Publications by authors named "Michel Toledano"

87 Publications

Hyperammonemia in Patients With Status Epilepticus Treated With or Without Valproic Acid.

Neurologist 2021 May 5;26(3):80-82. Epub 2021 May 5.

Department of Neurology, Mayo Clinic, Rochester, MN.

Background: Hyperammonemia is a common side effect of valproic acid (VPA) and can occur after generalized seizures, but the clinical significance is unclear. The aim of this study was to better understand the clinical practice and utility of ammonia testing in status epilepticus (SE) treated with or without VPA.

Methods: Charts of adult patients with SE from St. Mary's Hospital Intensive Care Units (ICUs) (Mayo Clinic, Rochester, MN) from 2011 to 2016 were reviewed. Clinical factors were compared between patients who had ammonia checked versus those who did not, and those with normal ammonia versus hyperammonemia (>50 µg/dL). Charts were reviewed to determine if hyperammonemia changed clinical management and if it was felt to be symptomatic.

Results: There were 304 patients identified: 94 received VPA, 142 had ammonia checked and receiving VPA was associated with ammonia testing (P<0.001). Hyperammonemia was identified in 32 and associated with younger age, being in a non-neurological intensive care unit, and liver disease, but was not statistically associated with VPA. Only one patient had valproate-induced hyperammonemic encephalopathy; however, many patients received treatment for hyperammonemia such as lactulose, levocarnitine, or VPA dose reductions.

Conclusions: This study demonstrated variability in ammonia testing and management changes in SE but does not support the routine monitoring of ammonia levels and showed that hyperammonemic encephalopathy was rare in this clinical setting.
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http://dx.doi.org/10.1097/NRL.0000000000000335DOI Listing
May 2021

Infectious Myelopathies.

Authors:
Michel Toledano

Continuum (Minneap Minn) 2021 02;27(1):93-120

Purpose Of Review: This article reviews infectious etiologies of spinal cord dysfunction, emphasizing the importance of recognizing common clinicoradiographic syndromes and interpreting them in the context of exposure risk and individual host susceptibilities.

Recent Findings: This article discusses the shifting spectrum of neurologic infectious diseases, the growing population of patients who are immunocompromised, and the emergence of effective antiretroviral therapies. In addition, it discusses new molecular and serologic tests that have the potential to enhance our ability to rapidly and accurately diagnose infectious diseases of the spine.

Summary: When evaluating patients with suspected infectious myelopathies, it is imperative to narrow the range of pathogens under consideration. The geography, seasonality, and clinicoradiographic presentation and immunocompetence status of the patient define the range of potential pathogens and should guide testing and initial management.
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http://dx.doi.org/10.1212/CON.0000000000000930DOI Listing
February 2021

Neuronal intermediate filament IgGs in CSF: Autoimmune Axonopathy Biomarkers.

Ann Clin Transl Neurol 2021 02 28;8(2):425-439. Epub 2020 Dec 28.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.

Objectives: To describe CSF-defined neuronal intermediate filament (NIF) autoimmunity.

Methods: NIF-IgG CSF-positive patients (41, 0.03% of 118599 tested, 1996-2019) were included (serum was neither sensitive nor specific). Criteria-based patient NIF-IgG staining of brain and myenteric NIFs was detected by indirect immunofluorescence assay (IFA); NIF-specificity was confirmed by cell-based assays (CBAs, alpha internexin, neurofilament light [NF-L]), heavy-[NF-H] chain).

Results: Sixty-one percent of 41 patients were men, median age, 61 years (range, 21-88). Syndromes were encephalopathy predominant (23), cerebellar ataxia predominant (11), or myeloradiculoneuropathies (7). MRI abnormalities (T2 hyperintensities of brain, spinal cord white matter tracts. and peripheral nerve axons) and neurophysiologic testing (EEG, EMG, evoked potentials) co-localized with clinical neurological phenotypes (multifocal in 29%). Thirty patients (73%) had ≥ 1 immunological perturbation: cancer (paraneoplastic), 22; systemic infection (parainfectious [including ehrlichosis, 3] or HIV), 7; checkpoint-inhibitor cancer immunotherapy, 4; other, 5. Cancers were as follows: neuroendocrine-lineage carcinomas, 12 (small cell, 6; Merkel cell, 5; pancreatic, 1 [11/12 had NF-L-IgG detected, versus 8/29 others, P = 0.0005]) and other, 11. Onset was predominantly subacute (92%) and accompanied by inflammatory CSF (75%), and immunotherapy response (77%). In contrast, CSF controls (15684 total) demonstrated NIF-IgG negativity (100% of test validation controls), and low frequencies of autoimmune diagnoses (20% of consecutively referred clinical specimens) and neuroendocrine-lineage carcinoma diagnosis (3.1% vs. 30% of NIF cases), P < 0.0001. Median NF-L protein concentration was higher in 8 NF-L-IgG-positive patients (median, 6718 ng/L) than 16 controls.

