Adverse Neurological Effects Research Articles

Air Pollution Particulate Matter Exposure and Chronic Cerebral Hypoperfusion and Measures of White Matter Injury in a Murine Model.

Background:Exposure to ambient air pollution particulate matter (PM) is associated with increased risk of dementia and accelerated cognitive loss. Vascular contributions to cognitive impairment are well recognized. Chronic cerebral hypoperfusion (CCH) promotes neuroinflammation and blood–brain barrier weakening, which may augment neurotoxic effects of PM.Objectives:This study examined interactions of nanoscale particulate matter (nPM; fine particulate matter with aerodynamic diameter ) and CCH secondary to bilateral carotid artery stenosis (BCAS) in a murine model to produce white matter injury. Based on other air pollution interactions, we predicted synergies of nPM with BCAS.Methods:nPM was collected using a particle sampler near a Los Angeles, California, freeway. Mice were exposed to 10 wk of reaerosolized nPM or filtered air (FA) for 150 h. CCH was induced by BCAS surgery. Mice (C57BL/6J males) were randomized to four exposure paradigms: a) FA, b) nPM, c) , and d) . Behavioral outcomes, white matter injury, glial cell activation, inflammation, and oxidative stress were assessed.Results:The joint group exhibited synergistic effects on white matter injury (2.3× the additive nPM and scores) with greater loss of corpus callosum volume on T2 magnetic resonance imaging (MRI) (30% smaller than FA group). Histochemical analyses suggested potential microglial-specific inflammatory responses with synergistic effects on corpus callosum C5 immunofluorescent density and whole brain nitrate concentrations (2.1× and 3.9× the additive nPM and effects, respectively) in the joint exposure group. Transcriptomic responses (RNA-Seq) showed greater impact of than individual additive effects, consistent with changes in proinflammatory pathways. Although nPM exposure alone did not alter working memory, the cohort demonstrated impaired working memory when compared to the group.Discussion:Our data suggest that nPM and CCH contribute to white matter injury in a synergistic manner in a mouse model. Adverse neurological effects may be aggravated in a susceptible population exposed to air pollution. https://doi.org/10.1289/EHP8792

Beta-Lactams Toxicity in the Intensive Care Unit: An Underestimated Collateral Damage?

Beta-lactams are the most commonly prescribed antimicrobials in intensive care unit (ICU) settings and remain one of the safest antimicrobials prescribed. However, the misdiagnosis of beta-lactam-related adverse events may alter ICU patient management and impact clinical outcomes. To describe the clinical manifestations, risk factors and beta-lactam-induced neurological and renal adverse effects in the ICU setting, we performed a comprehensive literature review via an electronic search on PubMed up to April 2021 to provide updated clinical data. Beta-lactam neurotoxicity occurs in 10–15% of ICU patients and may be responsible for a large panel of clinical manifestations, ranging from confusion, encephalopathy and hallucinations to myoclonus, convulsions and non-convulsive status epilepticus. Renal impairment, underlying brain abnormalities and advanced age have been recognized as the main risk factors for neurotoxicity. In ICU patients, trough concentrations above 22 mg/L for cefepime, 64 mg/L for meropenem, 125 mg/L for flucloxacillin and 360 mg/L for piperacillin (used without tazobactam) are associated with neurotoxicity in 50% of patients. Even though renal complications (especially severe complications, such as acute interstitial nephritis, renal damage associated with drug induced hemolytic anemia and renal obstruction by crystallization) remain rare, there is compelling evidence of increased nephrotoxicity using well-known nephrotoxic drugs such as vancomycin combined with beta-lactams. Treatment mainly relies on the discontinuation of the offending drug but in the near future, antimicrobial optimal dosing regimens should be defined, not only based on pharmacokinetics/pharmacodynamic (PK/PD) targets associated with clinical and microbiological efficacy, but also on PK/toxicodynamic targets. The use of dosing software may help to achieve these goals.

