was to characterize the course of epilepsy in patients with glioblastoma and the factors that influence it. METHODS: We retrospectively analyzed the medical records of glioblastoma patients treated at the University Hospital Erlangen between 01/2006 and 01/2020. RESULTS: In the final cohort of patients with glioblastoma (n = 520), 292 patients (56.2 %) suffered from tumor-related epilepsy (persons with epilepsy, PWE). Levetiracetam was the most commonly used first-line antiseizure medication (n = 245, 83.9 % of PWE). The onset of epilepsy was preoperative in 154/292 patients (52.7 %). 136 PWE (46.6 %) experienced only one single seizure while 27/292 PWE (9.2 %) developed drug-resistant epilepsy. Status epilepticus occurred in 48/292 patients (16.4 %). Early postoperative onset (within 30 days of surgery) of epilepsy and total gross resection (compared with debulking) were independently associated with a lower risk of further seizures. We did not detect dose-dependent pro- or antiseizure effects of radiochemotherapy. CONCLUSION: Tumor-related epilepsy occurred in more than 50% of our cohort, but drug-resistant epilepsy developed in less than 10% of cases. Epilepsy usually started before tumor surgery.

Anti-epileptic drug use during adjuvant chemo-radiotherapy is associated with poorer survival in patients with glioblastoma: A nationwide population-based cohort study.

INTRODUCTION: There are emerging but inconsistent evidences about anti-epileptic drugs (AEDs) as radio- or chemo-sensitizers to improve survival in glioblastoma patients. We conducted a nationwide population-based study to evaluate the impact of concurrent AED during post-operative chemo-radiotherapy on outcome. MATERIAL AND METHODS: A total of 1057 glioblastoma patients were identified by National Health Insurance Research Database and Cancer Registry in 2008-2015. Eligible criteria included those receiving surgery, adjuvant radiotherapy and temozolomide, and without other cancer diagnoses. Survival between patients taking concurrent AED for 14 days or more during chemo-radiotherapy (AED group) and those who did not (non-AED group) were compared, and subgroup analyses for those with valproic acid (VPA), levetiracetam (LEV), or phenytoin were performed. Multivariate analyses were used to adjust for confounding factors. RESULTS: There were 642 patients in the AED group, whereas 415 in the non-AED group. The demographic data was balanced except trend of more patients in the AED group had previous drug history of AEDs (22.6% vs. 18%, P 0.078). Overall, the AED group had significantly increased risk of mortality (HR = 1.18, P 0.016) compared to the non-AED group. Besides, an adverse dose-dependent relationship on survival was also demonstrated in the AED group (HR = 1.118, P 0.0003). In subgroup analyses, the significant detrimental effect was demonstrated in VPA group (HR = 1.29,P 0.0002), but not in LEV (HR = 1.18, P 0.079) and phenytoin (HR = 0.98, P 0.862). CONCLUSIONS: Improved survival was not observed in patients with concurrent AEDs during chemo-radiotherapy. Our real-world data did not support prophylactic use of AEDs for glioblastoma patients.

Effect of levetiracetam on DNA oxidation and glutathione content in a temporal lobe epilepsy model.

Levetiracetam (LEV) is a drug commonly used as an anticonvulsant. However, recent evidence points to a possible role as an antioxidant. We previously demonstrated the antioxidant properties of LEV by significantly increasing catalase and superoxide dismutase activities and decreasing the hydrogen peroxide (H2O2) levels in the hippocampus of rats with temporal lobe epilepsy (TLE) showing scavenging properties against the hydroxyl radical. The aim of the present work was to evaluate, the effect of LEV on DNA oxidation, by determining 8­hydroxy­2­deoxyguanosine (8­OHdG) levels, and glutathione content, through reduced (GSH) and oxidized (GSSG) glutathione levels, in the hippocampus of rats with TLE. Male Wistar rats were assigned to the control (CTRL), CTRL+LEV, epileptic (EPI) and EPI+LEV groups. TLE was induced using the lithium­pilocarpine model. Thirteen weeks after TLE induction, LEV was administered for one week through osmotic pumps implanted subcutaneously. The determination of 8­OHdG, GSH and GSSG levels were measured using spectrophotometric methods. We showed that LEV alone significantly increased 8­OHdG and GSSG levels in the hippocampus of control rats compared to those in epileptic condition. No significant differences in GSH levels were observed. LEV could induce changes in the hippocampus increasing DNA oxidation and GSSG levels under nonepileptic condition but not protecting against the mitochondrial dysfunction observed in TLE probably by mechanisms related to changes in chromatin structure, neuroinflammation and alterations in redox components.