Interpretation: Neurological autoimmunity, defined by CSF-detected NIF-IgGs, represents a continuum of treatable axonopathies, sometimes paraneoplastic or parainfectious.
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http://dx.doi.org/10.1002/acn3.51284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886032PMC
February 2021

Correction to: Central Nervous System Manifestations Associated with COVID-19.

Curr Neurol Neurosci Rep 2020 Nov 12;20(12):66. Epub 2020 Nov 12.

Departments of Clinical Neurological sciences, Western University, London, Canada.

The original version contained incorrect formatting of Dr. Napolis. His first name should be Mario and his last name should be Di Napoli.
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http://dx.doi.org/10.1007/s11910-020-01086-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661013PMC
November 2020

Central Nervous System Manifestations Associated with COVID-19.

Curr Neurol Neurosci Rep 2020 10 30;20(12):60. Epub 2020 Oct 30.

Departments of Clinical Neurological sciences, Western University, London, Canada.

Purpose Of Review: Coronavirus disease 2019 (COVID-19) has become a global health crisis of our time. The disease arises from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that binds to angiotensin-converting enzyme 2 (ACE2) receptors on host cells for its internalization. COVID-19 has a wide range of respiratory symptoms from mild to severe and affects several other organs, increasing the complexity of the treatment. There is accumulating evidence to suggest that SARS-CoV-2 can target the nervous system. In this review, we provide an account of the COVID-19 central nervous system (CNS) manifestations.

Recent Findings: A broad spectrum of the CNS manifestations including headache, impaired consciousness, delirium, loss of smell and taste, encephalitis, seizures, strokes, myelitis, acute disseminated encephalomyelitis, neurogenic respiratory failure, encephalopathy, silent hypoxemia, generalized myoclonus, neuroleptic malignant syndrome and Kawasaki syndrome has been reported in patients with COVID-19. CNS manifestations associated with COVID-19 should be considered in clinical practice. There is a need for modification of current protocols and standing orders to provide better care for COVID-19 patients presenting with neurological symptoms.
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http://dx.doi.org/10.1007/s11910-020-01079-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599061PMC
October 2020

Toxin-Induced Neuropathies.

Authors:
Michel Toledano

Neurol Clin 2020 11 12;38(4):749-763. Epub 2020 Sep 12.

Department of Neurology, Mayo Clinic, 200 1st Street, Rochester, MN 55905, USA. Electronic address:

Peripheral neuropathies secondary to neurotoxicants are frequently considered but can be difficult to diagnose. Accurate diagnosis is important to avoid unnecessary testing, prevent further exposure, and initiate treatment when available. This article reviews key features of some of the more common or representative toxic neuropathies, including those caused by occupational and environmental exposure, medications, and chemotherapeutic agents.
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http://dx.doi.org/10.1016/j.ncl.2020.06.002DOI Listing
November 2020

Retrospective Review of Clinical Utility of Shotgun Metagenomic Sequencing Testing of Cerebrospinal Fluid from a U.S. Tertiary Care Medical Center.

J Clin Microbiol 2020 11 18;58(12). Epub 2020 Nov 18.

Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA

Shotgun metagenomic sequencing can detect nucleic acids from bacteria, fungi, viruses, and/or parasites in clinical specimens; however, little data exist to guide its optimal application to clinical practice. We retrospectively reviewed results of shotgun metagenomic sequencing testing requested on cerebrospinal fluid samples submitted to an outside reference laboratory from December 2017 through December 2019. Of the 53 samples from Mayo Clinic patients, 47 were requested by neurologists, with infectious diseases consultation in 23 cases. The majority of patients presented with difficult-to-diagnose subacute or chronic conditions. Positive results were reported for 9 (17%) Mayo Clinic patient samples, with 6 interpreted as likely contamination. Potential pathogens reported included bunyavirus, human herpesvirus 7, and enterovirus D-68, ultimately impacting care in two cases. Twenty-seven additional samples were submitted from Mayo Clinic Laboratories reference clients, with positive results reported for three (11%): two with potential pathogens (West Nile virus and ) and one with species with other bacteria below the reporting threshold (considered to represent contamination). Of 68 negative results, 10 included comments on decreased sensitivity due to high DNA background ( = 5), high RNA background ( = 1), insufficient RNA read depth ( = 3), or quality control (QC) failure with an external RNA control ( = 1). The overall positive-result rate was 15% (12/80), with 58% (7/12) of these interpreted as being inconsistent with the patient's clinical presentation. Overall, potential pathogens were found in a low percentage of cases, and positive results were often of unclear clinical significance. Testing was commonly employed in cases of diagnostic uncertainty and when immunotherapy was being considered.
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http://dx.doi.org/10.1128/JCM.01729-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685881PMC
November 2020

Assessing Utilization of the Cerebrospinal Fluid Venereal Disease Research Laboratory Test for Diagnosis of Neurosyphilis: a Cohort Study.

