key: cord-0951624-qsrssoyt
authors: Esmaeili, Sara; Abbasi, Mohammad Hossein; Joghataei, Mohammad Taghi; Mirzaasgari, Zahra; Emamikhah, Maziar; Makiani, Mahin Jamshidi; Nazarian, Hossein
title: Acute disseminated encephalitis (ADEM) as the first presentation of COVID-19; a case report
date: 2022-03-28
journal: Ann Med Surg (Lond)
DOI: 10.1016/j.amsu.2022.103511
sha: 99f21e74e9cbb994a9a8f37f172f6f5d7822a987
doc_id: 951624
cord_uid: qsrssoyt

INTRODUCTION: and importance: Neurological ailments are reported during and after SARS-COV-2 infection. CASE PRESENTATION: We report a 67-year-old Iranian man with COVID-19 infection and Acute Disseminated Encephalomyelitis (ADEM) whose neurological symptoms appeared before clinical and radiological pulmonary manifestations. CLINICAL DISCUSSION: COVID-19 can cause neurological complication without entering the CNS via para infectious inflammatory mechanisms. CONCLUSIONS: This report shows that ADEM might be among primary presentations of COVID-19.

high signal lesions in T2W and FLAIR sequences on bilateral cerebral hemispheres, para ventricular and subcortical white matter, middle cerebellar peduncles, centrum semi vale, corpus callosum, the basal ganglia, thalami, midbrain, and pons. (Figure 1 Clinical and Image findings coupled with laboratory data, led to the diagnosis of Acute disseminated encephalomyelitis (ADEM) associated with COVID-19. Along with COVID-19 treatment, methylprednisolone 1 g IV daily for 5 days was instituted. Neurologic status was grossly unchanged. Thus, Intravenous Immunoglobulin (IVIG) 0.4 g/kg daily was administered for 5 more consecutive days after Methylprednisolone pulse therapy.

The patient eventually died after 4 weeks of hospital admission due to worsening of his respiratory and neurologic conditions. The methods are stated in accordance with SCARE 2020 guidelines (6) .

In this patient, the clinical presentation coupled with imaging characteristics is consistent with a diagnosis of an acute demyelinating event. Our patient was diagnosed with COVID-19 based on positive RT-PCR for SARS-CoV-2 virus on admission. Signs of lung involvement evolved only after CNS involvements. We hypothesize that SARS-CoV-2 infection might have been responsible J o u r n a l P r e -p r o o f for the post-infectious demyelinating CNS lesions, an entity known to occur in conjunction to many viral infections, and is in the spectrum of ADEM. This report is important, because it suggests that ADEM might be among primary presentations of SARS-COV-2. Nevertheless, establishing a coincidence or a cause-and-effect relationship may not be easily possible. This similar to some reports wherein the neurological syndrome appeared before clinical and/or radiological pulmonary manifestations. In some instances, the obvious clinical pulmonary symptoms never developed [7, 16] .

ADEM ,also known as postinfectious encephalomyelitis, is an infrequent para-or postinfectious autoimmune complications. (7) It is mainly a disorder of children. However, few cases in adults have also been reported. Clinically, it is heterogenous by nature and generally causes multifocal neurologic deficits in an acute manner, which often progresses rapidly. Typical MRI lesions consists of FLAIR hyperintensities in deep white matter and at the grey/white matter interface.

Post-contrast enhancement is not always detected and usually in the form of punctate or rim enhancing pattern. Restriction can be detected in DWI sequence, especially in early course of disease (8) . ADEM, as an immune-mediated demyelinating monophasic disorder, typically presents between 2-4 weeks after viral infections or immunizations [8, 9] Thus, the temporal relationship between COVID-19 symptoms and the onset of ADEM seems to be shorter than the classical picture described for other viral infections.

Acute Hemorrhagic Leukoencephalitis (AHLE), as a severe form of ADEM has been also reported in a COVID-19 patient (9). ADEM and AHLE share similar histologic features, however, in our patient, size of the lesions, lack of hemorrhage in the images, and normal CSF analysis are all in favor of ADEM diagnosis rather than AHLE, although the natural history was as grave as AHLE.

