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Event: 1841

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Encephalitis

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Encephalitis

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help
Organ term
brain

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Sars-CoV-2 causes encephalitis AdverseOutcome Anna Price (send email) Under development: Not open for comment. Do not cite

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help
Life stage Evidence
Adults High

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Term Evidence
Mixed High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

Encephalitis by definition is an inflammation of the brain tissue, most commonly caused by viral infections, and in some rare cases it can be caused by bacteria or even fungi. There are two main types of encephalitis: primary and secondary, with primary occurring when a virus directly infects the brain and the spinal cord. On the other hand, secondary encephalitis as a consequence of an infection occurring elsewhere in the body that then spread to the brain (Johnson, 2018).

Several causes may cause encephalitis, but the most common is a viral infection, and can be characterized by mild or severe flu-like symptoms, possibly causing confused thinking, seizures, or problems with movement or with senses, such as sight or hearing. In some cases, encephalitis can be life-threatening, and for this reason timely diagnosis and treatment are essential (Mayo, 2021).

Viral encephalitis refers to inflammatory lesions in the brain parenchyma caused by pathogens, including neuronal damage and nerve tissue lesions. It is characterized by acute onset, and common symptoms include headache, fever (mainly high fever), vomiting, convulsions, and consciousness disorders (Ellul and Solomon, 2018).

Encephalitis in the context of COVID19

Among various neurological adverse outcomes, SARS-CoV and SARS-CoV-2 can cause encephalitis (Moriguchi T et al. 2020; Efe et al. 2020; Najjar et al. 2020; Wu and Tang 2020; Bohmwald K, et al. 2020; Tsai LK et al. 2005; Xiang P. et al., 2020; Pilotto A et al. 2019; Ye M., et al. 2020; Das G, et al. 2020). Indeed, meningitis/meningoencephalitis has been observed in COVID19 patients (Iaconetta G et al. 2020). For instance, Moriguchi et al. have described SARS-CoV-2 encephalitis in a 24-year old man, 10 days after developing COVID19 symptoms, characterized by headache, fatigue, fever, and consciousness disturbance, and with MRI showing hyperintense signal changes in the hippocampus with slight hippocampal atrophy (Moriguchi T et al. 2020).

Early diagnosis of viral encephalitis is critical. In the ongoing pneumonia epidemic, the treatment team of Beijing Ditan Hospital confirmed the presence of SARS-CoV-2 in the cerebrospinal (CSF) fluid of patients with COVID-19 by genome sequencing, thereby clinically verifying viral encephalitis (Xiang et al., 2020). This provided a solid basis for CoV causing encephalitis.

CSF of COVID19 patients with encephalitis/meningoencephalitis often shows pleocytosis and elevated total protein and NfL levels (Espíndola et al. 2020) (Koralnik et al. 2020).

In SARS-CoV-2 infected patients with neurological manifestations, CSF pleocytosis is associated with para- or post-infectious encephalitis and polyradiculitis. Anti-GD1b and anti-Caspr2 autoantibodies can be identified in certain cases, raising the question of SARS-CoV-2-induced secondary autoimmunity (Guilmot et al., 2020).

Intracranial inoculation of murine coronavirus (mouse hepatic virus, MHV), induces optic neuritis and focal encephalitis leading to chronic demyelination in mice (Shindler KS, et al. 2008).

SARS-CoV responsible for the 2002–2004 outbreak was reported to induce encephalitis, along with polyneuropathy and ischemic stroke (Tsai et al. 2005).

Autopsy results of patients with SARS showed ischemic neuronal damage and demyelination. Viral RNA was detected in brain tissue, particularly accumulating in and around the hippocampus (Gu J, et al. 2005).

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

Encephalitis may be detected through the following diagnostic tests (https://www.columbianeurology.org/neurology/staywell/encephalitis):

  • Magnetic resonance imaging (MRI)
  • Computed tomography scan (CT or CAT scan)
  • Blood tests
  • Urine and stool tests
  • Electroencephalogram (EEG)
  • Spinal tap (lumbar puncture)
  • Brain biopsy
  • Intracranial pressure monitoring (ICP), measuring the pressure inside the skull. If there is a severe brain injury, head surgery, brain infection, or other problems, the brain may swell.

