Adverse Neurological Symptoms Research Articles

What Chemsex does to the brain - neural correlates (ERP) regarding decision making, impulsivity and hypersexuality.

Chemsex describes the use of specific substances (methamphetamine, GHB/GBL, mephedrone, ketamine) which initiate or enhance sexual experiences and is mainly prevalent among men who have sex with men. Many Chemsex users experience somatic complications (for example sexually transmitted diseases) and sometimes adverse sociological, psychological, and neurological symptoms, such as depression, impulse control disorders or hypersexuality. Changes in impulsivity and deficits in executive functions have demonstrated to be associated with addiction and impulse control disorders as well as frontal brain dysfunction and behavioral control deficits. This study aims to explore the effects of neurophysiological correlates of inhibition and decision making in Chemsex users with an EEG paradigm using event-related potentials (N2, P3). 15 Chemsex users and 14 matched control subjects, all of them men who have sex with man, participated in an auditory Go/NoGo/Voluntary Selection EEG paradigm. In addition, clinical data (e.g. regarding depression), demographic information as well as measures of well-being and sexual behavior were collected. The results demonstrated that clinical symptoms, hypersexuality, and sexual risk behavior were more pronounced in Chemsex users compared to non-users. P3 amplitudes did not differ significantly between groups. However, the Chemsex users showed decreased electrophysiological N2 responses in fronto-central brain regions during decision-making, indicating compromised executive function and inhibitory control. The observed impairments may lead to increased risk behavior regarding drug abuse and hypersexuality. Understanding the neurobiological mechanisms can contribute to targeted interventions in order to mitigate the negative consequences of engaging in Chemsex and improve general well-being.

IMMU-37. TARGETING NON-CATALYTIC ACTIVATORS OF THE PROTEASOME DECREASES TUMOR GROWTH AND ENHANCES ANTIGEN PRESENTATION IN GLIOBLASTOMA

Abstract Glioblastoma (GBM) is the most common adult primary brain tumor plagued by inevitable recurrence and poor survival. We recently performed a genome wide CRISPR/Cas9 essentiality screen in GBM stem cells, revealing a plethora of potential targets for further exploration. The proteasome is a multimeric protein complex that degrades cellular proteins contributing to homeostatic proteostasis, stress response, and antigen presentation. Most proteasomal subunits are essential for GBM stem cell growth in vitro, however, they are also essential for non-malignant neural cells, suggesting that inhibition of those subunits may lead to toxicity. Indeed, adverse neurological symptoms were prevalent in phase III clinical trials for the brain penetrant proteasome inhibitor, Marizomib, which may be linked to the vital role of proteasome subunits in non-malignant neural counterparts. Proteasome inhibitors target the catalytic subunits of the proteasome, however the role of individual proteasome activators, most of which are non-essential for growth in vitro, have not been fully elucidated in GBM. Here, we examined the functionality of non-essential proteasome activator subunits in GBM stem cells in vitro and in vivo. Surprisingly, despite lack of growth changes in vitro, we observed abrogated stem-cell self-renewal in vitro and improved survival in vivo in orthotopic xenograft models following targeting of specific activator subunits. Molecular profiling of targeted cells revealed an upregulation of interferon-γ signaling and upregulation of antigen presentation machinery. Thus, targeting specific activator subunits may inhibit malignant growth in vivo while sparing normal neural counterparts from proteotoxic stress. We are further investigating enhanced antigen presentation by targeting these proteasome activator subunits and examining changes in the tumor microenvironment and survival in syngeneic immunocompetent models of GBM. Further understanding of this mechanism may provide novel targets for GBM treatment or improve immunotherapies in GBM.

