A Preliminary Study Evaluating the Safety and Efficacy of Bumetanide, an NKCC1 Inhibitor, in Patients with Drug-Resistant Epilepsy The correct name of the co-author should be ‘‘Vajiheh Aghamollaii’’, and not ‘‘Vajihe Aghamollaii’’ as given in the original publication of the article.

Objective Derivation of the Morphology and Staging of Visual Field Loss Associated with Long-Term Vigabatrin Therapy Abstract Background The morphology and between-eye symmetry of the visual field loss associated with the antiepileptic drug vigabatrin (VAVFL) has received little attention. Objective Our objective was to model the appearance and ensuing staging of VAVFL derived with the European Medicines Agency-approved perimetric protocol. Methods This was a retrospective, cross-sectional, observational study that identified 123 adults who had received vigabatrin for refractory seizures and who had no evidence of co-existing retino-geniculo-cortical visual pathway abnormality. A further 38 adults with refractory seizures and identical inclusion criteria but no exposure to vigabatrin acted as controls. For each group, the median outcome at each stimulus location in each eye (of absolute loss, relative loss or Pattern Deviation probability level, as appropriate) was derived for each successive ten pairs of fields, ranked for severity. Between-eye symmetry was quantified by an index that accounted for severity of loss and that was referenced to the likelihood of the occurrence of symmetry due to chance. Results The modelled VAVFL was bilateral and highly symmetrical and was described by six stages that were all independent of the extent of vigabatrin exposure. The loss originated in the extreme temporal periphery and encroached centripetally along all meridians towards fixation. The initial appearance within the central field (Stage 2) occurred inferior-nasally. Subsequent stages exhibited increasing loss, which was greater nasally than temporally. Stage 6 described concentric loss extending to approximately 15° eccentricity from fixation. Conclusion The model exhibited a consistent pattern of VAVFL. The staging of the loss could assist the risk:benefit analysis of vigabatrin for the treatment of epilepsy.

Methylene Blue in the Treatment of Neuropsychiatric Disorders Abstract Methylene blue is a long-established drug with complex pharmacology and multiple clinical indications. Its diverse mechanisms of action are most likely responsible for the large variety of its clinical effects. Of interest to psychiatrists, methylene blue has antidepressant, anxiolytic, and neuroprotective properties documented by both animal and human studies. Its stabilizing effect on mitochondrial function and dose-dependent effect on the generation of reactive oxygen species are of significant heuristic value. For these reasons, methylene blue holds promise as a proof-of-concept treatment of organic/neurodegenerative disorders and as a neuroprotective agent in general. In psychiatry, methylene blue has been used for over a century. It was tried successfully in the treatment of psychotic and mood disorders and as a memory enhancer in fear-extinction training. Particularly promising results have been obtained in both short- and long-term treatment of bipolar disorder. In these studies, methylene blue produced an antidepressant and anxiolytic effect without risk of a switch into mania. Long-term use of methylene blue in bipolar disorder led to a better stabilization and a reduction in residual symptoms of the illness. It is usually well tolerated, but caution is needed in the light of its inhibitory effect on monoamine oxidase A.

Effects of Renal Impairment on the Pharmacokinetics of Once-Daily Amantadine Extended-Release Tablets Abstract Background An extended-release formulation of amantadine (Osmolex ER™, Osmotica Pharmaceutical US LLC) was approved in February 2018 to treat Parkinson’s disease and drug-induced extrapyramidal reactions in adults. Objectives To determine the pharmacokinetic profile of extended-release amantadine in subjects with varying degrees of renal impairment. Methods Adults with normal renal function (creatinine clearance > 89 mL/min/1.73 m2), moderate renal impairment (creatinine clearance 30–59 mL/min/1.73 m2), or severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m2) received a single 129-mg dose (160 mg amantadine hydrochloride) of extended-release amantadine. Blood and urine samples for pharmacokinetic analysis were taken at scheduled intervals. A two-compartment pharmacokinetic population model was employed to determine optimum extended-release amantadine dosing in subjects with renal impairment. Results Following a single oral dose of the 129-mg extended-release amantadine tablet, amantadine plasma concentration increased slowly, reaching a peak at approximately 11 h. Amantadine elimination was reduced in subjects with renal impairment. Renal clearance decreased from 10,965 to 2618 mL/h in subjects with severe renal impairment compared to those with normal renal function. Pharmacokinetic modeling and simulation methods were used to recommend the oral administration of 129-mg extended-release amantadine tablets at intervals of 24, 48, 72, 96, 120, or 168 h depending on the degree of renal function. Conclusions Renal impairment was associated with reduced amantadine clearance. Based on pharmacokinetic modeling and simulations, dose regimens were recommended for subjects with impaired renal function to provide systemic amantadine exposure similar to subjects with normal renal function taking a once-daily extended-release amantadine tablet.

