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      Serum neurofilament light as biomarker of seizure‐related neuronal injury in status epilepticus

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          Abstract

          Biomarkers of neuronal damage in status epilepticus (SE) would be of great relevance for clinical and research purposes. In a retrospective cross‐sectional study, serum neurofilament light chain (NfL) levels were measured in patients with SE (30 subjects), patients with drug‐resistant epilepsy (30 subjects), and healthy controls (30 subjects). Serum NfL levels were higher in patients with SE (median = 26.15 pg/ml) compared to both epilepsy patients (median = 7.35 pg/ml) and healthy controls (median = 6.81 pg/ml; p < .001). In patients with SE, serum NfL levels showed a high correlation with cerebrospinal fluid (CSF) NfL (τ = .68, p < .001) as well as with CSF total tau (t‐tau) levels (τ = .627, p < .001); they were higher in SE lasting >24 h ( p = .013), in refractory/superrefractory SE ( p = .004), and in patients who died within 30 days or who presented a worsening of clinical conditions ( p = .001). Values of >28.8 pg/ml predicted 30‐day clinical worsening or death (odds ratio [OR] = 10.83, 95% confidence interval [CI] = 1.96–59.83, p = .006) and SE refractoriness (OR = 9.33, 95% CI = 1.51–57.65, p = .016). In conclusion, serum NfL levels are increased in SE and correlate with SE treatment response, duration, and outcomes, therefore representing a promising biomarker of seizure‐related neuronal damage.

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          A definition and classification of status epilepticus--Report of the ILAE Task Force on Classification of Status Epilepticus.

          Eugen Trinka, Hannah Cock, Dale Hesdorffer … (2015)
          The Commission on Classification and Terminology and the Commission on Epidemiology of the International League Against Epilepsy (ILAE) have charged a Task Force to revise concepts, definition, and classification of status epilepticus (SE). The proposed new definition of SE is as follows: Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1 ). It is a condition, which can have long-term consequences (after time point t2 ), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures. This definition is conceptual, with two operational dimensions: the first is the length of the seizure and the time point (t1 ) beyond which the seizure should be regarded as "continuous seizure activity." The second time point (t2 ) is the time of ongoing seizure activity after which there is a risk of long-term consequences. In the case of convulsive (tonic-clonic) SE, both time points (t1 at 5 min and t2 at 30 min) are based on animal experiments and clinical research. This evidence is incomplete, and there is furthermore considerable variation, so these time points should be considered as the best estimates currently available. Data are not yet available for other forms of SE, but as knowledge and understanding increase, time points can be defined for specific forms of SE based on scientific evidence and incorporated into the definition, without changing the underlying concepts. A new diagnostic classification system of SE is proposed, which will provide a framework for clinical diagnosis, investigation, and therapeutic approaches for each patient. There are four axes: (1) semiology; (2) etiology; (3) electroencephalography (EEG) correlates; and (4) age. Axis 1 (semiology) lists different forms of SE divided into those with prominent motor systems, those without prominent motor systems, and currently indeterminate conditions (such as acute confusional states with epileptiform EEG patterns). Axis 2 (etiology) is divided into subcategories of known and unknown causes. Axis 3 (EEG correlates) adopts the latest recommendations by consensus panels to use the following descriptors for the EEG: name of pattern, morphology, location, time-related features, modulation, and effect of intervention. Finally, axis 4 divides age groups into neonatal, infancy, childhood, adolescent and adulthood, and elderly.
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            Neurofilaments and Neurofilament Proteins in Health and Disease.

            Aidong Yuan, Mala V. Rao, Veeranna … (2017)
            SUMMARYNeurofilaments (NFs) are unique among tissue-specific classes of intermediate filaments (IFs) in being heteropolymers composed of four subunits (NF-L [neurofilament light]; NF-M [neurofilament middle]; NF-H [neurofilament heavy]; and α-internexin or peripherin), each having different domain structures and functions. Here, we review how NFs provide structural support for the highly asymmetric geometries of neurons and, especially, for the marked radial expansion of myelinated axons crucial for effective nerve conduction velocity. NFs in axons extensively cross-bridge and interconnect with other non-IF components of the cytoskeleton, including microtubules, actin filaments, and other fibrous cytoskeletal elements, to establish a regionally specialized network that undergoes exceptionally slow local turnover and serves as a docking platform to organize other organelles and proteins. We also discuss how a small pool of oligomeric and short filamentous precursors in the slow phase of axonal transport maintains this network. A complex pattern of phosphorylation and dephosphorylation events on each subunit modulates filament assembly, turnover, and organization within the axonal cytoskeleton. Multiple factors, and especially turnover rate, determine the size of the network, which can vary substantially along the axon. NF gene mutations cause several neuroaxonal disorders characterized by disrupted subunit assembly and NF aggregation. Additional NF alterations are associated with varied neuropsychiatric disorders. New evidence that subunits of NFs exist within postsynaptic terminal boutons and influence neurotransmission suggests how NF proteins might contribute to normal synaptic function and neuropsychiatric disease states.
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              Neurofilaments: neurobiological foundations for biomarker applications.