Application of metagenomics for diagnosis of broilers displaying neurological symptoms

BackgroundThirty-two-day-old broiler chickens at a farm located in northwestern South Korea displayed adverse neurological symptoms including limping, lying down, and head shaking. Approximately 2.1% of chickens died or were culled due to severe symptoms. Five carcasses were submitted to the Avian Disease Division of the Animal and Plant Quarantine Agency (APQA) for disease diagnosis.ResultsBroilers displayed severe pericarditis and perihepatitis associated with gross lesions. Broilers also displayed microscopic lesions in the cerebrum and in the granular layer of the cerebellum, which were associated with multifocal perivascular cuffing and purulent necrosis in the cerebrum, and severe meningitis with heterophil and lymphocyte infiltration. Staphylococcus spp. were identified in the liver and heart using bacteriological culture. PCR/RT-PCR assays revealed that broilers were negative for avian Clostridium botulinum, Newcastle disease virus, and avian encephalomyelitis virus. Bacterial and viral metagenomic analysis of brain sample further revealed the presence of Pseudomonas spp. and Marek’s disease virus, which are known etiological agents of chicken meningoencephalitis.ConclusionsThis study reports a diagnostic analysis of gross and histopathological lesions from 32-day-old broilers displaying unique neurological symptoms that revealed the presence of the several neurological diseases including meningoencephalitis. The causative agents associated with meningoencephalitis of broilers that had not been identified by routine diagnostic methods could be diagnosed by metagenomics, which proves the usefulness of metagenomics as a diagnostic tool for unknown neurological diseases in broilers.

Critical pediatric neurological illness associated with COVID-19 (Omicron BA.2.3.7 variant) infection in Taiwan: immunological assessment and viral genome analysis in tertiary medical center

ObjectivesSince April 2022, another wave of the Omicron epidemic has struck Taiwanese society, and children with severe neurological complications have been reported frequently. A few cases even developed acute fulminant encephalitis. To investigate the possible causes of the increased incidence of such complications in Taiwan, we reviewed several cases of pediatric patients with severe neurological symptoms. MethodsWe collected the medical records of pediatric patients with COVID-19 infection who presented with severe neurological symptoms. The COVID-19 infection was diagnosed by nasal swab reverse transcriptase-polymerase chain reaction. The remaining samples were sent for whole genome sequencing and spike (S) protein amino acid variation mapping. ResultsThe increase of several inflammatory markers was observed in all patients included in this study. However, none of the cerebrospinal fluid samples tested positive for SARS-CoV-2. The result of whole genome sequencing showed that all the sequences belonged to the lineage BA.2.3.7. However, the sequences had a K97E mutation in the S protein that differed from other BA.2.3.7 lineage strains, which was located at the S protein N-terminal domain. ConclusionThe new mutation in the S protein, which had not previously been observed but was discovered in this study, potentially explains the sudden increase in incidence of extremely adverse neurological symptoms in pediatric patients.

Pre- and postnatal exposure to multiple ambient air pollutants and child behavioral problems at five years of age

Ambient air pollution is emerging as a risk factor for adverse neurological symptoms and early childhood diseases. This study aimed to evaluate the association between pre- and postnatal exposure to air pollutants and childhood behavior by using MOCEH prospective birth cohort data. In total, 353 mother-child pairs at birth, who completed child behavioral assessments using the Korean version of the Child Behavior Checklist at five years of age, were included in the study.Multivariate linear regression (MLR) for single pollutant and Bayesian kernel machine regression (BKMR) for multiple pollutants were conducted. MLR analysis showed that air pollutant exposures during the first trimester were significantly associated with the internalizing problems score after adjusting for covariates. The estimates were 0.19 (0.05–0.32) per 1 μg/m3 increase in PM2.5, 0.13 (0.04–0.22) per 1 μg/m3 increase in PM10, and 0.20 (0.02–0.37) per 1 ppb increase in NO2. The BKMR model analysis revealed that the overall effects of multiple air pollutants during the first trimester of pregnancy and 0–6 months of the infantile period were significantly associated with behavioral problems. Boys showed a stronger associations than girls.Taken together, these results showed that the first trimester of pregnancy and 0–6 months of the infantile period were important for air pollutant exposure because exposure at these periods was associated with behavioral problems in 5-year-old children. Future efforts are required to control air pollution levels and reduce the health burden of vulnerable populations, including pregnant women and children.