J Gen Intern Med 2021 01 31;36(1):77-83. Epub 2020 Aug 31.

Department of Neurology, Mayo Clinic, Rochester, MN, USA.

Background: Inappropriate use of diagnostic tests contributes to rising healthcare expenditures, and improving appropriate utilization rates is important for high-value patient care. The Venereal Disease Research Laboratory (VDRL) test performed in cerebrospinal fluid (CSF) has historically been improperly utilized, although there is no recent evaluation of its use in clinical practice.

Objectives: Quantify the rates of appropriate CSF-VDRL testing, determine the CSF-VDRL false-positivity rate, and describe the causes of false-positive CSF-VDRL reactivity.

Design: Retrospective cohort study PATIENTS: A total of 32,626 patients with CSF-VDRL testing at one of three Mayo Clinic sites (Rochester, MN; Jacksonville, FL; and Scottsdale, AZ) from January 1, 1994, to February 28, 2018.

Main Measures: Rate of appropriate CSF-VDRL test utilization from January 1, 2011, to December 31, 2017, and CSF-VDRL true- and false-positivity rates from January 1, 1994, to February 28, 2018.

Key Results: Among 8553 persons with negative CSF-VDRL results, testing was inappropriately ordered for 8399 (98.2%) of these patients. The word "syphilis" or "neurosyphilis" appeared in the notes of 1184 (13.8%) individuals with a negative CSF-VDRL result. From January 1994 through February 2018, 33,933 CSF-VDRL tests were performed on 32,626 individual patients. Among the 60 positive CSF-VDRL results, 43 (71.7%) were true-positives and 17 (28.3%) were false-positives. All patients with false-positive CSF-VDRL results were tested unnecessarily. Neoplastic meningitis was a common cause of false-positive CSF-VDRL results.

Conclusions: Inappropriate use of CSF-VDRL testing for the diagnosis of neurosyphilis remains problematic in clinical practice. Following recommended testing algorithms would prevent unnecessary testing and minimize false-positive results.
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http://dx.doi.org/10.1007/s11606-020-06127-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859160PMC
January 2021

Peroxiredoxin promotes longevity and HO-resistance in yeast through redox-modulation of protein kinase A.

Elife 2020 07 14;9. Epub 2020 Jul 14.

Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden.

Peroxiredoxins are HO scavenging enzymes that also carry out HO signaling and chaperone functions. In yeast, the major cytosolic peroxiredoxin, Tsa1 is required for both promoting resistance to HO and extending lifespan upon caloric restriction. We show here that Tsa1 effects both these functions not by scavenging HO, but by repressing the nutrient signaling Ras-cAMP-PKA pathway at the level of the protein kinase A (PKA) enzyme. Tsa1 stimulates sulfenylation of cysteines in the PKA catalytic subunit by HO and a significant proportion of the catalytic subunits are glutathionylated on two cysteine residues. Redox modification of the conserved Cys243 inhibits the phosphorylation of a conserved Thr241 in the kinase activation loop and enzyme activity, and preventing Thr241 phosphorylation can overcome the HO sensitivity of Tsa1-deficient cells. Results support a model of aging where nutrient signaling pathways constitute hubs integrating information from multiple aging-related conduits, including a peroxiredoxin-dependent response to HO.
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http://dx.doi.org/10.7554/eLife.60346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392609PMC
July 2020

Clinical Reasoning: Multifocal neuropathies in a patient with Waldenstrom macroglobulinemia and prior borreliosis.

Neurology 2020 07 11;95(1):44-48. Epub 2020 Jun 11.

From the Departments of Neurology (B.C.C., M.L.M., M.T.) and Laboratory Medicine and Pathology (E.S.T.), Mayo Clinic, Rochester, MN.

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http://dx.doi.org/10.1212/WNL.0000000000009741DOI Listing
July 2020

Noninfectious neurologic complications of hematopoietic cell transplantation: A systematic review.

Hematol Oncol Stem Cell Ther 2021 Jun 21;14(2):87-94. Epub 2020 May 21.

Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; Department of Medicine, Mayo Clinic, Rochester, MN, USA.

Objective/background: Neurological complications occur at a high frequency after hematopoietic cell transplantation (HCT). However, an absence is noted in the published literature as regards the quantification of the exact burden and the outcomes thereof. In this systematic review, we endeavored to detail if the recipients of HCT developed any noninfectious neurological events/complications.

Methods: According to the PICO criteria, medical literature was searched. Complications that were evaluated included: stroke, peripheral neuropathy, myasthenia gravis, seizures, and posterior reversible encephalopathy syndrome. After strictly defining relevant variables and parameters, data from 173 eligible articles were then extracted accordingly, from the full text for each, for quantitative analysis; additionally, two American Society of Hematology conference abstracts were also subject to data extraction.

Results: As is evident from the results of the data analysis, an increased frequency of these complications was seen in the HCT recipient population in comparison to the general population. The relative risk ranged from 1.33× to 142× depending on the complication studied.