To our knowledge, ADEM has been reported in association with COVID-19 in a few children and adult patients (10-15). The prognosis of these patients has been mostly favorable. However, our case had a poor outcome because of severe pulmonary involvement and respiratory distress as a result of COVID-19. We believe the presentation of COVID-19 as ADEM, which was not reported previously, may imply the severity of viral and/or inflammatory multi-system COVID-19 infection and can be considered an index for poor outcome. However, large scale multi-center studies are required in this regard.

It is likely that more than one immune mechanism is involved in triggering ADEM in susceptible patients and the exact mechanism of ADEM in case of COVID-19 infection is largely hypothetical and needs further research.

One of the potential underlying mechanisms of ADEM in association with SARS-CoV-2 is the cytokine pathway activation, which is known to be involved in the pathology of ADEM. It has been stated to result from T cells affected by SARS-CoV-2 inducing a storm of cytokines, especially IL-6 (16) (17) (18) . This results in sequences of immune responses that may play an important role in the pathogenesis of ADEM (19) .

Other mechanisms being discussed elsewhere includes post-infectious inflammatory process leading to the production autoantibody production to neuronal antigens (20) .This mechanism is stated as "molecular mimicry" whereby an infectious organism contains numerous epitopes mimicking the structure of endogenous myelin epitopes (21) . Some of the T-cells points toward the infectious epitopes during an immune response against the entering organism. As an undesirable consequence, some T-cells become skilled at cross-reacting with self-myelin peptides (21) . These cross-reactive T-cells grow in numbers in response to self-antigenic stimulation and release chemokines that further recruit added lymphocytes and macrophages to the site of activation all of which enhances the demyelination process and neuronal injury [7, 21] . Based on few histopathological studies (22) , the corresponding mechanism has been noticed in six postmortem patients in forms of lymphocytic panencephalitis and meningitis along with brainstem perivascular and interstitial inflammatory alteration with neuronal loss as major features [7, 21] .

It has long been accepted that the term ADEM should not be utilized in cases of acute encephalitis, which are caused by direct invasion of the viruses into the CNS (7) . Still, few evidence of direct viral invasion with supportive histopathological features have been claimed, albeit very rare (23, 24) . It has been hypnotized that SARS-CoV-2 dictates tissue tropism using the angiotensinconverting enzyme type 2 (ACE-2) receptor to bind to cells. The ACE-2 receptor can be found in nervous system tissue as well as endothelial cells among tissues of many other organs (25, 26). In the current report, the COVID-19 RNA was not detected using CSF, using RT-PCR method, thereby this mechanism may not comply to this case.

In addition, some studies have showed vascular-thrombotic complications associated with COVID-19 infection [6] . Histopathological findings of the postmortem brain study of a patient with diagnosis of SARS-COV-2 without specific signs of ADEDM suggested a vascular origin J o u r n a l P r e -p r o o f with secondary myelin loss, and the neocortical microscopic infarcts identified raise the possibility of micro thromboembolic events, probably related to COVID-19 related complications. However, in that study, the clinical presentation of ADEM was not apparent and the biopsy solely resembled an acute disseminated encephalomyelitis (ADEM)-like histological appearance.

Since we did not perform a postmortem study, we cannot verify the exact reason, although the pattern of DWI and ADC-map sequences of brain MRI may suggest micro thromboembolic events.

For treatment, high dose corticosteroid followed by IVIG seemed to be effective (12) . However, controversy remains regarding the optimal treatment options including the use of high dose corticosteroids in viremic, and often lymphopenic patients. The potential risks of using IVIG for ADEM, in patients with pro-thrombotic risk factors such as elevated D-dimer levels should be taken into consideration. (27) Since this condition is potentially associated with high mortality, ADEM should be taken into account as a serious possible complication of COVID-19 infection during pandemic and prompt treatment should be initiated.