A Case Report on: Non-Symptomatic SARS-CoV-2 Results in Adverse Neurological Symptoms - Von Willebrand Factor (VWF) May Have A Casual or Causal Link

A Case Report on: Non-Symptomatic SARS-CoV-2 Results in Adverse Neurological Symptoms - Von Willebrand Factor (VWF) May Have A Casual or Causal Link

Cytotoxicity of cobalt chloride in brain cell lines - a comparison between astrocytoma and neuroblastoma cells

High levels of circulating cobalt ions in blood have been reported to induce systemic reactions in patients with metal-on-metal (MoM) hip implants. We still lack information regarding these adverse effects, which may specifically impact on patients showing adverse neurological symptoms. To investigate this, we used a battery of in vitro viability and proliferation assays to identify toxic cobalt chloride (CoCl2) concentrations in two different brain cell types: SH-SY5Y neuroblastoma and U-373 astrocytoma cells. Cobalt cytotoxicity was characterised by MTT and Neutral Red (NR) assays at concentrations ranging from 0 to 500 μM after 24, 48, and 72 h exposure. MTT and NR showed a dose- and time-dependent toxicity with cobalt decreasing cell viability at high concentrations. IC50s for MTT at 72 h (astrocytes: 333.15 ± 22.88; neurons: 100.01 ± 5.91 μM) and for BrdU proliferation assays (astrocytes: 212.89 ± 9.84; neurons: 88.86 ± 19.03 μM) demonstrate that SH-SY5Y neurons are significantly more vulnerable to cobalt than astrocytes. Increased BrdU and MTT assay sensitivity suggested that DNA synthesis and metabolism disruption were involved in Co toxicity.Intracellular cobalt level measured by ICP-MS was significant after 100 μM treatment. Astrocytes displayed improved resistance to cobalt toxicity and higher uptake, which may reflect their neuroprotective nature. In summary, exposure to high concentrations of extracellular cobalt has deleterious effects in neurons and astrocytes, with neurons showing particular sensitivity.

Multifunctional Supramolecular Hydrogel for Prevention of Epidural Adhesion after Laminectomy.

Postoperative epidural adhesion remains a clinically challenging problem in spine surgery. Currently there are no effective and safe antifibrotic and antiadhesion biomaterials that have been specifically developed for this complication in clinical practice. Herein we designed and engineered an advanced antiadhesion hydrogel with multiple functionalities, including temperature-responsive gelation, self-healing, tissue adhesiveness, antioxidation, anti-inflammation, and antifibrosis. This multifunctional supramolecular hydrogel can be facilely constructed by integrating three functional modules, i.e., a thermosensitive triblock copolymer, poloxamer 407 (PX); a reactive oxygen species-eliminating and anti-inflammatory nanoparticle (TPCD NP); and an adhesion-enhancing compound, tannic acid (TA). The optimal formulation (PXNT) was hierarchically screened based on in vitro properties and in vivo activities. Therapeutically, local treatment with PXNT hydrogel effectively prevented epidural fibrosis and adhesion after laminectomy in both rats and rabbits. Of note, PXNT hydrogel showed more beneficial efficacy than different control thermosensitive hydrogels and a commercially available barrier product, Interceed. Mechanistically, PXNT hydrogel significantly attenuated local oxidative stress, inhibited inflammatory responses, and reduced fibrotic tissue formation. Moreover, treatment with PXNT hydrogel did not cause systemic adverse effects and neurological symptoms. Consequently, PXNT hydrogel is a highly promising biomaterial for preventing postlaminectomy epidural adhesion and adhesions after other surgeries.