Conclusion: These findings demonstrate that the recipients of HCT had a significantly higher risk of neurological complications and that their early recognition can enhance the monitoring of HCT survivors for the early developmental signs of neurological toxicity. This would facilitate timely interventions, thus ensuring a better quality of life.
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http://dx.doi.org/10.1016/j.hemonc.2020.05.006DOI Listing
June 2021

Dynamics of a Key Conformational Transition in the Mechanism of Peroxiredoxin Sulfinylation.

ACS Catal 2020 Mar 31;10(5):3326-3339. Epub 2020 Jan 31.

IMoPA, Université de Lorraine, CNRS, Biopole, Campus Biologie Sante', F-54000 Nancy, France.

Peroxiredoxins from the Prx1 subfamily (Prx) are moonlighting peroxidases that operate in peroxide signaling and are regulated by sulfinylation. Prxs offer a major model of protein-thiol oxidative modification. They react with HO to form a sulfenic acid intermediate that either engages into a disulfide bond, committing the enzyme into its peroxidase cycle, or again reacts with peroxide to produce a sulfinic acid that inactivates the enzyme. Sensitivity to sulfinylation depends on the kinetics of these two competing reactions and is critically influenced by a structural transition from a fully folded (FF) to locally unfolded (LU) conformation. Analysis of the reaction of the Tsa1 Prx with HO by Trp fluorescence-based rapid kinetics revealed a process linked to the FF/LU transition that is kinetically distinct from disulfide formation and suggested that sulfenate formation facilitates local unfolding. Use of mutants of distinctive sensitivities and of different peroxide substrates showed that sulfinylation sensitivity is not coupled to the resolving step kinetics but depends only on the sulfenic acid oxidation and FF-to-LU transition rate constants. In addition, stabilization of the active site FF conformation, the determinant of sulfinylation kinetics, is only moderately influenced by the Prx C-terminal tail dynamics that determine the FF → LU kinetics. From these two parameters, the relative sensitivities of Prxs toward hyperoxidation with different substrates can be predicted, as confirmed by in vitro and in vivo patterns of sulfinylation.
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http://dx.doi.org/10.1021/acscatal.9b04471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189429PMC
March 2020

The importance of naturally attenuated SARS-CoV-2in the fight against COVID-19.

Environ Microbiol 2020 06;22(6):1997-2000

Viral Pathogenesis and Biosafety Unit, San Raffaele Scientific Institute, Via Olgettina 58, Milan, 20132, Italy.

The current SARS-CoV-2 pandemic is wreaking havoc throughout the world and has rapidly become a global health emergency. A central question concerning COVID-19 is why some individuals become sick and others not. Many have pointed already at variation in risk factors between individuals. However, the variable outcome of SARS-CoV-2 infections may, at least in part, be due also to differences between the viral subspecies with which individuals are infected. A more pertinent question is how we are to overcome the current pandemic. A vaccine against SARS-CoV-2 would offer significant relief, although vaccine developers have warned that design, testing and production of vaccines may take a year if not longer. Vaccines are based on a handful of different designs (i), but the earliest vaccines were based on the live, attenuated virus. As has been the case for other viruses during earlier pandemics, SARS-CoV-2 will mutate and may naturally attenuate over time (ii). What makes the current pandemic unique is that, thanks to state-of-the-art nucleic acid sequencing technologies, we can follow in detail how SARS-CoV-2 evolves while it spreads. We argue that knowledge of naturally emerging attenuated SARS-CoV-2 variants across the globe should be of key interest in our fight against the pandemic.
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http://dx.doi.org/10.1111/1462-2920.15039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267670PMC
June 2020

GFAP IgG associated inflammatory polyneuropathy.

J Neuroimmunol 2020 06 1;343:577233. Epub 2020 Apr 1.

Department of Neurology, Mayo Clinic, Rochester, MN, United States of America; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America. Electronic address:

Background: GFAP (glial fibrillary acidic protein)-IgG is predominantly associated with meningoencephalomyelitis, and neuropathy presentations are rare.

Methods: We reviewed clinical, electrodiagnostic and histopathological presentations of GFAP-IgG associated peripheral neuropathy.

Results: We identified six cases, five of whom had peripheral neuropathy as the initial presentation. Acute/subacute polyradicluoneuropathy or proximal nerve involvement was a common presentation. Three had demyelinating neuropathies on electrophysiological studies. Nerve biopsies (n = 2) demonstrated T-cell predominant perivascular inflammatory collections, and all patients with clinical follow up responded favorably to immunotherapy.

Conclusion: GFAP neuropathy represents a potentially treatable immune-mediated neuropathy and can occur with or without co-existing meningoencephalomyelitis.
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http://dx.doi.org/10.1016/j.jneuroim.2020.577233DOI Listing
June 2020

A Redox-Sensitive Thiol in Wis1 Modulates the Fission Yeast Mitogen-Activated Protein Kinase Response to HO and Is the Target of a Small Molecule.