Miscellaneous (Others) P-OT001. Polymyxin-induced neurotoxicity masquerading as myasthenia gravis

Introduction. We describe a patient with polymyxin-induced neurotoxicity manifesting with a myasthenia-like syndrome. Objective: With the emergence of multi-drug resistant gram- negative bacilli, the use of polymyxins have renewed relevance, especially in the treatment of nosocomial infections. Frequently reported neurological adverse effects of polymyxin include paraesthesias, polyneuropathy and ataxia. Rarely, it can cause weakness secondary to neuromuscular blockade. Methods. We present a patient who had ventilation-dependent respiratory failure following polymyxin use. Results. A 62-year-old male was admitted for cholecystitis complicated by multi-drug resistant Escherichia Coli bacteraemia. Five days after initiation of polymyxin B, he developed two episodes of hypercarbic respiratory failure leading to recurrent cardiac arrests. Neurological examination revealed bilateral ptosis and fatiguable proximal weakness (proximal power MRC grade 1, distal power MRC grade 4), suggestive of a neuromuscular junction pathology. Repetitive nerve stimulation (RNS) revealed a decremental response and a characteristic U- shaped envelope pattern. The patient was started on a course of intravenous immunoglobulin due to concerns of myasthenic crisis unmasked by polymyxin, which was also promptly discontinued given the differential diagnosis of polymyxin-related neurotoxicity. Within 48 hours, he rapidly improved. Five days after cessation of polymyxin, he had full strength and complete resolution of ptosis. Interval RNS performed at this juncture normalised and acetylcholinesterase receptor antibodies returned negative. Further history taken after recovery revealed that he did not have history of droopy eyelids, diplopia or weakness prior to this presentation. Conclusion. Whilst few studies have highlighted weakness and respiratory failure from neuromuscular blockade as adverse effects of polymyxin, majority of these cases were reported between 1962 and 1973. With the renewed use of polymyxin in the era of antimicrobial resistance, physicians should have heightened awareness of this potentially serious complication. The clinical features of polymyxin-induced neurotoxicity may be difficult to distinguish from myasthenic crisis. Recognition and prompt discontinuation of polymyxin is essential.

A Rapid Review on the Efficacy and Safety of Pharmacological Treatments for Chagas Disease.

Chagas disease remains a neglected tropical disease, causing significant burden in the Americas and countries that receive immigrants from endemic nations. Current pharmaceutical treatments are suboptimal, not only varying drastically in efficacy, depending on the stage of disease, but also presenting significant risk of adverse events. The objective of this review is to provide a timely update on the efficacy and safety of current trypanocidals. Eligible studies published from January 2015 to December 2020 were retrieved by one reviewer from six electronic databases. Ana-lysis was done with review management software and risk of bias was assessed using tools appropriate for the type of study (i.e., experimental or observational). Thirteen studies (10 observational and three RCTs) were included in the analysis. All 13 studies tested Benznidazole (BNZ) or Nifurtimox (NFX), and two studies also tested Posaconazole (POS) or E1224 (Ravucanazole). BNZ was found to be the most efficacious trypanocidal drug compared to Nifurtimox, POS, and E1224; it also resulted in the highest percentage of adverse effects (AEs) and treatment discontinuation due to its toxicity. Adults experienced higher frequency of neurological AEs while taking BNZ or NFX compared to children. Children had a higher frequency of general AEs compared to adults while taking BNZ. Overall, BNZ is still the most efficacious, but development of new, less toxic drugs is paramount for the quality of life of patients. Studies testing combination therapies and shorter regimens are needed, as is the devising of better clinical parameters and laboratory biomarkers to evaluate treatment efficacy. Considering the variability in methodology and reporting of the studies included in the present analysis, we offer some recommendations for the improvement and replicability of clinical studies investigating pharmacological treatment of Chagas disease. These include full disclosure of methodology, standardization of outcome measures, and always collecting and reporting data on both the efficacy of trypanocidals and on safety outcomes.

Autologous Hematopoietic Stem Cell Transplantation (AHSCT) in Advanced, Treatment Refractory Multiple Sclerosis (MS) — a Phase II Clinical Trial