Association study of genetic polymorphisms in proteins involved in oseltamivir transport, metabolism, and interactions with adverse reactions in Mexican patients with acute respiratory diseases

Oseltamivir, a pro-drug, is the best option for treatment and chemoprophylaxis for influenza outbreaks. However, many patients treated with oseltamivir developed adverse reactions, including hypersensitivity, gastritis, and neurological symptoms. The aim of this study was to determine the adverse drug reactions (ADRs) in Mexican patients treated with oseltamivir and whether these ADRs are associated with SNPs of the genes involved in the metabolism, transport, and interactions of oseltamivir. This study recruited 310 Mexican patients with acute respiratory diseases and treated them with oseltamivir (75 mg/day for 5 days) because they were suspected to have influenza A/H1N1 virus infection. Clinical data were obtained from medical records and interviews. Genotyping was performed using real-time polymerase chain reaction and TaqMan probes. The association was assessed under genetic models with contingency tables and logistic regression analysis. Out of 310 patients, only 38 (12.25%) presented ADRs to oseltamivir: hypersensitivity (1.9%), gastritis (10%), and depression and anxiety (0.9%). The polymorphism ABCB1-rs1045642 was associated with adverse drug reactions under the recessive model (P = 0.017); allele C was associated with no adverse drug reactions, while allele T was associated with adverse drug reactions. The polymorphisms SLC15A1-rs2297322, ABCB1-rs2032582, and CES1-rs2307243 were not consistent with Hardy–Weinberg equilibrium, and no other associations were found for the remaining polymorphisms. In conclusion, the polymorphism rs1045642 in the transporter encoded by the ABCB1 gene is a potential predictive biomarker of ADRs in oseltamivir treatment.

SUN-407 A Clinical Lesson in Adipsic Diabetes Insipidus

Background: Adipsic diabetes insipidus (ADI) is a rare condition with approximately 100 reported cases word wide. Inpatient management can be challenging as patients are predisposed to dysnatremia during this time. Societal guidelines offer little guidance in management of this complex disease. Case: A 62-year-old woman with a history of acromegaly with transphenoidal resection more than 20 years ago, complicated by post-operative hypothyroidism, adrenal insufficiency and adipsic diabetes insipidus presented for admission for a planned cycle on of chemotherapy for her recently diagnosed diffuse large B-cell lymphoma. At admission her initial serum sodium was 130 mmol/L (reference 135-145 mmol/L) near her baseline level. During her 8 day stay she experienced significant fluctuations of serum sodium with a peak level of 151 mmol/L and a nadir of 123 mmol/L. Despite these shifts she experienced no adverse neurological symptoms. 3 weeks later she was again admitted for planned chemotherapy. During this admission she received the same medication treatment protocol as her prior stay, however, the management principles for ADI suggested by Cuesta et al. were applied. The result was a more stable serum sodium with a range of 130-145 mmol/L and no change in concentration by more than 5 mmol/L in a single 24 hour period. Patient was clinically stable and asymptomatic throughout her hospital stay Discussion: When compared to diabetes insipidus with intact thirst sensation, patients with ADI have been shown to be at increased risk for both hypernatremia and hyponatremia during inpatient admission. The risk is further increased when the admission is for an illness not related to pituitary dysfunction. This case represents an important clinical lesson in ADI where simple management principles led to a drastic change in the patient’s serum sodium. Fortunately, this patient tolerated the sodium shifts well, and did not require critical care interventions to correct her dysnatremia. Among the most important principles were transition from intranasal to oral DDAVP for a more predictable treatment response and the use of oral fluids instead of IV whenever possible. Applying these principles at the time of admission allowed for a better understanding of the treatment goals by the multidisciplinary healthcare team. Although ADI is rare, applying these simple interventions at the time of admission is likely to benefit all patients with diabetes insipidus.