Mol Cell Biol 2020 03 16;40(7). Epub 2020 Mar 16.

University of Gothenburg, Department of Chemistry and Molecular Biology, Gothenburg, Sweden

Oxidation of a highly conserved cysteine (Cys) residue located in the kinase activation loop of mitogen-activated protein kinase kinases (MAPKK) inactivates mammalian MKK6. This residue is conserved in the fission yeast MAPKK Wis1, which belongs to the HO-responsive MAPK Sty1 pathway. Here, we show that HO reversibly inactivates Wis1 through this residue (C458) We found that C458 is oxidized and that serine replacement of this residue significantly enhances Wis1 activation upon addition of HO The allosteric MAPKK inhibitor INR119, which binds in a pocket next to the activation loop and C458, prevented the inhibition of Wis1 by HO and significantly increased Wis1 activation by low levels of HO We propose that oxidation of C458 inhibits Wis1 and that INR119 cancels out this inhibitory effect by binding close to this residue. Kinase inhibition through the oxidation of a conserved Cys residue in MKK6 (C196) is thus conserved in the MAPKK Wis1.
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http://dx.doi.org/10.1128/MCB.00346-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076255PMC
March 2020

Physiologically relevant reconstitution of iron-sulfur cluster biosynthesis uncovers persulfide-processing functions of ferredoxin-2 and frataxin.

Nat Commun 2019 08 8;10(1):3566. Epub 2019 Aug 8.

Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, Université Paris-Saclay, 91198, Gif-sur-Yvette cedex, France.

Iron-sulfur (Fe-S) clusters are essential protein cofactors whose biosynthetic defects lead to severe diseases among which is Friedreich's ataxia caused by impaired expression of frataxin (FXN). Fe-S clusters are biosynthesized on the scaffold protein ISCU, with cysteine desulfurase NFS1 providing sulfur as persulfide and ferredoxin FDX2 supplying electrons, in a process stimulated by FXN but not clearly understood. Here, we report the breakdown of this process, made possible by removing a zinc ion in ISCU that hinders iron insertion and promotes non-physiological Fe-S cluster synthesis from free sulfide in vitro. By binding zinc-free ISCU, iron drives persulfide uptake from NFS1 and allows persulfide reduction into sulfide by FDX2, thereby coordinating sulfide production with its availability to generate Fe-S clusters. FXN stimulates the whole process by accelerating persulfide transfer. We propose that this reconstitution recapitulates physiological conditions which provides a model for Fe-S cluster biosynthesis, clarifies the roles of FDX2 and FXN and may help develop Friedreich's ataxia therapies.
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http://dx.doi.org/10.1038/s41467-019-11470-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687725PMC
August 2019

Infectious encephalitis: mimics and chameleons.

Pract Neurol 2019 Jun 16;19(3):225-237. Epub 2019 Mar 16.

Department of Neurology, Chelsea and Westminster Hospital, London, UK

Click here to listen to the Podcast 'Query encephalitis' is a common neurological consultation in hospitalised patients. Identifying the syndrome is only part of the puzzle. Although historically encephalitis has been almost synonymous with infection, we increasingly recognise parainfectious or postinfectious as well as other immune-mediated causes. We must also distinguish encephalitis from other causes of encephalopathy, including systemic infection, metabolic derangements, toxins, inherited metabolic disorders, hypoxia, trauma and vasculopathies. Here, we review the most important differential diagnoses (mimics) of patients presenting with an encephalitic syndrome and highlight some unusual presentations (chameleons) of infectious encephalitis.
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http://dx.doi.org/10.1136/practneurol-2018-002114DOI Listing
June 2019

Parsing protein sulfinic acid switches.

Nat Chem Biol 2018 11;14(11):991-993

Institute for Integrative Biology of the Cell (I2BC), CEA-Saclay, CNRS, Université Paris-Saclay, DBJC/SBIGEM, Oxidative Stress & Cancer, Gif-sur-Yvette, France.

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http://dx.doi.org/10.1038/s41589-018-0151-zDOI Listing
November 2018

Population-based study of "no evident disease activity" in MS.

Neurol Neuroimmunol Neuroinflamm 2018 Nov 16;5(6):e495. Epub 2018 Aug 16.

Department of Neurology (N.E.P., S.J.P., O.H.K., C.F.L., B.G.W., B.M.K., W.O.T., J.M.T., M.T., E.P.F.), Department of Laboratory Medicine & Pathology (S.J.P., E.P.F.), and Department of Biomedical Statistics and Informatics (J.M.), Mayo Clinic, Rochester, MN; and Department of Medicine (Division of Neurology) (N.E.P.), Dalhousie University, Halifax, Canada.

Objective: To determine the persistence of no evident disease activity (NEDA) in a population-based relapsing-remitting MS (RRMS) cohort.