Neurological and Psychiatric Adverse Effects of Antimicrobials Abstract Antimicrobials are a widely used class of medications, but several of them are associated with neurological and psychiatric side effects. The exact incidence of neurotoxicity with anti-infectives is unknown, although it is estimated to be < 1%. Neurotoxicity occurs with all classes of antimicrobials, such as antibiotics, antimycobacterials, antivirals, antifungals and antiretrovirals, with side effects ranging from headaches, anxiety and depression to confusion, delirium, psychosis, mania and seizures, among others. It is important to consider these possible side effects to prevent misdiagnosis or delayed treatment as drug withdrawal can be associated with reversibility in most cases. This article highlights the different neurotoxic effects of a range of antimicrobials, discusses proposed mechanisms of onset and offers general management recommendations. The effects of antibiotics on the gut microbiome and how they may ultimately affect cognition is also briefly examined.

Intravenous Brivaracetam in the Treatment of Status Epilepticus: A Systematic Review Abstract Background Brivaracetam is a high-affinity synaptic vesicle glycoprotein 2A ligand with high brain permeability and rapid onset of action. These properties make brivaracetam potentially an ideal compound in the emergency setting. Objective The objective of our study was to review the evidence about the clinical efficacy and tolerability of intravenous brivaracetam in the treatment of status epilepticus. Methods We systematically searched MEDLINE, EMBASE, Google Scholar, ClinicalTrials.gov, and conference proceedings to identify studies evaluating intravenous brivaracetam as treatment for status epilepticus of any type in patients of any age. Searches were conducted on 3 December, 2018. Results Seven studies were included (37 patients; aged 22–85 years; 21 were female). The type and etiology of status epilepticus varied across studies. The number of drugs used prior to brivaracetam to treat status epilepticus ranged from 1 to 8. The time from status epilepticus onset to brivaracetam administration ranged from 0.5 h to 105 days. The initial brivaracetam dose ranged from 50 to 400 mg. In case series, the proportion of patients achieving clinical status epilepticus cessation when brivaracetam was administered as the last drug varied from 27 to 50%; in case reports, all patients had status epilepticus cessation. The time from brivaracetam administration to status epilepticus cessation ranged from 15 min to 94 h. No serious adverse effects were reported. Conclusions The available data suggested that brivaracetam can be a safe treatment option in patients with status epilepticus. The current evidence is however hampered by several confounding factors, and controlled studies are warranted to define the actual benefit of brivaracetam for the treatment of status epilepticus.

Temporal Trends and Predictors of Drug Utilization and Outcomes in First-Ever Stroke Patients: A Population-Based Study Using the Singapore Stroke Registry Abstract Introduction Drug utilization and outcomes research in multi-ethnic Asian stroke populations is lacking. Objectives Our objective was to examine temporal trends and predictors of drug utilization and outcomes in a multi-ethnic Asian stroke population. Methods This registry-based study included ischemic and hemorrhagic first-ever stroke patients hospitalized between 2009 and 2016. Utilization of medications included in-hospital thrombolytic agents, early antithrombotics (antiplatelets, anticoagulants) within 48 h of admission, and antithrombotics and statins at discharge. Outcomes analyzed were in-hospital all-cause mortality; 28-day, 90-day, and 1-year case fatality (CF); and discharge destination. Results Of the 36,615 included patients, 81.6% had ischemic stroke and 18.4% had hemorrhagic stroke (15.5% intracerebral hemorrhage [ICH] and 2.8% subarachnoid hemorrhage [SAH]). For ischemic stroke, the combined use of all three guideline medications (in-hospital thrombolytic therapy, as well as antithrombotics and statins at discharge) increased (P = 0.006). Being on the stroke pathway was associated with prescription of all three guideline medications in ischemic stroke. Decreasing trends for in-hospital mortality, 28-day, 90-day, and 1-year CF and proportion of patients discharged home without rehabilitation appointment were observed in ischemic stroke (P < 0.05) but not in ICH or SAH (apart from 28-day CF). Ischemic stroke patients who received guideline medications were less likely to die or be discharged to nursing homes and chronic sick hospitals. Hemorrhagic stroke patients prescribed statins at discharge were less likely to have 28-day and 1-year CF. Conclusions Prescription of secondary stroke preventive medications (particularly in ischemic stroke) was associated with more favorable outcomes, highlighting the importance of physician adherence to evidence-based pharmacotherapy.