Issue Cover (February 2018)

Front cover: Background: Alcohol abuse disorders are associated with adverse neurological symptoms and neurotoxicity. However, despite being one of the most commonly abused substances, the physiological effects of ethanol are not well defined. Main finding: By combining Drosophila, an ideal system for modelling ethanol disorders given their strong homology with mammals and natural response to ethanol, with high spatiotemporal resolution live-imaging of vesicle motility, we found that acute, low doses of ethanol result in increased flux of fluorescently-labeled neuropeptide vesicles toward neuromuscular junctions. Pharmacological treatments to increase (wortmannin) or decrease (LiCl) active GSK-3 levels revealed that GSK-3 is critical in mediating this stimulatory effect of ethanol. Implications: These results yield novel insight into the neurophysiological effects of ethanol and provide a possible link between behavioral responses to ethanol and neuropeptide transport. Image content: Time (y axis, 30 seconds) versus distance (x axis, 90 μm) graph of real-time movement of GFP-tagged neuropeptide vesicles in living Drosophila larvae. The reduced vesicle motility by wortmannin feeding is partially rescued by acute treatment with low dose ethanol. Read the full article ‘Ethanol stimulates the in vivo axonal movement of neuropeptide dense-core vesicles in Drosophila motor neurons’ by G. J. Iacobucci and S. Gunawardena (J. Neurochem. 2018, vol. 144(4), pp. 466–482) on doi: 10.1111/jnc.14230

Role of paediatric assist device in bridge to transplant.

While heart transplantation has gained recognition as the gold standard therapy for advanced heart failure, the scarcity of donor organs has become an important concern. The evolution of surgical alternatives such as ventricular assist devices (VADs), allow for recovery of the myocardium and ensure patient survival until heart transplantation becomes possible. This report elaborates the role of VADs as a bridge to heart transplantation in infants and children (≤18 years old) with end-stage heart failure. A retrospective review of the medical records of 201 heart transplant recipients between May 1986 and September 2014 identified 78 children [38.8%; mean age 7.2 (7.8±6.0) years old; IQR: 2.6-11.8 years] with advanced heart failure who were supported with a VAD [left VAD (LVAD) =21; biventricular VAD (BVAD) =57] as a bridge to heart transplantation. Fourteen (17.9%) patients were less than 1 year old; 15 (19.2%) children had a cardiac arrest and underwent cardiopulmonary resuscitation, with 7 of these patients also requiring extracorporeal membrane oxygenation (ECMO) support prior to implantation of a VAD. The aetiology of heart failure was primarily cardiomyopathy (dilative, restrictive from endocardial fibrosis, idiopathic or toxic-induced), reported in 56 (71.8%) patients. The VADs employed were primarily Berlin Heart EXCOR® (n=63), HeartWare (n=13), Berlin Heart INCOR® (n=1), and Toyobo (n=1). Mean duration of VAD support was 59 (133.37±191.57) days (range, 1-945 days; IQR: 23-133 days) before a donor heart became available. The primary complication encountered while patients were being bridged to transplant was mediastinal bleeding (7.8%). The main indication for pump exchanges was thrombus formation in the valves. There was no incidence of technical failure of the blood pump or driving system components. Skin infections around the cannulae occurred in 2.5%. Adverse neurological symptoms (thromboembolism 11.1%, cerebral haemorrhage 3.6%) that occurred did not have any permanent neurological sequelae that could be detected on clinical examination in this study. Mean duration of follow-up was 9.4 (10.3±7.6) years (IQR: 3.74-15.14 years). Cumulative survival rates of patients bridged to transplantation with VAD were 93.6%±2.8%, 84.6%±4.1%, 79.1%±4.7%, 63.8%±6.2%, 61.6%±7.1%, and 52.1%±9.3% at 30 days, 1, 5, 10, 15 and 20 years, respectively. There was no statistically significant difference (P=0.79) in survival rates of patients bridged to heart transplantation with VAD compared to those who underwent primary heart transplantation. Post-transplant survival rates stratified according to the type of VAD implanted and number of ventricles supported were not statistically different (P=0.93 and 0.73, respectively). In addition, post-transplant survival rates were not significantly different when age, gender and diagnosis were adjusted for. Furthermore, no statistically significant difference was found when post-transplant survival rates of children who had episodes of rejection were compared to those who did not have episodes of rejection. The results in this series demonstrate that VADs satisfactorily support paediatric patients with advanced heart failure from a variety of aetiologies until heart transplantation. The data further suggests that patients bridged with VADs have comparable long-term post-transplant survival as those undergoing primary heart transplantation.