Methods: All incident cases of RRMS in Olmsted County between 2000 and 2011 were identified using a medical records linkage system. Persistence of NEDA after RRMS diagnosis was determined by retrospective chart review. MRI activity, relapse, or Expanded Disability Status Scale (EDSS) worsening resulted in failure of NEDA.

Results: We identified 93 incident cases of RRMS including 82 individuals with sufficient follow-up to determine the persistence of NEDA. There were 44 individuals not on disease-modifying therapy (DMT), whereas 37 individuals were prescribed an injectable DMT and 1 received mitoxantrone during the interval over which NEDA was maintained. NEDA was maintained by 63% at 1 year, 38% at 2 years, 19% at 5 years, and 12% at 10 years according to routine care assessment. At 10 years, there was no difference in EDSS disability among patients who maintained NEDA vs those who failed NEDA at 1 year ( = 0.3).

Conclusions: NEDA infrequently persists beyond 2 years in a population-based cohort of newly diagnosed patients with RRMS.
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http://dx.doi.org/10.1212/NXI.0000000000000495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134213PMC
November 2018

West Nile Neuroinvasive Disease Presenting as Elsberg Syndrome.

Neurologist 2018 Sep;23(5):152-154

Division of Critical Care Neurology.

Introduction: Elsberg syndrome (ES) is a rarely recognized cause of cauda equina syndrome and lower thoracic myelitis, mainly linked to reactivation, or occasionally primary, infection with herpes simplex virus type 2. West Nile virus neuroinvasive disease is rarely considered in the differential diagnosis of patients with ES.

Case Report: A 63-year-old man with pancreatic cancer in remission and polymyalgia rheumatica on low-dose prednisone presented with a 10-day history of low-back pain and a viral-type illness with low-grade fever, nausea, and vomiting. Days later, he developed left leg monoparesis, neurogenic bladder, and bowel. Magnetic resonance imaging of the lumbar spine revealed a hyperintense signal abnormality within the central spinal cord and conus medullaris with mild swelling of the conus. Cells, proteins, and glucose in cerebrospinal fluid were 67/mm, 70 mg/dL, and 58 mg/dL, respectively. Serology was positive for West Nile virus IgM. Nerve conduction studies and electromyography showed an acute motor neurogenic process affecting left lumbosacral segments.

Conclusions: West Nile virus neuroinvasive disease is an uncommon condition that should be considered in patients with ES. Determining the etiology of ES in the acute setting may avoid unnecessary diagnostic investigations and treatments.
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http://dx.doi.org/10.1097/NRL.0000000000000189DOI Listing
September 2018

Nrf2-activated expression of sulfiredoxin contributes to urethane-induced lung tumorigenesis.

Cancer Lett 2018 09 15;432:216-226. Epub 2018 Jun 15.

Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY, 40536, USA. Electronic address:

Lung cancer is the leading cause of cancer death worldwide. Cigarette smoking and exposure to chemical carcinogens are among the risk factors of lung tumorigenesis. In this study, we found that cigarette smoke condensate and urethane significantly stimulated the expression of sulfiredoxin (Srx) at the transcript and protein levels in cultured normal lung epithelial cells, and such stimulation was mediated through the activation of nuclear related factor 2 (Nrf2). To study the role of Srx in lung cancer development in vivo, mice with Srx wildtype, heterozygous or knockout genotype were subjected to the same protocol of urethane treatment to induce lung tumors. By comparing tumor multiplicity and volume between groups of mice with different genotype, we found that Srx knockout mice had a significantly lower number and smaller size of lung tumors. Mechanistically, we demonstrated that loss of Srx led to a decrease of tumor cell proliferation as well as an increase of tumor cell apoptosis. These data suggest that Srx may have an oncogenic role that contributes to the development of lung cancer in smokers or urethane-exposed human subjects.
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http://dx.doi.org/10.1016/j.canlet.2018.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886468PMC
September 2018

Demographics and clinical characteristics of episodic hypothermia in multiple sclerosis.

Mult Scler 2019 04 23;25(5):709-714. Epub 2018 Mar 23.

Department of Neurology, University of Utah, Salt Lake City, UT, USA.

Background: Episodic hypothermia (EH) can occur in multiple sclerosis (MS). The putative mechanism is impairment of thermoregulation due to a presumed demyelinating hypothalamic lesion.

Objective: To describe a cohort of patients with MS, who developed EH.

Methods: Patients were identified through review of the Mayo Clinic electronic medical record (1996 to July 2015). Search terms were [multiple sclerosis] or [MS] within the diagnoses field and [hypothermia] within any field. We reviewed records for accuracy of diagnoses and abstracted relevant data. Magnetic resonance imaging (MRI) was reviewed for presence of hypothalamic lesions.

Results: Of 156 patients, 34 had concurrent MS and hypothermia. Thirty-two (94%) had progressive disease at EH onset. Median MS duration was 19.9 years, and median expanded disability status scale (EDSS) was 8.0. Most patients presented with alterations in consciousness. Infection was suspected as the precipitating factor in 19 (56%), but clinically/laboratory supported in only 9 (28%). MRI lesions were evident within the hypothalamus in only 4 (14%).