Aim: Ablation of auto-reactive immune cells followed by autologous hematopoietic stem cell transplantation (AHSCT) in the treatment of multiple sclerosis (MS) has been explored for the previous two decades. Morbidity and mortality rates originally limited referral for AHSCT in auto-immune disease but a reduction in treatment toxicity has facilitated increased clinical trials in the field. Here we present the outcomes of patients withadvanced, treatment refractory MS undergoing AHSCT in a Phase II study at our institute. We evaluate the safety and efficacy of AHSCT with intermediate-intensity immunosuppression in patients with highly aggressive MS.Methods: A single-centre, phase II clinical trial of AHSCT for patients with active relapsing remitting (RRMS) and secondary progressive MS (SPMS) commenced at St Vincent's Hospital in December 2010. Patients eligible for AHSCT had an Expanded Disability Status Scale (EDSS) of 2.0-7, had failed two prior disease-modifying therapies and displayed evidence of ongoing disease activity manifesting as clinical relapses and/or new MRI lesions in the year prior to AHSCT. CD34+ mobilisation with cyclophosphamide and G-CSF was performed, followed by conditioning with a BEAM (carmustine, etoposide, cytarabine, melphalan) + ATG (antithymocyte globulin) chemotherapeutic regimen. Patients underwent clinical assessment and peripheral blood collection for tissue banking at 3, 6, 12 months and yearly to 5 years. Gadolinium enhanced MRI was performed at 6, 12 months and yearly to 5 years. The primary outcomes were event-free survival and overall survival. Event free survival (EFS) was defined as no clinical or radiological relapses and no evidence of disability progression (by EDSS). Polychromic multi-parameter flow cytometry was performed for evaluation of post-transplant immune reconstitution.Results: Forty patients (26 with RRMS and 14 with SPMS) completed AHSCT, with a median follow-up of 24 months (range 3 to 63 months). Median EDSS prior to AHSCT was 6, with 17/40 having an EDSS >6, indicating a significant burden of neurologic disability. Patients were heavily pre-treated with immunosuppressive drugs (DMTs). Fifty-six percent of patients failed >4 disease modifying therapies prior to AHSCT with 2/3 having failed high efficacy treatment with Natalizumab (alpha-4 integrin inhibitor).Progression-free survival, clinical relapse-free survival (RFS), and MRI activity-free survival for the cohort were 80%, 90% and 95% respectively. Event free survival in the RRMS cohort was 90%. Sustained improvement in neurologic function by EDSS was seen in 15/40 (37.5%) of patients; 11 (42.3%) RRMS patients and 4 (28.6%) SPMS patients. MS quality of life score (MSQOL) - physical improved by 14.4 points (p=0.004) and MSQOL - mental improved by 10.3 points (p=0.08). Treatment related mortality was 0%. Adverse effects due to AHSCT were consistent with expected toxicities. One patient required admission to the intensive care unit in the post-transplant period due to serum sickness. There were no significant late neurologic adverse effects noted and no recorded cases of progressive multifocal leukoencephalopathy noted.Conclusion: The relapse-free survival (RFS) in our treatment refractory MS cohort undergoing AHSCT is significantly higher compared to RFS rates in MS patients treated with high-efficacy immunosuppressive therapies. Patients undergoing AHSCT at our institution had comparable rates of EFS to other recent prospective, single centre trials of AHSCT in spite of having higher baseline EDSS, greater evidence of pre-AHSCT disease activity, more heavily pre-treated (Burt et al. 2015, Atkins et al 2016) and use of a less aggressive conditioning regimen (Atkins et al. 2016). In summary, results of this phase II study suggest that AHSCT is effective in inducing sustained remission in the majority of aggressive RRMS and SPMS patients who failed multiple DMTs. DisclosuresNo relevant conflicts of interest to declare.

Ciclesonide activates glucocorticoid signaling in neonatal rat lung but does not trigger adverse effects in the cortex and cerebellum

Synthetic glucocorticoids (sGCs) such as dexamethasone (DEX), while used to mitigate inflammation and disease progression in premature infants with severe bronchopulmonary dysplasia (BPD), are also associated with significant adverse neurologic effects such as reductions in myelination and abnormalities in neuroanatomical development. Ciclesonide (CIC) is a sGC prodrug approved for asthma treatment that exhibits limited systemic side effects. Carboxylesterases enriched in the lower airways convert CIC to the glucocorticoid receptor (GR) agonist des-CIC. We therefore examined whether CIC would likewise activate GR in neonatal lung but have limited adverse extra-pulmonary effects, particularly in the developing brain. Neonatal rats were administered subcutaneous injections of CIC, DEX or vehicle from postnatal days 1–5 (PND1-PND5). Systemic effects linked to DEX exposure, including reduced body and brain weight, were not observed in CIC treated neonates. Furthermore, CIC did not trigger the long-lasting reduction in myelin basic protein expression in the cerebral cortex nor cerebellar size caused by neonatal DEX exposure. Conversely, DEX and CIC were both effective at inducing the expression of select GR target genes in neonatal lung, including those implicated in lung-protective and anti-inflammatory effects. Thus, CIC is a promising, novel candidate drug to treat or prevent BPD in neonates given its activation of GR in neonatal lung and limited adverse neurodevelopmental effects. Furthermore, since sGCs such as DEX administered to pregnant women in pre-term labor can adversely affect fetal brain development, the neurological-sparing properties of CIC, make it an attractive alternative for DEX to treat pregnant women severely ill with respiratory illness, such as with asthma exacerbations or COVID-19 infections.

A Critical Review and Scientific Prospective on Contraceptive Therapeutics from Ayurveda and Allied Ancient Knowledge.