Status epilepticus: what's new for the intensivist.

PURPOSE OF REVIEW: Status epilepticus (SE) is a common neurologic emergency affecting about 36.1/100 000 person-years that frequently requires intensive care unit (ICU) admission. There have been advances in our understanding of epidemiology, pathophysiology, and EEG monitoring of SE, and there have been large-scale treatment trials, discussed in this review. RECENT FINDINGS: Recent changes in the definitions of SE have helped guide management protocols and we have much better predictors of outcome. Observational studies have confirmed the efficacy of benzodiazepines and large treatment trials indicate that all routinely used second line treatments (i.e., levetiracetam, valproate and fosphenytoin) are equally effective. Better understanding of the pathophysiology has indicated that nonanti-seizure medications aimed at underlying pathological processes should perhaps be considered in the treatment of SE; already immunosuppressant treatments are being more widely used in particular for new onset refractory status epilepticus (NORSE) and Febrile infection-related epilepsy syndrome (FIRES) that sometimes revealed autoimmune or paraneoplastic encephalitis. Growing evidence for ICU EEG monitoring and major advances in automated analysis of the EEG could help intensivist to assess the control of electrographic seizures. SUMMARY: Research into the morbi-mortality of SE has highlighted the potential devastating effects of this condition, emphasizing the need for rapid and aggressive treatment, with particular attention to cardiorespiratory and neurological complications. Although we now have a good evidence-base for the initial status epilepticus management, the best treatments for the later stages are still unclear and clinical trials of potentially disease-modifying therapies are long overdue.

Los cambios climáticos: ¿pueden afectar en epilepsia? Revisión del tema con presentación de 2 casos clínicos / Climate change: can it affect epilepsy? Review of the topic with presentation of 2 clinical cases

Muchas enfermedades neurológicas son condiciones crónicas complejas influenciadas en muchos niveles por cambios en el medio ambiente. El cambio climático (CC) se refiere a la gama más amplia de cambios locales, regionales y globales en los patrones climáticos promedio, impulsados principalmente, en los últimos 100 años, por actividades antropogénicas. Diversas variables climáticas se asocian con una mayor frecuencia de convulsiones en personas con epilepsia. Es probable que los riesgos se vean modificados por muchos factores, que van desde la variación genética individual y la función del canal dependiente de la temperatura, hasta la calidad de la vivienda y las cadenas de suministro globales. Los diferentes tipos de epilepsia parecen tener una distinta susceptibilidad a las influencias estacionales. El aumento de la temperatura corporal, ya sea en el contexto de la fiebre o no, tiene un papel crítico en el umbral convulsivo. Es probable que los vínculos entre el cambio climático y la epilepsia sean multifactoriales, complejos y, a menudo, indirectos, lo que dificulta las predicciones. Actualmente necesitamos más datos sobre los posibles riesgos en enfermedades; entre ellas la epilepsia. Se presentan 2 casos clínicos que refieren cambios en la frecuencia de sus crisis en relación a las altas temperaturas registradas.