Conclusion: EH occurs predominantly in patients with advanced secondary progressive MS. The major manifestation is altered consciousness. Infection is often suspected as causal, but infrequently confirmed. Although commonly implicated, hypothalamic lesions were rarely evident on MRI and were absent in two post-mortem evaluations.
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http://dx.doi.org/10.1177/1352458518767045DOI Listing
April 2019

Clinical presentation of autoimmune and viral encephalitides.

Curr Opin Crit Care 2018 04;24(2):80-90

Department of Neurology.

Purpose Of Review: We describe clinical and diagnostic features of various autoimmune and viral encephalitis subtypes.

Recent Findings: Population-based studies have demonstrated both autoimmune and viral causes have similar prevalence and incident rates. Repertoire of autoimmune biomarkers has considerably increased with discovery of many novel neural antibodies including glial fibrillary acidic proteinα-immunoglobulin G. Similarly, with use of next generation sequencing and DNA libraries, many viral causes are being detected which would have been categorized as encephalitis of unknown cause a decade ago.

Summary: Autoimmune and viral encephalitides can resemble one another and sometimes autoimmune encephalitis may be triggered by viral infections. Early diagnosis and treatment is the key to both causes, which emphasizes the importance of clinical diagnosis before laboratory confirmation.
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http://dx.doi.org/10.1097/MCC.0000000000000483DOI Listing
April 2018

Guidelines and recommendations on yeast cell death nomenclature.

Microb Cell 2018 Jan 1;5(1):4-31. Epub 2018 Jan 1.

Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, Bari, Italy.

Elucidating the biology of yeast in its full complexity has major implications for science, medicine and industry. One of the most critical processes determining yeast life and physiology is cel-lular demise. However, the investigation of yeast cell death is a relatively young field, and a widely accepted set of concepts and terms is still missing. Here, we propose unified criteria for the defi-nition of accidental, regulated, and programmed forms of cell death in yeast based on a series of morphological and biochemical criteria. Specifically, we provide consensus guidelines on the differ-ential definition of terms including apoptosis, regulated necrosis, and autophagic cell death, as we refer to additional cell death rou-tines that are relevant for the biology of (at least some species of) yeast. As this area of investigation advances rapidly, changes and extensions to this set of recommendations will be implemented in the years to come. Nonetheless, we strongly encourage the au-thors, reviewers and editors of scientific articles to adopt these collective standards in order to establish an accurate framework for yeast cell death research and, ultimately, to accelerate the pro-gress of this vibrant field of research.
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http://dx.doi.org/10.15698/mic2018.01.607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772036PMC
January 2018

Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis.

Ann Neurol 2018 01;83(1):166-177

Departments of Neurology.

Objective: To evaluate the incidence and prevalence of autoimmune encephalitis and compare it to that of infectious encephalitis.

Methods: We performed a population-based comparative study of the incidence and prevalence of autoimmune and infectious encephalitis in Olmsted County, Minnesota. Autoimmune encephalitis diagnosis and subgroups were defined by 2016 diagnostic criteria, and infectious encephalitis diagnosis required a confirmed infectious pathogen. Age- and sex-adjusted prevalence and incidence rates were calculated. Patients with encephalitis of uncertain etiology were excluded.

Results: The prevalence of autoimmune encephalitis on January 1, 2014 of 13.7/100,000 was not significantly different from that of all infectious encephalitides (11.6/100,000; p = 0.63) or the viral subcategory (8.3/100,000; p = 0.17). The incidence rates (1995-2015) of autoimmune and infectious encephalitis were 0.8/100,000 and 1.0/100,000 person-years, respectively (p = 0.58). The number of relapses or recurrent hospitalizations was higher for autoimmune than infectious encephalitis (p = 0.03). The incidence of autoimmune encephalitis increased over time from 0.4/100,000 person-years (1995-2005) to 1.2/100,000 person-years (2006-2015; p = 0.02), attributable to increased detection of autoantibody-positive cases. The incidence (2.8 vs 0.7/100,000 person-years, p = 0.01) and prevalence (38.3 vs 13.7/100,000, p = 0.04) of autoimmune encephalitis was higher among African Americans than Caucasians. The prevalence of specific neural autoantibodies was as follows: myelin oligodendrocyte glycoprotein, 1.9/100,000; glutamic acid decarboxylase 65, 1.9/100,000; unclassified neural autoantibody, 1.4/100,000; leucine-rich glioma-inactivated protein 1, 0.7/100,000; collapsin response-mediator protein 5, 0.7/100,000; N-methyl-D-aspartate receptor, 0.6/100,000; antineuronal nuclear antibody type 2, 0.6/100,000; and glial fibrillary acidic protein α, 0.6/100,000.