Commonly used synthetic or prescribed hormonal drugs are known to interfere with the endocrine system and may have adverse reproductive, neurological, developmental, and metabolic effects in the body. These may also produce adverse effects such as polycystic ovarian disorder, endometriosis, early puberty, infertility or toxicity to gonads, testicular germ cell cancer, breast or prostate cancer, brain developmental problems, and even birth defects. Globally, the emergence of renewed interest in natural products for reproductive health is on the rise, which offers opportunities for new contraceptive developments. The search for alternate, safer contraceptive products or agents of natural origin is of scientific interest. Ayurvedic classical texts offer knowledge and information about the reproductive function and therapeutics including those for enhancement and limiting male and female fertility. Review of ancient, medieval, and recent—including texts on erotica that provide information on approaches and large numbers of formulations and drugs of plant, mineral or animal origin—claimed to have sterilizing, contraceptive, abortifacient, and related properties is presented. Few among these are known to be toxic and few are not so common. However, most of the formulations, ingredients, or modes of administration have remained unattended to, due to issues related to consumer compliance and limitations of standardization and lack of appropriate validation modalities. Several of these ingredients have been studied for their phytoconstituents and for the variety of pharmacological activities. Efforts to standardize several classical dosage forms and attempts to adapt to modern technologies have been made. List of formulations, ingredients, and their properties linked with known constituents, pharmacological, biological, and toxicity studies have been provided in a series of tables. The possible effectiveness and safety of selected formulations and ingredients have been examined. Suggestions based on new drug delivery systems integrated with advances in biotechnology, to provide prospects for new therapeutics for contraception, have been considered. Ayurveda is built on a holistic paradigm of biological entity rather than limited gonadal functions. Graphic presentation of a few carefully chosen possibilities has been depicted. New approaches to standardization and ethnopharmacological validation of natural contraceptive therapeutics may offer novel mechanisms and modalities and therapeutic opportunities to satisfy unmet needs of contraception.

New Drugs on the Horizon for Functional and Motility Gastrointestinal Disorders

New Drugs on the Horizon for Functional and Motility Gastrointestinal Disorders

Monitoring for valproate and phenytoin toxicity in hypoalbuminaemia: A retrospective cohort study.

Equations to calculate albumin-adjusted total concentrations have been validated to correlate with measured free concentrations for both phenytoin and valproate, but there is a lack of data to assess correlation with clinical outcomes. We aimed to assess the association of hypoalbuminaemia and albumin-adjusted total concentrations with concentration-dependent toxicity for phenytoin and valproate and review the impact on management decisions following concentration monitoring in hypoalbuminaemia. Patients undergoing concentration monitoring for phenytoin or valproate between January and December 2018 were included. Patients were identified using a centralised laboratory database with data extracted from medical records. Total phenytoin concentrations were measured for 144 patients, with hypoalbuminaemia (≤30 g L-1 ) recorded in 59 (41%) patients. Albumin-adjusted phenytoin concentration >20 mg L-1 was associated with increased neurological adverse effects (77% vs. 43%, P < .001). On logistic regression, higher albumin-adjusted phenytoin concentration was an independent risk factor for neurotoxicity (OR 1.06, 95% CI 1.01-1.12, P = .011). Total valproate concentrations were measured for 383 patients, with hypoalbuminaemia (≤30 g L-1 ) noted in 53 (14%) patients. For the valproate cohort, hypoalbuminaemia (42% vs. 28%, P = .039) and albumin-adjusted valproate concentration >100 mg L-1 (49% vs. 23%, P < .001) were both associated with increased neurotoxicity. On multiple logistic-regression, valproate daily dose (aOR = 1.01, 95% CI 1.00-1.02, P = .006) and albumin-adjusted valproate concentration (aOR 1.01, 95% CI 1.00-1.02, P = .033) were independent risk factors for neurotoxicity after accounting for confounders. While measuring free drug concentrations in hypoalbuminaemia would be ideal, the adjustment equations can help identify vulnerable patients needing further assessment of potential concentration-dependent toxicity.