Many neurological diseases are complex chronic conditions influenced on many levels by changes in the environment. Climate change refers to the widest range of local, regional, and global changes in average weather patterns, driven primarily, over the past 100 years, by anthropogenic activities. Various climatic variables are associated with an increased frequency of seizures in people with epilepsy. Risks are likely to be modified by many factors, ranging from individual genetic variation and temperature-dependent channel function, to housing quality and global supply chains. Different types of epilepsy appear to have different susceptibility to seasonal influences. Increased body temperature, whether in the context of fever or not, plays a critical role in the seizure threshold. The links between climate change and epilepsy are likely to be multifactorial, complex, and often indirect, making predictions difficult. We currently need more data on the possible risks of disease; among them epilepsy. We present 2 clinical cases that refer to changes in the frequency of their seizures in relation to the high temperatures recorded.

Behavioral and neurotransmitter changes on antiepileptic drugs treatment in the zebrafish pentylenetetrazol-induced seizure model.

Epilepsy, a recurrent neurological disorder involving abnormal neurotransmitter kinetics in the brain, has emerged as a global health concern. The mechanism of epileptic seizures is thought to involve a relative imbalance between excitatory and inhibitory neurotransmitters. Despite the recent advances in clinical and basic research on the pathogenesis of epilepsy, the complex relationship between the neurotransmitter changes and behavior with and without antiepileptic drugs (AEDs) during seizures remains unclear. To investigate the effects of AEDs such as levetiracetam (LEV), carbamazepine (CBZ), and fenfluramine (FFR) on key neurotransmitters in the pentylenetetrazol (PTZ)-induced seizures in adult zebrafish, we examined the changes in glutamic acid, gamma-aminobutyric acid (GABA), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), choline, acetylcholine, norepinephrine, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and adenosine. In this study, we observed that 5-HT and DA levels in the brain increased immediately after PTZ-induced seizures. Behavioral tests clearly showed that all of these AEDs suppressed the PTZ-induced seizures. Upon treatment of PTZ-induced seizures with these AEDs, CBZ decreased the glutamic acid and FFR increased the GABA levels; however, no neurotransmitter changes were observed in the brain after LEV administration. Thus, we demonstrated a series of neurotransmitter changes linked to behavioral changes during PTZ-induced epileptic seizures when LEV, CBZ, or FFR were administered. These findings will lead to a more detailed understanding of the pathogenesis of epilepsy associated with behavioral and neurotransmitter changes under AED treatment.

Antiepileptic Strategies for Patients with Primary and Metastatic Brain Tumors.

OPINION STATEMENT: Seizure activity is common in patients with primary and metastatic brain tumors, affecting more than 50% of cases over the course of their disease. Several mechanisms contribute to brain tumor-related epilepsy (BTRE), including a pro-inflammatory environment, excessive secretion of glutamate and an increase in neuronal excitatory tone, reduction of GABAergic inhibitory activity, and an increase in 2-hydroxygluturate production in isocitrate dehydrogenase mutant tumors. After a verified seizure in a brain tumor patient, the consensus is that BTRE has developed, and it is necessary to initiate an antiepileptic drug (AED). It is not recommended to initiate AED prophylaxis. Second- and third-generation AEDs are the preferred options for initiation, due to a lack of hepatic enzyme induction and reduced likelihood for drug-drug interactions, especially in regard to neoplastic treatment. The efficacy of appropriate AEDs for patients with BTRE is fairly equivalent, although some data suggests that levetiracetam may be slightly more active in suppressing seizures than other AEDs. The consensus among most Neuro-Oncology providers is to initiate levetiracetam monotherapy after a first seizure in a brain tumor patient, as long as the patient does not have any psychiatric co-morbidities. If levetiracetam is not tolerated well or is ineffective, other appropriate initial AED options for monotherapy or as an add-on anticonvulsant include lacosamide, valproic acid, briviracetam, lamotrigine, and perampanel.

Enhanced renal clearance impacts levetiracetam concentrations in patients with traumatic brain injury with and without augmented renal clearance.