              Arie Gafson, Nicolas R Barthélemy, Pascale Bomont … (2020)
              Interest in neurofilaments has risen sharply in recent years with recognition of their potential as biomarkers of brain injury or neurodegeneration in CSF and blood. This is in the context of a growing appreciation for the complexity of the neurobiology of neurofilaments, new recognition of specialized roles for neurofilaments in synapses and a developing understanding of mechanisms responsible for their turnover. Here we will review the neurobiology of neurofilament proteins, describing current understanding of their structure and function, including recently discovered evidence for their roles in synapses. We will explore emerging understanding of the mechanisms of neurofilament degradation and clearance and review new methods for future elucidation of the kinetics of their turnover in humans. Primary roles of neurofilaments in the pathogenesis of human diseases will be described. With this background, we then will review critically evidence supporting use of neurofilament concentration measures as biomarkers of neuronal injury or degeneration. Finally, we will reflect on major challenges for studies of the neurobiology of intermediate filaments with specific attention to identifying what needs to be learned for more precise use and confident interpretation of neurofilament measures as biomarkers of neurodegeneration.
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                Author and article information

                Contributors
                Stefano Meletti:
                ORCID: https://orcid.org/0000-0003-0334-539X
                stefano.meletti@unimore.it
                Journal
                Journal ID (nlm-ta): Epilepsia
                Journal ID (iso-abbrev): Epilepsia
                Journal ID (doi): 10.1111/(ISSN)1528-1167
                Journal ID (publisher-id): EPI
                Title: Epilepsia
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 0013-9580
                ISSN (Electronic): 1528-1167
                Publication date (Electronic): 21 November 2021
                Publication date (Print): January 2022
                Volume: 63
                Issue: 1 ( doiID: 10.1111/epi.v63.1 )
                Pages: e23-e29
                Affiliations
                [ 1 ] Neurology Unit Ospedale Civile Baggiovara Hospital University Hospital Modena Italy
                [ 2 ] Department of Biomedical, Metabolic, and Neural Science University of Modena and Reggio Emilia Modena Italy
                [ 3 ] PhD Program in Clinical and Experimental Medicine University of Modena and Reggio Emilia Modena Italy
                Author notes
                [*] [* ] Correspondence

                Professor Stefano Meletti, Department of Biomedical, Metabolic, and Neural Sciences, Center for Neurosciences and Neurotechnology, University of Modena and Reggio Emilia, Modena, Italy.

                Email: stefano.meletti@ 123456unimore.it

                Author information
                https://orcid.org/0000-0002-3585-5872
                https://orcid.org/0000-0003-4818-3806
                https://orcid.org/0000-0002-6280-7526
                https://orcid.org/0000-0003-0334-539X
                Article
                Publisher ID: EPI17132
                DOI: 10.1111/epi.17132
                PMC ID: 9299158
                PubMed ID: 34806176
                SO-VID: b67fa5c1-5bc9-42d5-8ce3-68f2bbe8dadf
                Copyright © © 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                Date revision received : 08 November 2021
                Date received : 23 June 2021
                Date accepted : 08 November 2021
                Page count
                Figures: 1, Tables: 1, Pages: 7, Words: 3627
                Categories
                Subject: Brief Communication
                Subject: Brief Communication
                Custom metadata
                source-schema-version-number 2.0
                cover-date January 2022
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.1.7 mode:remove_FC converted:20.07.2022

                ScienceOpen disciplines: Neurology
                Keywords: biomarkers,neurofilaments,status epilepticus
                Data availability:
                ScienceOpen disciplines: Neurology
                Keywords: biomarkers, neurofilaments, status epilepticus

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