Multi‐organ effects of SARS‐CoV2, more than a respiratory virus: effects on human astrocytes

The coronavirus disease‐2019 (COVID‐19) has led to one of the major outbreaks in modern history. The etiological agent of COVID‐19 is the novel severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2). SARS‐CoV‐2 infects the respiratory system's epithelial cells via the angiotensin‐converting enzyme 2 (ACE2) receptor, causing from non or mild symptoms to severe viral pneumonia, and in some cases, death. Based on evolving clinical evidence, it is now unfitting to label SARS‐CoV‐2 as just a respiratory virus, as lately, various reports substantiate its pathogenicity in other organs of the body, including the central nervous system (CNS). Despite conflicting results regarding ACE2 expression in brain tissue, the latest data show that ACE2 is robustly expressed by CNS cells, suggesting that CNS is a potential target for SARS‐CoV‐2 infection. Astrocytes are the most abundant glial cell type within the CNS and play a role in axon guidance and synaptic support, control the blood‐brain barrier flow, and regulate neuroinflammation. To test if SARS‐CoV‐2 can enter into the CNS via astrocytes and then elicit adverse neurological effects, we have initiated studies to test if astrocytes express ACE2 and whether SARS‐CoV‐2 can infect human astrocytes via this receptor. We have found that astrocytes robustly express ACE2 at the mRNA and protein levels. We are currently testing if astrocytes are susceptible to SARS‐CoV‐2 infection, which could subsequently lead to neuronal damage and possibly account for some of the neurological symptoms observed in COVID‐19 patients. We hope to contribute to gain insights into the mechanisms of SARS‐CoV‐2 infection in the CNS and its potential physiological effects with this work.

Correlation between breakthrough seizures and serum level of phenytoin and valproate in Indian patients

Objectives: To determine the optimum range of phenytoin (PHT) and valproate (VAP) levels and find out the critical drug levels below which chances of breakthrough seizures increase in North Indian population. Methodology: A cross-sectional, case-controlled, record-based study was conducted in a quaternary care hospital from September 2018–2019. The case group comprised epilepsy patients on monotherapy with PHT/VAP presenting with breakthrough seizures after at least 6 months of seizure control. Noncompliant, overdose, toxicity, no or partial response, any other psychiatric or neurological disorder, adverse effects, and patients taking two or more antiepileptic drugs were excluded. Results: Data of 100 patients in each group were analyzed. Significantly lower mean levels in cases were observed in PHT (5.74 ± 3.68 mg/L vs. 13.75 ± 4.27 mg/L control) and VAP (24.13 ± 27.39 mg/L vs. 76.37 ± 17.71 mg/L control). A negative correlation of drug levels was observed with age and weight in both the groups. The level/dose ratio in controls (0.05 ± 0.03; 0.09 ± 0.06) was significantly (P

Is a Switch to Cyclosporine from Tacrolimus a Risk in Heart Transplant Recipients?

<h3>Purpose</h3> Cyclosporine (CsA) became available in the US in 1983 and improved clinical outcomes. Another calcineurin inhibitor, tacrolimus (TAC), became available in the 1990s and demonstrated benefit in further reducing rejection. In most heart transplant (HTx) programs, TAC is currently the drug of choice for immunosuppression. However, a switch to CsA does occur due to adverse effects from TAC. It is not well-established that this switch to CSA results in subsequent non-inferior outcomes. Therefore, we reviewed our single center experience to assess for <i>real world</i> potential outcomes. <h3>Methods</h3> Between 2010 and 2017, we identified 58 HTx patients who were administered CsA in place of TAC mostly due to neurologic adverse effects from TAC. For comparison, a TAC group was matched based on age, sex, baseline renal function and time from transplant. The average time of this switch occurred at 6.6 ± 1.1 months post-transplant. Outcomes included subsequent 1-year freedom from any treated rejection (ATR), acute cellular rejection (ACR), and antibody-mediated rejection (AMR) and 3-year subsequent survival, freedom from cardiac allograft vasculopathy (CAV, as defined by stenosis ≥30% by angiography), and freedom non-fatal major adverse cardiac event (NF-MACE: myocardial infarction, new congestive heart failure, percutaneous coronary intervention, implantable cardioverter defibrillator/pacemaker implant, stroke). <h3>Results</h3> The CsA/MMF group compared to the TAC/MMF group had significantly lower subsequent 3-year survival and worse renal function at 1-year (after the switch to CsA). There was similar subsequent 3-year freedom from CAV and NF-MACE and 1-year rejections between the two groups. (see table) <h3>Conclusion</h3> In the current era in a large, single center study there are indications that a switch to CsA from TAC may be inferior in heart transplant recipients. Further investigation with larger numbers is needed to confirm these findings.