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

Evidence for Perturbation by Stressor

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. For KEs that are designated as an AO, one additional field of information (regulatory significance of the AO) should be completed, to the extent feasible. If the KE is being described is not an AO, simply indicate “not an AO” in this section.A key criterion for defining an AO is its relevance for regulatory decision-making (i.e., it corresponds to an accepted protection goal or common apical endpoint in an established regulatory guideline study). For example, in humans this may constitute increased risk of disease-related pathology in a particular organ or organ system in an individual or in either the entire or a specified subset of the population. In wildlife, this will most often be an outcome of demographic significance that has meaning in terms of estimates of population sustainability. Given this consideration, in addition to describing the biological state associated with the AO, how it can be measured, and its taxonomic, life stage, and sex applicability, it is useful to describe regulatory examples using this AO. More help

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help

Bohmwald K, et al. Neurologic Alterations Due to Respiratory Virus Infections. Front Cell Neurosci. 2018 Oct 26;12:386.

Das G, et al. Neurological Insights of COVID-19 Pandemic. ACS Chem Neurosci. 2020 May 6; 11(9):1206-1209.

Efe et al. COVID-19-Associated Encephalitis Mimicking Glial Tumor. World Neurosurg. 2020 Aug; 140: 46–48.

Ellul M., Solomon T. Acute encephalitis - diagnosis and management. Clin. Med. (Lond) 2018;18(2):155–159.

Encephalitis, available at: https://www.columbianeurology.org/neurology/staywell/encephalitis

Espíndola OM et al. Patients with COVID-19 and neurological manifestations show undetectable SARS-CoV-2 RNA levels in the cerebrospinal fluid. Int J Infect Dis. 2020 Jul;96:567-569.

Gu J, et al. Multiple organ infection and the pathogenesis of SARS. J Exp Med. 2005;202:415–424.

Guilmot A, et al. Immune-mediated neurological syndromes in SARS-CoV-2-infected patients. J Neurol. 2020 Jul 30;1-7.

Iaconetta G et al. Meningoencephalitis Associated with SARS-Coronavirus-2. Transl Med UniSa. 2020 Dec 31;23:42-47.

Johnson S. What is encephalitis? Healthline, 2018 available at https://www.healthline.com/health/encephalitis

Koralnik et al. COVID-19: A Global Threat to the Nervous System. Ann Neurol. 2020 Jul;88(1):1-11.

Mayo Clinic, Encephalitis. 2021, available at https://www.mayoclinic.org/diseases-conditions/encephalitis/symptoms-causes/syc-20356136

Moriguchi T et al. A first case of meningitis/encephalitis associated with SARS-Coronavirus-2. Int J Infect Dis. 2020;94:55–58.

Najjar et al. Central nervous system complications associated with SARS-CoV-2 infection: integrative concepts of pathophysiology and case reports. J Neuroinflammation. 2020 Aug 6;17(1):231.

Pilotto A et al. Steroid-Responsive Encephalitis in Coronavirus Disease 2019. Ann Neurol. 2020 Aug;88(2):423-427.

Shindler KS, et al. Experimental optic neuritis induced by a demyelinating strain of mouse hepatitis virus. J Virol. 2008 Sep; 82(17):8882-6.

Tsai L.-K., et al. Neurological manifestations in severe acute respiratory syndrome. Acta Neurol Taiwanica. 2005;14:113–119

Wu J. and Tang Y. Revisiting the Immune Balance Theory: A Neurological Insight Into the Epidemic of COVID-19 and Its Alike. Front Neurol. 2020 Oct 15;11:566680.

Xiang P., et al. First case of 2019 novel coronavirus disease with Encephalitis. ChinaXiv. 2020;T202003:00015.

Ye M., et al. Encephalitis as a clinical manifestation of COVID-19. Brain, Behavior, and Immunity. 2020 S0889159120304657.