Perampanel Confirms to Be Effective and Well-Tolerated as an Add-On Treatment in Patients With Brain Tumor-Related Epilepsy (PERADET Study)

Background: Epilepsy is one of the most common symptoms of brain tumors. It is often drug resistant and generally worsen patients' quality of life (QoL). Brain tumors release glutamate among other mediators, contributing to seizures onset, and this is accompanied by an increased AMPA receptors' expression on neuronal cells' membrane. Perampanel (PER) is a relatively new antiseizure medication (ASM) that acts as a selective non-competitive AMPA receptors' antagonist. Given its mechanism of action, we aimed to evaluate through a prospective, observational study, the efficacy and safety of PER as an add-on treatment in patients with brain tumor-related epilepsy (BTRE). The study was called PERADET. Methods: Thirty-six adult patients (intention to treat population-ITT) affected by BTRE, with uncontrolled focal-onset seizures treated with 1–3 ASMs were recruited from four Italian epilepsy centers. Perampanel was added-on, titrated from 2 mg/day up to a maximum of 12 mg/day. Tumor history and therapy, type, and seizures frequency, previous ASMs were collected at 6 and 12 months. A battery of QoL tests were administered at baseline, 6 and 12 months. The primary endpoint was to assess the efficacy of PER by calculating the percent change in seizure frequency and the responder rate. The secondary endpoints were tolerability, retention rate at 12 months, and improvement in quality of life. Results: At the end of 12 months, 21 patients (per protocol population-PP) were available for evaluation. In this population the responder rate (percentage of patients who experienced a 50% or greater reduction in seizure frequency) was 90.4 with 33.3% of patients being seizure-free. In the ITT group the responder rate at the end of 12 months was 66.6 with 25% of patients being seizure free. PER was well tolerated (30.6% of patients experienced an adverse event, none was severe; three needed a treatment interruptions). Conclusions: Our study indicate that PER may be efficacious against BTRE as suggested by its mechanism of action and our current knowledge on mechanisms of brain tumor epileptogenicity. Trial Registration Number (TRN): (Prot. n° 0008872.25-06-2019); RS 919/17

Silver sulfadiazine eradicates antibiotic-tolerant Staphylococcus aureus and Pseudomonas aeruginosa biofilms in patients with infected diabetic foot ulcers

Infections are among the most frequent and challenging events in diabetic foot ulcers (DFUs). Pathogenic bacteria growing in biofilms within host tissue are highly tolerant to environmental and chemical agents, including antibiotics. The present study was aimed at assessing the use of silver sulfadiazine (SSD) for wound healing and infection control in 16 patients with DFUs harboring biofilm-growing Staphylococcus aureus and Pseudomonas aeruginosa. All patients received a treatment based on a dressing protocol including disinfection, cleansing, application of SSD, and application of nonadherent gauze, followed by sterile gauze and tibio-breech bandage, in preparation for toilet surgery after 30 days of treatment. Clinical parameters were analyzed by the T.I.M.E. classification system. In addition, the activity of SSD against biofilm-growing S. aureus and P. aeruginosa isolates was assessed in vitro. A total of 16 patients with S. aureus and P. aeruginosa infected DFUs were included in the study. Clinical data showed a statistically significant (p < 0.002) improvement of patients’ DFUs after 30 days of treatment with SSD with significant amelioration of all the parameters analyzed. Notably, after 30 days of treatment, resolution of infection was observed in all DFUs. In vitro analysis showed that both S. aureus and P. aeruginosa isolates developed complex and highly structured biofilms. Antibiotic susceptibility profiles indicated that biofilm cultures were significantly (p ≤ 0.002) more tolerant to all tested antimicrobials than their planktonic counterparts. However, SSD was found to be effective against fully developed biofilms of both S. aureus and P. aeruginosa at concentrations below those normally used in clinical preparations (10 mg/mL). These results strongly suggest that the topical administration of SSD may represent an effective alternative to conventional antibiotics for the successful treatment of DFUs infected by biofilm-growing S. aureus and P. aeruginosa

Comparing MRI metrics to quantify white matter microstructural damage in multiple sclerosis

Quantifying white matter damage in vivo is becoming increasingly important for investigating the effects of neuroprotective and repair strategies in multiple sclerosis (MS). While various approaches are available, the relationship between MRI‐based metrics of white matter microstructure in the disease, that is, to what extent the metrics provide complementary versus redundant information, remains largely unexplored. We obtained four microstructural metrics from 123 MS patients: fractional anisotropy (FA), radial diffusivity (RD), myelin water fraction (MWF), and magnetisation transfer ratio (MTR). Coregistration of maps of these four indices allowed quantification of microstructural damage through voxel‐wise damage scores relative to healthy tissue, as assessed in a group of 27 controls. We considered three white matter tissue‐states, which were expected to vary in microstructural damage: normal appearing white matter (NAWM), T2‐weighted hyperintense lesional tissue without T1‐weighted hypointensity (T2L), and T1‐weighted hypointense lesional tissue with corresponding T2‐weighted hyperintensity (T1L). All MRI indices suggested significant damage in all three tissue‐states, the greatest damage being in T1L. The correlations between indices ranged from r = 0.18 to r = 0.87. MWF was most sensitive when differentiating T2L from NAWM, while MTR was most sensitive when differentiating T1L from NAWM and from T2L. Combining the four metrics into one, through a principal component analysis, did not yield a measure more sensitive to damage than any single measure. Our findings suggest that the metrics are (at least partially) correlated with each other, but sensitive to the different aspects of pathology. Leveraging these differences could be beneficial in clinical trials testing the effects of therapeutic interventions