BACKGROUND: The purpose of this study was to examine the impact of ARC on levetiracetam concentrations during the first week following acute TBI. The hypothesis was levetiracetam concentrations are significantly lower in TBI patients with augmented renal clearance (ARC) compared to those with normal renal clearance. METHODS: This is a prospective cohort pharmacokinetic study of adults with moderate to severe TBI treated with levetiracetam during the first week after injury. Serial blood collections were performed daily for analysis of levetiracetam, cystatin C, and 12-hr creatinine clearance (CrCl) determinations. Patients were divided into two cohorts: with (CrCl ≥130 ml/min/1.73 m2) and without ARC. RESULTS: Twenty-two patients with moderate to severe TBI were included. The population consisted primarily of young male patients with severe TBI (mean age 40 years old, 68% male, median admission GCS 4). Each received levetiracetam 1000 mg IV every 12 h for the study period. ARC was present in 77.3% of patients, with significantly lower levetiracetam concentrations in ARC patients and below the conservative therapeutic range (< 6mcg/mL) for all study days. In patients without ARC, the serum concentrations were also below the expected range on all but two study days (Days 4 and 5). Four of the 22 (18.2%) patients exhibited seizure activity during the study period (two of these patients exhibited ARC). Cystatin C concentrations were significantly lower in patients with ARC, though the mean for all patients was within the typical normal range. CONCLUSIONS: ARC has a high prevalence in patients with moderate to severe TBI. Levetiracetam concentrations after standard dosing were low in all TBI patients, but significantly lower in patients with ARC. This study highlights the need to consider personalized drug dosing in TBI patients irrespective of the presence of ARC. CLINICAL TRIAL REGISTRATION: This study was registered at cliicaltrials.gov (NCT02437838) Registered on 08/05/2015, https://clinicaltrials.gov/ct2/show/NCT02437838 .

Levetiracetam: A Potent Sword against Microglia Polarization in Gliomas.

Crosstalk between tumor cells and peritumoral cells contributes to immunosuppressive microenvironment formation in glioblastomas (GBM). A recent study revealed that glioma stem cells activated neuronal activity to promote microglial M2 polarization, leading to GBM progression, which could be pharmacologically blocked by levetiracetam, providing a practical strategy for GBM immunotherapy. See related article by Guo et al., p. 1160.

Epilepsy in cardiofaciocutaneous syndrome: Clinical burden and response to anti-seizure medication.

Treatment-resistant epilepsy is among the most serious complications of cardiofaciocutaneous syndrome (CFCS), a rare disorder caused by germline variants in the RAS-MAPK signaling pathway. This study analyzed the clinical characteristics of epilepsy and response to anti-seizure medications (ASMs) in a multinational CFCS cohort. A caregiver survey provided data regarding seizure history, use of ASMs and other treatment approaches, adverse effects, caregiver perception of treatment response, and neurological disease burden impact among individuals with CFCS. Results from 138 survey responses were quantitatively analyzed in conjunction with molecular genetic results and neurological records. The disease burden impact of CFCS was higher among individuals with epilepsy (n = 74/138), especially those with more severe seizure presentation. Oxcarbazepine, a sodium-channel blocker, had the best seizure control profile with relatively infrequent adverse effects. The most commonly prescribed ASM, levetiracetam, demonstrated comparatively poor seizure control. ASM efficacy was generally similar for individuals with BRAF and MAP2K1 gene variants. The high proportion of patients with CFCS who experienced poor seizure control despite use of multiple ASMs highlights a substantial unmet treatment need. Prospective study of ASM efficacy and clinical trials of therapies to attenuate RAS-MAPK signaling may improve avenues for clinical management.

Neuronal Activity Promotes Glioma Progression by Inducing Proneural-to-Mesenchymal Transition in Glioma Stem Cells.