B12 deficiency is common in infants and is accompanied by serious neurological symptoms

Adverse neurological symptoms have been linked to vitamin B12 deficiency in infants. This explorative study described the clinical presentation associated with vitamin B12 deficiency in this age group. The study comprised infants who were born between 2004 and 2012 and were tested for vitamin B12 levels after they were admitted to a hospital with neurological symptoms at less than one year of age. Vitamin B12 deficiency was defined as low cobalamin in serum and/or increased homocysteine and/or increased methylmalonate. It was diagnosed according to the applicable International Classification of Diseases, 10th revision, and recorded as vitamin B12 deficiency in the medical records. All information was retrieved from medical records and compared to symptomatic infants with normal levels. Of the 121 infants tested, 35 had vitamin B12 deficiency and 86 had normal levels. Vitamin B12 deficiency was diagnosed at an average age of 1.7 months and was more common among boys. Seizures and apparent life-threatening events were the most common symptoms among infants with B12 deficiency compared to infants with normal levels. Vitamin B12 deficiency was more common in infants than we expected and presented with severe symptoms, such as seizures and apparent life-threatening events.

Malignant Lymphoma of the Brain, and Dementia

A differential diagnosis of acute and subacute progressive dementias includes malignant lymphoma of the brain. We reviewed primary central nervous system lymphoma (PCNSL), intravascular lymphomatosis (IVL), lymphomatosis cerebri, and the relapse and invasion of systemic lymphomas. PCNSL is confined to the central nervous system; the infiltration and compression by the lymphoma result in adverse neurological symptoms. IVL is a rare form of malignant lymphoma that is characterized by the proliferation of primarily B-cell type lymphoma cells within the blood vessels of various organs. This causes ischemia and results in the associated neurological symptoms. Medical history and neuroimaging studies provide crucial informations to distinguish the lymphomas from other diseases that cause dementia, such an Alzheimer's disease. MRI imaging of the brain using contrast agent, and the biopsy of diseased tissues are essential for the diagnosis of the lymphomas. A histopathological examination is the most effective way to diagnose malignant lymphomas of the brain. Presently, the treatment of choice for PCNSL is the intravenous administration of high dose methotrexate with and without radiation therapy. Futhermore, Rituximab-containing chemotherapy has proved to greatly improve the prognosis of IVL. A better outcome can be achieved with the earlier diagnosis and treatment of the malignant lymphoma of the brain.

Actin-myosin network influences morphological response of neuronal cells to altered osmolarity.

Acute osmotic fluctuations in the brain occur during a number of clinical conditions and can result in a variety of adverse neurological symptoms. Osmotic perturbation can cause changes in the volumes of intra- and extracellular fluid and, due to the rigidity of the skull, can alter intracranial pressure thus making it difficult to analyze purely osmotic effects in vivo. The present study aims to determine the effects of changes in osmolarity on SH-SY5Y human neuroblastoma cells in vitro, and the role of the actin-myosin network in regulating this response. Cells were exposed to hyper- or hypoosmotic media and morphological and cytoskeletal responses were recorded. Hyperosmotic shock resulted in a drop in cell body volume and planar area, a persisting shape deformation, and increases in cellular translocation. Hypoosmotic shock did not significantly alter planar area, but caused a transient increase in cell body volume and an increase in cellular translocation via the development of small protrusions rich in actin. Disruption of the actin-myosin network with latrunculin and blebbistatin resulted in changes to volume and shape regulation, and a decrease in cellular translocation. In both osmotic perturbations, no apparent disruptions to cytoskeletal integrity were observed by light microscopy. Overall, because osmotically induced changes persisted even after volume regulation occurred, it is possible that osmotic stress may play a larger role in neurological dysfunction than currently believed.