Demyelinating and thrombotic diseases of the central nervous system: common pathogenic and triggering factors

Context: Copper deficiency myelopathy represents an often underdiagnosed, acquired neurological syndrome, clinically characterized by posterior column dysfunction. The main causes of copper deficiency are bariatric surgery, increased consumption of zinc, and malabsorption. However, even after a careful history taking and extensive laboratory researches, the etiology of copper deficiency remains undetermined in a significant percentage of cases. Patients affected by copper deficiency myelopathy usually present with sensory ataxia due to dorsal column dysfunction and sometimes with mild leg spasticity. In such patients, spinal cord magnetic resonance imaging (MRI) may show hyperintense lesions in T2-weighted sequences involving the posterior columns of cervical and thoracic cord. These MRI findings are not distinguishable from those of subacute combined degeneration associated with vitamin B12 deficiency. Findings: Here, we describe two patients with gait ataxia and sensory symptoms in which a diagnosis of copper deficiency myelopathy was made. Both patients showed a significant clinical, neuroradiological, and neurophysiological improvement after proper supplementation therapy. Conclusion: The patients herein described underline the importance to include serum copper and ceruloplasmin levels as part of the myelopathy diagnostic workup, especially in the cases of otherwise unexplained subacute myelopathy involving the posterior columns. Since copper deficiency myelopathy is a progressive syndrome, early diagnosis is mandatory in order to promptly provide a proper supplementation therapy and, thus, prevent an irreversible neurological damage

Brain fibrinogen deposition plays a key role in MS pathophysiology. Commentary

Numerous studies focused on the proinflammatory functions of several clotting components have recently highlighted the role of coagulation system in experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) pathogenesis.1 The contributions from Davalos et al.2 and Göbel and Meuth3 in this controversy look at these data from different angles. Davalos et al.2 underline the pathogenetic role of brain fibrinogen deposition in MS. Fibrinogen enters and spreads in the central nervous system (CNS) after blood–brain barrier disruption, rapidly converting to fibrin and persisting in the parenchyma.4 Perivascular fibrinogen deposits are observed in post-mortem studies in pre-active, active, chronic active and chronic inactive MS lesions prevalently in white but also in deep grey matter. Likely due to fibrinolysis, fibrinogen spreads even more in the brain when active white matter lesions evolve into chronic lesions and remains scattered in the re-myelinated lesions and in the cortex of patients with progressive MS. In the early phase, fibrinogen deposits appear attached to axonal nodes and co-localize with activated microglia, prior to peripheral immune cell infiltration or any detectable tissue damage. Fibrinogen induces microglial clustering and promotes chemokine secretion and recruitment of peripheral macrophages and myelin-specific Th1 cells into the CNS.5 It impairs tissue repair by inhibiting oligodendrocyte precursor cell differentiation and inducing NADPH/ROS-mediated neurodegeneration. Treatment with a monoclonal antibody specifically targeting the inflammatory but not the clotting function of fibrinogen can prevent and treat EAE.6 On the other hand, Göbel and Meuth argue that the role of fibrinogen could be overvalued in MS pathophysiology because other coagulation proteins are shown to be dysregulated in both brain and blood of MS patients.3 In particular, circulating levels of several coagulation factors such as prothrombin (Factor II), thrombin, factor X and Factor XII are significantly increased in relapsing-remitting and secondary progressive MS patients compared to healthy controls, and this rise is correlated with disease activity.7,8 The thrombin increase, similar to fibrinogen deposition, precedes demyelination and clinical signs in EAE. EAE ameliorates either after thrombin inhibition by anticoagulant hirudin due to a decrease in both immune cell proliferation and cytokine secretion or after FX inhibition with rivaroxaban leading to a decrease in microglial activation and reduced T-cell infiltration as well as after FXII inhibition by recombinant human albumin tagged infestin-4. Thrombin acts not only by cleaving fibrinogen but also by activating a proinflammatory signalling cascade through protease-activated receptors widely expressed in the CNS. Yet, the authors considered FXII as a critical trigger of autoimmune inflammation, which acts by shifting the cytokine profile of dendritic cells necessary to induce the differentiation of interleukin-17A-producing effector T-helper cells.9 In our opinion, even if fibrinogen is the key element of a complex chain, other procoagulant factors including antiphospholipid antibodies and platelets as well as anticoagulants factors and fibrinolysis play an important role in MS and EAE pathogenesis.1 These observations are in line with recent evidence that no longer considers coagulation system and innate immunity as separate entities.10 So far only a few of the many molecular and cellular pathways linking coagulation/inflammation and the innate immune system were studied. The role of the endothelial cells expressing anticoagulant and procoagulant molecules as well as of several cell surfaces and intracellular signalling pathways should be better understood.10 The vision of these systems as almost inseparable would lead to a more complete and objective aetiopathogenetic understanding of this complex multifactorial disease. As a subsequent step, it will be necessary to design a convenient treatment approach that can complement available MS anti-inflammatory therapies