Neuronal activity can drive progression of high-grade glioma by mediating mitogen production and neuron-glioma synaptic communications. Glioma stem cells (GSC) also play a significant role in progression, therapy resistance, and recurrence in glioma, which implicates potential cross-talk between neuronal activity and GSC biology. Here, we manipulated neuronal activity using chemogenetics in vitro and in vivo to study how it influences GSCs. Neuronal activity supported glioblastoma (GBM) progression and radioresistance through exosome-induced proneural-to-mesenchymal transition (PMT) of GSCs. Molecularly, neuronal activation led to elevated miR-184-3p in neuron-derived exosomes that were taken up by GSCs and reduced the mRNA N6-methyladenosine (m6A) levels by inhibiting RBM15 expression. RBM15 deficiency decreased m6A modification of DLG3 mRNA and subsequently induced GSC PMT by activating the STAT3 pathway. Loss of miR-184-3p in cortical neurons reduced GSC xenograft growth, even when neurons were activated. Levetiracetam, an antiepileptic drug, reduced the neuronal production of miR-184-3p-enriched exosomes, inhibited GSC PMT, and increased radiosensitivity of tumors to prolong survival in xenograft mouse models. Together, these findings indicate that exosomes derived from active neurons promote GBM progression and radioresistance by inducing PMT of GSCs. SIGNIFICANCE: Active neurons secrete exosomes enriched with miR-184-3p that promote glioblastoma progression and radioresistance by driving the proneural-to-mesenchymal transition in glioma stem cells, which can be reversed by antiseizure medication levetiracetam.

Hypoxia-Induced Neuronal Activity in Glioma Patients Polarizes Microglia by Potentiating RNA m6A Demethylation.

PURPOSE: Neuronal activity in the brain has been reported to promote the malignant progression of glioma cells via nonsynaptic paracrine and electrical synaptic integration mechanisms. However, the interaction between neuronal activity and the immune microenvironment in glioblastoma (GBM) remains largely unclear. EXPERIMENTAL DESIGN: By applying chemogenetic techniques, we enhanced and inhibited neuronal activity in vitro and in a mouse model to study how neuronal activity regulates microglial polarization and affects GBM progression. RESULTS: We demonstrate that hypoxia drove glioma stem cells (GSC) to produce higher levels of glutamate, which activated local neurons. Neuronal activity promoted GBM progression by facilitating microglial M2 polarization through enriching miR-200c-3p in neuron-derived exosomes, which decreased the expression of the m6A writer zinc finger CCCH-type containing 13 (ZC3H13) in microglia, impairing methylation of dual specificity phosphatase 9 (DUSP9) mRNA. Downregulation of DUSP9 promoted ERK pathway activation, which subsequently induced microglial M2 polarization. In the mouse model, cortical neuronal activation promoted microglial M2 polarization whereas cortical neuronal inhibition decreased microglial M2 polarization in GBM xenografts. miR-200c-3p knockdown in cortical neurons impaired microglial M2 polarization and GBM xenograft growth, even when cortical neurons were activated. Treatment with the anti-seizure medication levetiracetam impaired neuronal activation and subsequently reduced neuron-mediated microglial M2 polarization. CONCLUSIONS: These findings indicated that hypoxic GSC-induced neuron activation promotes GBM progression by polarizing microglia via the exosomal miR-200c-3p/ZC3H13/DUSP9/p-ERK pathway. Levetiracetam, an antiepileptic drug, blocks the abnormal activation of neurons in GBM and impairs activity-dependent GBM progression. See related commentary by Cui et al., p. 1073.

Patterns of Antiseizure Medication Use Following Meningioma Resection: A Single-Institution Experience.