Interpretation: This study shows that the prevalence and incidence of autoimmune encephalitis are comparable to infectious encephalitis, and its detection is increasing over time. Ann Neurol 2018;83:166-177.
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http://dx.doi.org/10.1002/ana.25131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6011827PMC
January 2018

Endoplasmic Reticulum Transport of Glutathione by Sec61 Is Regulated by Ero1 and Bip.

Mol Cell 2017 Sep 14;67(6):962-973.e5. Epub 2017 Sep 14.

Institute for Integrative Biology of the Cell (I2BC), CEA-Saclay, CNRS, Université Paris-Saclay, ISVJC/SBIGEM, Laboratoire Stress Oxydant et Cancer, 91191 Gif-sur-Yvette, France. Electronic address:

In the endoplasmic reticulum (ER), Ero1 catalyzes disulfide bond formation and promotes glutathione (GSH) oxidation to GSSG. Since GSSG cannot be reduced in the ER, maintenance of the ER glutathione redox state and levels likely depends on ER glutathione import and GSSG export. We used quantitative GSH and GSSG biosensors to monitor glutathione import into the ER of yeast cells. We found that glutathione enters the ER by facilitated diffusion through the Sec61 protein-conducting channel, while oxidized Bip (Kar2) inhibits transport. Increased ER glutathione import triggers HO-dependent Bip oxidation through Ero1 reductive activation, which inhibits glutathione import in a negative regulatory loop. During ER stress, transport is activated by UPR-dependent Ero1 induction, and cytosolic glutathione levels increase. Thus, the ER redox poise is tuned by reciprocal control of glutathione import and Ero1 activation. The ER protein-conducting channel is permeable to small molecules, provided the driving force of a concentration gradient.
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http://dx.doi.org/10.1016/j.molcel.2017.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772773PMC
September 2017

The Unfinished Puzzle of Glutathione Physiological Functions, an Old Molecule That Still Retains Many Enigmas.

Antioxid Redox Signal 2017 Nov;27(15):1127-1129

2 Institut Curie, PSL Research University , CNRS UMR3348, Université Paris Sud, Université Paris-Saclay, Orsay, France .

Glutathione (GSH) is the most abundant nonprotein thiol found in living organisms. Since its discovery 130 years ago, understanding its cellular functions has been the subject of intensive research. Common scientific knowledge states that GSH is a major nonenzymatic antioxidant and redox buffer. Recent approaches that consider GSH compartmentation in the eukaryotic cell challenge this traditional view and reveal novel unexpected insights into GSH metabolism and physiology. This Forum on GSH features six review articles that focus on GSH metabolism and functions in mitochondria and the endoplasmic reticulum; its connection to cellular iron homeostasis, carcinogenesis, and anticancer drug resistance; a revisited view of GSH degradation pathways; and reconsiders old concepts of its mode of action by highlighting the importance of kinetics over thermodynamic redox equilibria. Antioxid. Redox Signal. 27, 1127-1129.
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http://dx.doi.org/10.1089/ars.2017.7230DOI Listing
November 2017

Reexamining the Function of Glutathione in Oxidative Protein Folding and Secretion.

Antioxid Redox Signal 2017 Nov 26;27(15):1178-1199. Epub 2017 Sep 26.

Institute for Integrative Biology of the Cell (I2BC), LSOC, SBIGEM, CEA, CNRS, Université Paris-Sud , Université Paris-Saclay, Gif-sur-Yvette, France .

Significance: Disturbance of glutathione (GSH) metabolism is a hallmark of numerous diseases, yet GSH functions are poorly understood. One key to this question is to consider its functional compartmentation. GSH is present in the endoplasmic reticulum (ER), where it competes with substrates for oxidation by the oxidative folding machinery, composed in eukaryotes of the thiol oxidase Ero1 and proteins from the disulfide isomerase family (protein disulfide isomerase). Yet, whether GSH is required for proper ER oxidative protein folding is a highly debated question. Recent Advances: Oxidative protein folding has been thoroughly dissected over the past decades, and its actors and their mode of action elucidated. Genetically encoded GSH probes have recently provided an access to subcellular redox metabolism, including the ER.

Critical Issues: Of the few often-contradictory models of the role of GSH in the ER, the most popular suggest it serves as reducing power. Yet, as a reductant, GSH also activates Ero1, which questions how GSH can nevertheless support protein reduction. Hence, whether GSH operates in the ER as a reductant, an oxidant, or just as a "blank" compound mirroring ER/periplasm redox activity is a highly debated question, which is further stimulated by the puzzling occurrence of GSH in the Escherichia coli periplasmic "secretory" compartment, aside from the Dsb thiol-reducing and oxidase pathways.

Future Directions: Addressing the mechanisms controlling GSH traffic in and out of the ER/periplasm and its recycling will help address GSH function in secretion. In addition, as thioredoxin reductase was recently implicated in ER oxidative protein folding, the relative contribution of each of these two reducing pathways should now be addressed. Antioxid. Redox Signal. 27, 1178-1199.
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http://dx.doi.org/10.1089/ars.2017.7148DOI Listing
November 2017