Neurological and chest symptoms following sclerotherapy: A single centre experience

Documentation and analysis of adverse neurological and chest symptoms in a large single centre series of sclerotherapy treatments. In this retrospective study, patient-reported adverse events occurring during liquid or foam sclerotherapy were recorded over a 30 month period and subsequently analyzed. The relevant patient records were reviewed to determine patient characteristics, treatment details and results of subsequent investigations. A total of 1744 ultrasound guided sclerotherapy treatments were performed during the study period. Almost all treatments were done with air-based sodium tetradecyl sulphate foam. During the same time period, 6504 direct vision surface vein sclerotherapy treatments were completed. Approximately 1/4 of these utilized air-based foam in varying concentrations. There were 14 adverse events in 14 patients involving neurological or chest symptoms for an incidence of 0.17%. Five patients injected with foam complained of isolated chest discomfort, tightness or shortness of breath. Nine patients reported various brief neurological symptoms. These events occurred with both liquid and foam, although the majority involved foam. More neurological events were associated with direct vision sclerotherapy of smaller superficial veins than with ultrasound guided injection of intrafascial truncular veins. Seven patients who experienced neurological symptoms had a history of migraine. Five of the patients who had neurological events were investigated for right to left shunts and found to be positive. These events were uncommon and brief. The incidence of neurological and chest symptoms was higher with foam sclerotherapy than with liquid. A history of migraine with aura was associated with an increased risk of post-treatment neurological symptoms. Events occurred with both large vein and small vein treatment. Some events were associated with liquid sclerotherapy rather than foam and with carbon dioxide based foam as well as air foam. There were no long-term adverse consequences.

Mefloquine neurotoxicity is mediated by non-receptor tyrosine kinase

Among several available antimalarial drugs, mefloquine has proven to be effective against drug-resistant Plasmodium falciparum and remains the drug of choice for both therapy and chemoprophylaxis. However, mefloquine is known to cause adverse neurological and/or psychiatric symptoms, which offset its therapeutic advantage. The exact mechanisms leading to the adverse neurological effects of mefloquine are poorly defined. Alterations in neurotransmitter release and calcium homeostasis, the inhibition of cholinesterases and the interaction with adenosine A2A receptors have been hypothesized to play prominent roles in mediating the deleterious effects of this drug. Our recent data have established that mefloquine can also trigger oxidative damage and subsequent neurodegeneration in rat cortical primary neurons. Furthermore, we have utilized a system biology-centered approach and have constructed a pathway model of cellular responses to mefloquine, identifying non-receptor tyrosine kinase 2 (Pyk2) as a critical target in mediating mefloquine neurotoxicity. In this study, we sought to establish an experimental validation of Pyk2 using gene-silencing techniques (siRNA). We have examined whether the downregulation of Pyk2 in primary rat cortical neurons alters mefloquine neurotoxicity by evaluating cell viability, apoptosis and oxidative stress. Results from our study have confirmed that mefloquine neurotoxicity is associated with apoptotic response and oxidative injury, and we have demonstrated that mefloquine affects primary rat cortical neurons, at least in part, via Pyk2. The implication of these findings may prove beneficial in suppressing the neurological side effects of mefloquine and developing effective therapeutic modalities to offset its adverse effects.

Identification of Malaria Retinopathy Improves the Specificity of the Clinical Diagnosis of Cerebral Malaria: Findings from a Prospective Cohort Study

The diagnosis of cerebral malaria (CM) is difficult to confirm in endemic regions with limited neurodiagnostics. Accurate diagnoses are critical for trials and outcomes studies. Findings from an autopsy-based study suggest that identifying malaria retinopathy in children satisfying the standard clinical case definition of CM improves our ability to accurately diagnose CM in vivo. In a post hoc analysis of a prospective exposure-control study to evaluate CM as a risk factor for epilepsy, we stratified children meeting the standard case definition by their retinopathy status (presence versus absence) and compared these groups for pre-existing risk factors for epilepsy. We also compared them to the concurrently enrolled, non-comatose controls. Children meeting the standard case definition of CM who lacked malaria retinopathy had a higher prevalence of pre-existing developmental problems and family history of epilepsy. This subset of patients may represent children with a pre-existing propensity to adverse neurologic symptoms and outcomes.