OBJECTIVE: To investigate antiseizure medication (ASM) practice behavior for patients who present with seizures before meningioma resection and to review postoperative ASM management. METHODS: A retrospective study was performed of 112 consecutive patients with meningiomas who underwent resection at a single institution between October 2016 and January 2020. Data were collected through detailed chart review. RESULTS: Of 112 patients, 35 (31%) had a preoperative seizure, and 43 (38%) were prescribed a preoperative ASM. At discharge, 96 patients (86%) were prescribed an ASM, most often 1000 mg daily of levetiracetam (64%, 61/96) and less often higher doses of levetiracetam or other ASMs. By the 6-month postoperative visit, 55 patients (49%) were taking at least 1 ASM, most commonly levetiracetam monotherapy (65%) at 500 mg twice daily (47%). This number further decreased to 45 (40%) patients by 1-year follow-up and 36 (32%) patients by last-known follow-up. By last follow-up (median 27.3 months; range 5.4-57.4 months), 24 patients (21%) had experienced a postoperative seizure, and 36 patients (32%) were never able to discontinue ASMs. Of patients remaining on levetiracetam monotherapy, only 36% remained on levetiracetam 500 mg twice daily. CONCLUSIONS: Approximately two thirds (68%) of patients who underwent surgical resection of meningioma were eventually able to completely discontinue their postoperative ASM regimen. However, nearly one third (32%) of patients required long-term ASM management. Levetiracetam monotherapy was the most common ASM prescribed during the postoperative period, and the proportion of patients requiring either higher doses of levetiracetam or alternative ASMs increased over time.

Apolipoprotein E3 functionalized lipid-drug conjugated nanoparticles of Levetiracetam for enhanced delivery to the brain: In-vitro cell line studies and in-vivo study.

A significant portion of brain-tumor patients suffer from 'brain-tumor-related epilepsy (BTE)' which results in depression, anxiety and hampered quality of life. Conventional anti-epileptic drugs indicate negative interaction with other drugs augmenting the poor outcome of overall therapy. Levetiracetam (LVM) has evidenced effectiveness for BTE but its hydrophilicity restricts the passage into blood-brain barrier. The majority of lipid nanoparticles fails to load hydrophilic drug sufficiently. Therefore, lipid-drug conjugates (LDC) were synthesized using stearic acid via amide bond formation confirmed by FTIR and NMR. The nanoparticles of synthesized LDC were prepared by solvent injection method followed by functionalization with Apolipoprotein E3 (ApoE3@LDC-NP). The nanoparticles were characterized by DSC, XRD, particle size (131.6 ± 1.24 nm), zeta potential (-15.6 ± 0.09 mV), and for storage stability. In-vitro release study indicated initial burst release of 20 ± 0.63 % followed by sustained release up to 30 h (66 ± 1.40 %) for ApoE3@LDC-NP. The cell-line study on HEK293 indicated no significant cytotoxic effect and greater cell uptake through U87MG cell line. The pharmacokinetic and bio-distribution study indicated 2.5-fold greater brain-targeting of ApoE3@LDC-NP as compared to LVM solution. It proved safe in the haemolysis study and exhibited the absence of tissue necrosis. Thus, ApoE3@LDC-NP might be a promising approach for effective brain-targeting of LVM for improved clinical response in BTE.

Management of Complications in Neuro-oncology Patients.

OBJECTIVE: The purpose of this article is to familiarize the reader with the spectrum of neurologic and medical complications relevant to the care of patients with neurologic cancer while highlighting best practices to prevent morbidity and mortality. Topics include tumor-related epilepsy, vasogenic edema, complications of corticosteroid use, disruption of the hypothalamic-pituitary axis, venous thromboembolism, and opportunistic infection. LATEST DEVELOPMENTS: In 2021, a joint guideline from the Society for Neuro-Oncology and the European Association of Neuro-Oncology reaffirmed recommendations first established in 2000 that patients with newly diagnosed brain tumors should not be prescribed an antiseizure medication prophylactically. For those with tumor-related epilepsy, monotherapy with a non-enzyme-inducing anticonvulsant is the preferred initial treatment, and levetiracetam remains the preferred first choice. Surveys of physician practice continue to demonstrate excessive use of glucocorticoids in the management of patients with both primary and metastatic central nervous system malignancy. This is particularly concerning among patients who require checkpoint inhibitors as the efficacy of these agents is blunted by concomitant glucocorticoid use, resulting in a reduction in overall survival. Finally, direct oral anticoagulants have been shown to be safe in patients with brain tumors and are now favored as first-line treatment among those who require treatment for venous thromboembolism. ESSENTIAL POINTS: Medical care for patients impacted by primary and secondary central nervous system malignancy is complex and requires a committed team-based approach that routinely calls upon the expertise of physicians across multiple fields. Neurologists have an important role to play and should be familiar with the spectrum of complications impacting these patients as well as the latest recommendations for management.