Branched-Chain Amino Acids and Seizures: A Systematic Review of the Literature Abstract Background Up to 40% of patients with epilepsy experience seizures despite treatment with antiepileptic drugs; however, branched-chain amino acid (BCAA) supplementation has shown promise in treating refractory epilepsy. Objectives The purpose of this systematic review was to evaluate all published studies that investigated the effects of BCAAs on seizures, emphasizing therapeutic efficacy and possible underlying mechanisms. Methods On 31 January, 2017, the following databases were searched for relevant studies: MEDLINE (OvidSP), EMBASE (OvidSP), Scopus (Elsevier), the Cochrane Library, and the unindexed material in PubMed (National Library of Medicine/National Institutes of Health). The searches were repeated in all databases on 18 February, 2019. We only included full-length preclinical and clinical studies that were published in the English language that examined the effects of BCAA administration on seizures. Results Eleven of 2045 studies met our inclusion criteria: ten studies were conducted in animal models and one study in human subjects. Seven seizure models were investigated: the strychnine (one study), pentylenetetrazole (two studies), flurothyl (one study), picrotoxin (two studies), genetic absence epilepsy in rats (one study), kainic acid (two studies), and methionine sulfoximine (one study) paradigms. Three studies investigated the effect of a BCAA mixture whereas the other studies explored the effects of individual BCAAs on seizures. In most animal models and in humans, BCAAs had potent anti-seizure effects. However, in the methionine sulfoximine model, long-term BCAA supplementation worsened seizure propagation and caused neuron loss, and in the genetic absence epilepsy in rats model, BCAAs exhibited pro-seizure effects. Conclusions The contradictory effects of BCAAs on seizure activity likely reflect differences in the complex mechanisms that underlie seizure disorders. Some of these mechanisms are likely mediated by BCAA’s effects on glucose, glutamate, glutamine, and ammonia metabolism, activation of the mechanistic target of rapamycin signaling pathway, and their effects on aromatic amino acid transport and neurotransmitter synthesis. We propose that a better understanding of mechanisms by which BCAAs affect seizures and neuronal viability is needed to advance the field of BCAA supplementation in epilepsy.

Immune Globulin Subcutaneous (Human) 20% (Hizentra ® ): A Review in Chronic Inflammatory Demyelinating Polyneuropathy Abstract Intravenous immunoglobulin (IVIg) is well-established in the treatment of patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Immune globulin subcutaneous (human) 20% liquid (Hizentra®; referred to as IgPro20 hereafter) has recently been approved in a number of countries, including the USA and those of the EU, as maintenance therapy in patients with CIDP. In the pivotal phase III PATH trial in adults with CIDP who were first stabilized on IVIg therapy, maintenance therapy with IgPro20 for 24 weeks significantly reduced CIDP relapse or study withdrawal rates versus placebo. Efficacy was sustained during ≤ 48 weeks of additional treatment with IgPro20 in the open-label PATH extension study. IgPro20 was generally well tolerated, with low rates of systemic adverse events (AEs); the most common AEs were local reactions (e.g. infusion-site erythema, infusion-site swelling). In PATH, more than one-half of IgPro20 recipients preferred this therapy to their previous IVIg therapy. IgPro20 offers a convenient alternative to IVIg with a better systemic AEs profile and thus extends the options for maintenance therapy in CIDP.

Rotigotine Transdermal Patch: A Review in Parkinson’s Disease Abstract Rotigotine (Neupro®), a non-ergolinic dopamine agonist (DA), is administered once daily via a transdermal patch (TP) that delivers the drug over a 24-h period. In the EU, the rotigotine TP is approved as monotherapy for the treatment of early Parkinson’s disease (PD) and as combination therapy with levodopa throughout the course of the disease. It is also approved for the treatment of PD in numerous other countries, including Australia, the USA, China and Japan. Rotigotine TP effectively improved motor and overall functioning in clinical trials in Caucasian and Asian patients with early PD (as monotherapy) or advanced PD (in combination with levodopa); treatment benefits appeared to be maintained in open-label extensions that followed patients for up to 6 years. Rotigotine TP was not consistently non-inferior to ropinirole and pramipexole in studies that included these oral non-ergolinic DAs as active comparators. Rotigotine TP variously improved some non-motor symptoms of PD, in particular sleep disturbances and health-related quality of life (HRQOL), based on findings from individual studies and/or a meta-analysis. Rotigotine TP was generally well tolerated, with an adverse event profile characterized by adverse events typical of dopaminergic stimulation and transdermal patch application. Available for more than a decade, rotigotine TP is a well-established, once-daily DA formulation for use in the short- and longer-term treatment of PD. It offers a convenient alternative when non-oral administration of medication is preferred and may be particularly useful in patients with gastrointestinal disturbances that reduce the suitability of oral medication.