Modafinil for the treatment of hypersomnia associated with myotonic muscular dystrophy in adults: A multicenter, prospective, randomized, double-blind, placebo-controlled, 4-week trial

Background: Myotonic muscular dystrophy type 1 (MMD1) is the most common form of adult MD, with a mean prevalence of 1 in 8000. Excessive daytime sleepiness (ie, hypersomnia) is a common complication of MMD1. Objective: The aim of this study was to evaluate the efficacy and tolerability of modafinil for the treatment of hypersomnia in adults with MMD1. Methods: This multicenter, prospective, randomized, double-blind, placebo-controlled study consisted of a prerandomization period (90 to 2 days before randomization) and a 4-week randomization period in which patients were assigned to receive either active treatment (modafinil 300 mg/d) or placebo. The study was conducted at 3 clinics in France between February 2000 and June 2002. Adult patients aged ≥18 years, with genetically proven MMD1, an Epworth Sleepiness Scale (ESS) score >10, and a mean latency to sleep onset ≤8 minutes measured by the Multiple Sleep Latency Test (MSLT) were eligible. The primary efficacy end point was the Maintenance of Wakefulness Test (MWT) score at 4 weeks. Secondary end points included the mean MSLT score and scores from the ESS, physician's assessment of the therapeutic effect and the patient's global self-assessment via visual analog scale, the 17-item Hamilton Depression Rating Scale, and the Short Form Health Survey (SF-36) quality-of-life assessment. Results: A total of 28 patients (15 men, 13 women; mean [SD] age, 40 [12.7] years [range, 18–69 years]; 100% white; modafinil group, 13; placebo group, 15) completed the study without protocol violations. Of the 28 patients with MMD1 included in the analysis, 21 had adult-onset MMD1. At 4 weeks, the mean MWT score was 16.4 (3.3) minutes in the modafinil group and 15.8 (3.8) minutes in the placebo group ( P = NS). At the end of the randomization period, there were no significant between-group differences in any secondary outcome. A total of 8 patients (4 in each group) reported ≥1 adverse event, including digestive, neurologic, and skin symptoms. Weight loss was reported in 1 patient (2 kg). Conclusion: In this small study conducted in an adult population with MMD1 and a high prevalence of hyper-somnia, modafinil had no significant effects on daytime somnolence measured using objective MWTs.

Natural History of Dural Arteriovenous Shunts

Dural arteriovenous shunts with cortical venous reflux or drainage may cause neurological symptoms and death with or without intracranial hemorrhage. Present knowledge about the natural history of these lesions is limited, however. We investigated the incidences of intracranial hemorrhage, progressive dementia syndrome, and death in patients diagnosed in our neurovascular center. We evaluated the records of 85 patients with dural arteriovenous shunts with cortical venous drainage or reflux hospitalized in our institution from 1978 to 2007. The annual incidences of intracranial hemorrhage, progressive dementia syndrome, and death were calculated. Fifty-three patients did not have an intracranial hemorrhage as the presenting event. One of these patients bled after diagnosis. Thirty-two patients had an intracranial hemorrhage as the presenting event. Three patients bled after diagnosis. One of these patients died. Apart from deficits caused by hemorrhage, no patient reported adverse neurological symptoms. In patients presenting with an intracranial hemorrhage the annual risk for hemorrhage is approximately 7.4% and in those not presenting with a hemorrhage it is approximately 1.5%. The risk of intracranial hemorrhage from a dural arteriovenous shunt with cortical venous drainage is most likely smaller than previously proposed. Presentation with hemorrhage is a risk factor for hemorrhage. The risks of developing neurological symptoms not related to hemorrhage are also less than previously reported.