Mioclonías positivas y negativas en paciente con enfermedad renal crónica / Positive and negative myoclonus in a patient with end stage renal disease

Introducción: Las mioclonías son contracciones musculares paroxísticas de corta duración o pérdida abrupta del tono muscular, denominadas mioclonías positivas y negativas, respectivamente. Se presenta un caso clínico de mioclonías positivas y negativas generalizadas y se pretende describir los múltiples mecanismos fisiopatológicos y etiologías que lo desencadenan. Presentación del caso: Hombre de 35 años, con diabetes mellitus tipo 1 complicada con enfermedad renal diabética en hemodiálisis, desarrolló una bacteriemia asociada a catéter por Staphylococcus aureus y presentó mioclonías positivas y negativas. Se identificaron como posibles desencadenantes la uremia, la infección y los fármacos con potencial promioclónico; el hallazgo incidental de una lesión isquémica en núcleo caudado no explicaba la semiología encontrada en el paciente. Se hizo el control y retiro de todos los factores promioclónicos enunciados, junto a manejo farmacológico con levetiracetam, y con ello se logró el control de los síntomas. Discusión: Los pacientes con enfermedad renal crónica son susceptibles a la acumulación de productos tóxicos de tipo guanidinas, que tienen potencial para producir mioclonías. Además, las infecciones, el uso de fármacos con potencial promioclónico y lesiones estructurales como las isquemias corticales son etiologías que deben considerarse en el diagnóstico diferencial. El mayor impacto en los síntomas se observa con el control del factor desencadenante, y, en caso de persistir, la terapia farmacológica proporciona buenos resultados. Conclusión: Las mioclonías son trastornos del movimiento relativamente comunes en la enfermedad renal crónica. La identificación del desencadenante es crucial para su manejo junto al uso de fármacos con actividad antimioclónica.

Introduction: Myoclonus are paroxysmal muscle contractions of short duration or abrupt loss of muscle tone, called positive and negative myoclonus respectively. A clinical case of generalized positive and negative myoclonus is presented and the aim is to describe the multiple pathophysiological mechanisms and etiologies that trigger it. Case presentation: A 35-year-old man with type 1 diabetes mellitus complicated by diabetic kidney disease on hemodialysis developed catheter-associated bacteremia due to Staphylococcus aureus and presented positive and negative myoclonus. Uremia, infection, and drugs with pro-myoclonic potential were identified as possible triggers; The incidental finding of an ischemic lesion in the caudate nucleus did not explain the semiology found in the patient. The control and removal of all the pro-myoclonic factors mentioned was carried out, along with pharmacological management with levetiracetam, thus achieving control of the symptoms. Discussion: Patients with chronic kidney disease are susceptible to the accumulation of guanidine-type toxic products, which have the potential to produce myoclonus. Furthermore, infections, the use of drugs with pro-myoclonic potential and structural lesions such as cortical ischemia are etiologies that should be considered in the differential diagnosis. The greatest impact on symptoms is observed with the control of the triggering factor and if it persists, pharmacological therapy provides good results. Conclusion: Myoclonus are relatively common movement disorders in chronic kidney disease. Identification of the trigger is crucial for its management along with the use of drugs with anti-myoclonic activity.