Chronic Lithium Neurotoxicity Presenting as Dementia: A Case Report

<h3>Introduction</h3> Treatment with Lithium can be associated with a continuum of neurological side effects, ranging from benign tremors to early reversible lithium neurotoxicity, to chronic irreversible lithium neurotoxicity. Among chronic systemic adverse effects of Lithium, neurotoxicity has been reported to be the most common, followed by renal and cardiovascular toxicity (Sunn et al). Data on lithium toxicity in the elderly is limited but available data indicates that adverse effects occur more commonly in the context of chronic therapeutic administration of lithium rather than instances of overdose (Oakly et al). EEG and nerve conduction studies show notable changes that correlate with the increased duration of Li therapy (Fountoulakis et al). Older adults are more susceptible to side effects even with "normal" lithium levels for reasons such as declined renal function, reduced volume of distribution, medical comorbidities, concomitant medications, and drug interactions. Here we present a case of an elderly man with chronic lithium neurotoxicity associated with significant cognitive changes and severe disability. This will be followed by a review of literature of chronic lithium neurotoxicity in the geriatric population. <h3>Methods</h3> Case of Mr. A: We present the case of a 72 year old man who presented to the Memory Clinic with a diagnosis of Alzheimer's disease (AD) since the age of 55. His presentation was also notable for progressive aphasia and he had a PEG tube placed for feeding. His cognitive deficits were most significant in the domains of executive and visuospatial functioning, memory, and language. Physical exam findings were notable for mild left hand tremor, difficulties with balance, slow gait with short steps and a decreased arm swing, limited vertical gaze, and dysphagia. He was independent with his ADLs but dependent on IADLs due to aforementioned cognitive and physical findings. Other psychiatric diagnoses included Bipolar Disorder, Substance Use Disorder in remission. At the time of his evaluation, Mr. A had been on Lithium for over 20 years with records for the past three years showing therapeutic levels .5-1.1mmol/L. Although the patient had been previously diagnosed with AD, his relatively stable neuropsychological profile over the last 15 years called the diagnosis of AD into question and this was confirmed by negative amyloid imaging. The patient had yearly therapeutic levels of Lithium until his wife's concern for further insidious cognitive decline in the domains of language and memory, along with worsening gait and tremor prompted checking a Lithium level which was 1.8. Patient was subsequently weaned off Lithium over several months. At the time of this writing this abstract, Mr. A's cognition and motor function are significantly improving, to the extent of no longer requiring PEG for dysphagia. Electronic searches of The Cochrane Central Register of Controlled Trials and the standard bibliographic databases PubMed, MEDLINE, EMBASE, and PsycINFO will be performed for papers focusing on chronic lithium neurotoxicity in older adults. Keywords include "lithium" and "adverse effects" or neurotoxicity" or "neurological manifestations." Original research, case reports, and reviews will be included. Data focusing on older adults will be extracted and presented. <h3>Results</h3> Initial search for literature focusing on chronic lithium neurotoxicity yielded 4 papers. Data from these papers will be extracted. The range of neurological adverse effects, both physical and mental, will be described. This will be followed by a discussion of risk and precipitating factors for lithium neurotoxicity. Association with lithium doses, duration of treatment, and serum lithium levels will be elucidated. Lastly, diagnosis and treatment considerations will be highlighted. <h3>Conclusions</h3> Chronic lithium Neurotoxicity is more common in the elderly and can occur at normal to even sub therapeutic doses. It is imperative to have an optimal index of suspicion if an individual on chronic lithium therapy presents with cognitive deficits. <h3>Funding</h3> not applicable

Immune and Nervous Systems Interaction in Endocrine Disruptors Toxicity: The Case of Atrazine.

Endocrine disruptors (ED) are natural and anthropogenic chemicals that can interfere with hormonal systems at different levels. As such, ED-induced alterations in hormone functions have been implicated in many diseases and pathological conditions, including adverse developmental, reproductive, neurological, cardiovascular, and immunological effects in mammals. The fact that ED may compete with several endogenous hormones for multiple receptors and pathways is not always fully considered. This results in a complex response that depends on the cellular context in terms of receptors and interacting proteins and, thus, may differ between tissues and circumstances. Microglia, neurons, and other immune cells are potential targets and still underappreciated actors in endocrine disruption. Due to the large scale of this topic, this review is not intended to provide a comprehensive review nor a systematic review of chemicals identified as endocrine disruptors. It focuses on the immune-neuro-endocrine network in ED toxicity and research gaps, using atrazine as an example to highlight this complexity and the interrelationship between the immune, endocrine, and nervous systems, and ED.

Treatment outcome and adverse effects of colistin in adult patients with carbapenem-resistant gram-negative bacteremia from Pakistan

BackgroundPolymyxins (colistin) have emerged for the treatment of carbapenem resistant (CR) gram-negative infections. There is a paucity of data on treatment outcomes and adverse effects of high-dose colistin treatment in Pakistan. The aim of this study was to determine the efficacy and toxicity of colistin in CR bacteremia, including patients with renal failure and on hemodialysis, and to determine patient outcomes. MethodsThis prospective cohort study was performed from May to December 2017 at Sindh Institute of Urology and Transplantation, Karachi, Pakistan. Patients aged >18 years with documented gram-negative bacteremia were included. Data were compared between those who received colistin and those who did not, including risk factors for CR bacteremia, bacterial clearance, adverse effects, and all-cause mortality up to 14 days of follow-up. ResultsThe study included 137 patients, 73 (53.3%) in the colistin group and 64 (46.7%) in the non-colistin group. Patients in the colistin group were 1.47 times more likely to have died by day 14 of follow-up as compared to those in the non-colistin group (19.2% vs 7.8%; relative risk 1.47, p= 0.05). Patients in both groups achieved more than 80% bacteriological clearance. The colistin group patients were less likely to have received appropriate empirical antibiotics as compared to the non-colistin group patients (4.1% vs 62.5%; relative risk 0.09, p< 0.001). Factors significantly associated with mortality were inappropriate empirical antibiotics and acute renal failure. Of the 73 patients in the colistin group, 27 (37.0%) developed reversible neurological adverse effects. Patients with renal insufficiency, not on hemodialysis, were evaluated for colistin nephrotoxicity. Creatinine decreased from 8.08 mg/dl at baseline to 4.85 mg/dl on day 7 in the colistin group, and from 6.5 mg/dl to 3.9 mg/dl in the non-colistin group. Patients with normal renal function had no significant rise in serum creatinine. ConclusionsColistin is efficacious in clearing bacteremia even in patients with impaired renal function. The adverse effects were found to be minimal and reversible. We recommend the use of colistin in combination with carbapenems for CR gram-negative bacteria in renal failure. Most importantly, however, this study highlights the role of empirical colistin treatment in patients with risk factors for CR bacteremia.

Abstract P221: First-In-Class Anti-Spastic Drug Candidate (MPH-220) Efficiently Relaxes Spastic Muscles and Improves Motor Functions in Gait Disorder in Preclinical Studies

Post-stroke muscle spasticity affects 37% of stroke survivors and disables self-supporting life management. There is a high unmet medical need for an efficient antispastic drug because current muscle relaxants are often of limited efficacy and cause severe neurological and cardiovascular side effects due to targeting the central or peripheral nervous system. We developed a new-generation anti-spastic oral drug, MPH-220, which efficiently relaxes spastic skeletal muscles and lacks cardiovascular and neurological adverse effects because it selectively targets skeletal myosin, the contractile protein of muscles. MPH-220 is an efficient skeletal muscle specific actomyosin relaxant demonstrated on human muscle samples. Orally administered MPH-220 reduces muscle force of living rats without cardiovascular side effects. Brain-damage induced spastic animals showed drastic improvement in gait disorders upon oral MPH-220 treatment resulting in significantly straightened body posture, reduced number of spontaneous falling and cramping, and more ordered limb positions. Due to selective accumulation of MPH-220 in skeletal muscle tissues, antispastic effect was maintained for more than 10 hours. Due to its mechanism of action MPH-220 does not cause complete loss of muscle tone even at high doses. Furthermore, MPH-220 has excellent ADMET properties for oral administration: it is highly absorptive, non-mutagenic and has no effects on hERG channels, kinases, nuclear hormone receptors and GPCRs. Considering these results, MPH-220 is a promising anti-spastic oral drug candidate, which provides potential nervous system-independent therapies for spasticity and muscle stiffness without cardiovascular and neuronal side effects. Phase I clinical trials are scheduled for the beginning of 2021. Funded by the Hungarian National Research, Development and Innovation Office (NVKP 16-1-2016-0051 and PIACI-KFI-2019-00488).

Prediction of the dose range for adverse neurological effects of amiodarone in patients from an in vitro toxicity test by in vitro\u2013in vivo extrapolation

Amiodarone is an antiarrhythmic agent inducing adverse effects on the nervous system, among others. We applied physiologically based pharmacokinetic (PBPK) modeling combined with benchmark dose modeling to predict, based on published in vitro data, the in vivo dose of amiodarone which may lead to adverse neurological effects in patients. We performed in vitro–in vivo extrapolation (IVIVE) from concentrations measured in the cell lysate of a rat brain 3D cell model using a validated human PBPK model. Among the observed in vitro effects, inhibition of choline acetyl transferase (ChAT) was selected as a marker for neurotoxicity. By reverse dosimetry, we transformed the in vitro concentration–effect relationship into in vivo effective human doses, using the calculated in vitro area under the curve (AUC) of amiodarone as the pharmacokinetic metric. The upper benchmark dose (BMDU) was calculated and compared with clinical doses eliciting neurological adverse effects in patients. The AUCs in the in vitro brain cell culture after 14-day repeated dosing of nominal concentration equal to 1.25 and 2.5 µM amiodarone were 1.00 and 1.99 µg*h/mL, respectively. The BMDU was 385.4 mg for intravenous converted to 593 mg for oral application using the bioavailability factor of 0.65 as reported in the literature. The predicted dose compares well with neurotoxic doses in patients supporting the hypothesis that impaired ChAT activity may be related to the molecular/cellular mechanisms of amiodarone neurotoxicity. Our study shows that predicting effects from in vitro data together with IVIVE can be used at the initial stage for the evaluation of potential adverse drug reactions and safety assessment in humans.

Image Guidance in Deep Brain Stimulation Surgery to Treat Parkinson's Disease: A Comprehensive Review.

Deep brain stimulation (DBS) is an effective therapy as an alternative to pharmaceutical treatments for Parkinson's disease (PD). Aside from factors such as instrumentation, treatment plans, and surgical protocols, the success of the procedure depends heavily on the accurate placement of the electrode within the optimal therapeutic targets while avoiding vital structures that can cause surgical complications and adverse neurologic effects. Although specific surgical techniques for DBS can vary, interventional guidance with medical imaging has greatly contributed to the development, outcomes, and safety of the procedure. With rapid development in novel imaging techniques, computational methods, and surgical navigation software, as well as growing insights into the disease and mechanism of action of DBS, modern image guidance is expected to further enhance the capacity and efficacy of the procedure in treating PD. This article surveys the state-of-the-art techniques in image-guided DBS surgery to treat PD, and discusses their benefits and drawbacks, as well as future directions on the topic.

Protein Expression of Angiotensin-Converting Enzyme 2 (ACE2) is Upregulated in Brains with Alzheimer's Disease.

Alzheimer’s disease is a chronic neurodegenerative disorder and represents the main cause of dementia globally. Currently, the world is suffering from the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a virus that uses angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the host cells. In COVID-19, neurological manifestations have been reported to occur. The present study demonstrates that the protein expression level of ACE2 is upregulated in the brain of patients with Alzheimer’s disease. The increased ACE2 expression is not age-dependent, suggesting the direct relationship between Alzheimer’s disease and ACE2 expression. Oxidative stress has been implicated in the pathogenesis of Alzheimer’s disease, and brains with the disease examined in this study also exhibited higher carbonylated proteins, as well as an increased thiol oxidation state of peroxiredoxin 6 (Prx6). A moderate positive correlation was found between the increased ACE2 protein expression and oxidative stress in brains with Alzheimer’s disease. In summary, the present study reveals the relationships between Alzheimer’s disease and ACE2, the receptor for SARS-CoV-2. These results suggest the importance of carefully monitoring patients with both Alzheimer’s disease and COVID-19 in order to identify higher viral loads in the brain and long-term adverse neurological consequences.

Protective Effects of Intravenous Magnesium Sulfate in Stroke Patients Receiving Amiodarone: A Randomized Controlled Trial.

Anti-arrhythmic agents, like amiodarone, interfere at different stages of the ischemic stroke. However, amiodarone was accompanied with immunological pulmonary complications and adverse neurological effects. We hypothesize that magnesium sulfate in combination with amiodarone holds promise for stroke treatment. Thirty-six patients with confirmed diagnosis of ischemic stroke and atrial fibrillation who received bolus amiodarone were randomly assigned to magnesium sulfate every 24h or similar volume of normal saline (as placebo) for 5days. Various severity test scores were used to evaluate the symptoms. Routing biochemistry were also measured at days 1 and 5. Treatment with MgSO4 results in a significant reduction in serum levels of NGAL, Hb, T.Bill, IL-6, IL-8, SNSE, S100B, EGF, PAF, CRP and IgG. Also, MgSO4 treatment significantly improved the RASS, Candida, SOFA, NIHSS and APACHE scores. Moreover, reduction of IL-6, IL-8, SNSE, EGF and APACHE score and increase in RASS score were significantly higher in MgSO4 group compared with placebo. Intravenous administration of MgSO4 in amiodarone-treated stroke patients improved the inflammatory, immunological and neurological indicators and reduced disability in ICU-admitted AIS patients, suggesting that this treatment scheme may prevent amiodarone-induced complications in these patients.