Our understanding of the Para infectious neuropathology of SARS CoV-2 continues to evolve, but as a cause of devastating outcome in many patients that do survive, there must be special attention to the phenomenology, pathophysiology and treatment of CNS involvement in COVID-19 patients (28) .

Special awareness is warranted in patients presenting with any possible neurological manifestation in the current pandemic situation to prevent mortality and severe morbidity. 

Clinical Characteristics of Coronavirus Disease 2019 in China

Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms

Neurological associations of COVID-19

Neurological Involvement in COVID-19 and Potential Mechanisms: A Review

Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease

The SCARE 2020 Guideline: Updating Consensus Surgical CAse REport (SCARE) Guidelines

Acute disseminated encephalomyelitis

The magnetic resonance imaging appearance of monophasic acute disseminated encephalomyelitis: an update post application of the 2007 consensus criteria

A Rare Case of

COVID-19-associated acute disseminated encephalomyelitis (ADEM)

The association of SARS-CoV-2 infection and acute disseminated encephalomyelitis without prominent clinical pulmonary symptoms

Evolution and resolution of brain involvement associated with SARS-CoV2 infection: A close Clinical -Paraclinical follow up study of a case. Multiple sclerosis and related disorders

Lifting the mask on neurological manifestations of COVID-19

Encephalomyelitis associated with Covid-19 infection: case report

COVID-19: consider cytokine storm syndromes and immunosuppression

Does COVID19 activates previous chronic pain? A case series

Can l-carnitine reduce post-COVID-19 fatigue

The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients

Molecular mimicry may explain multi-organ damage in COVID-19

Amino acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity

Early evidence of pronounced brain involvement in fatal COVID-19 outcomes

Detection of Coronavirus in the Central Nervous System of a Child With Acute Disseminated Encephalomyelitis

Cerebrospinal fluid findings in neurological diseases associated with COVID-19 and insights into mechanisms of disease development. International Journal of Infectious Diseases. 25. Berger JR. COVID-19 and the nervous system

The Role of Angiotensin-Converting Enzyme in Immunity: Shedding Light on Experimental Findings. Endocrine, Metabolic & Immune Disorders -Drug Targets(Formerly Current Drug Targets -Immune

The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings

Neuropathology of COVID-19: a spectrum of vascular and acute disseminated encephalomyelitis (ADEM)-like pathology

Guarantor The Guarantor is the one or more people who accept full responsibility for the work and/or the conduct of the study

Authors must obtain written and signed consent to publish a case report from the patient (or, where applicable, the patient's guardian or next of kin) prior to submission. We ask Authors to confirm as part of the submission process that such consent has been obtained, and the manuscript must J o u r n a l P r e -p r o o f include a statement to this effect in a consent section at the end of the manuscript, as follows: "Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request".Patients have a right to privacy. Patients' and volunteers' names, initials, or hospital numbers should not be used. Images of patients or volunteers should not be used unless the information is essential for scientific purposes and explicit permission has been given as part of the consent. If such consent is made subject to any conditions, the Editor in Chief must be made aware of all such conditions.Even where consent has been given, identifying details should be omitted if they are not essential. If identifying characteristics are altered to protect anonymity, such as in genetic pedigrees, authors should provide assurance that alterations do not distort scientific meaning and editors should so note.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Please specify the contribution of each author to the paper, e.g. study concept or design, data collection, data analysis or interpretation, writing the paper, others, who have contributed in other ways, should be listed as contributors.Dr. Sara Esmaeili and Dr. Mahin Jamshidi Makiani and DrHossein Nazarian.: conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript.Dr. Mohammad Hossein Abbasi and Dr. Maziar Emamikhah: Designed the data collection instruments, collected data, carried out the initial analyses, and reviewed and revised the manuscript.Dr. Mohammad Taghi Joghataei and Dr. Zahra Mirzaasgari: Coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content.

In accordance with the Declaration of Helsinki 2013, the Editors of IJS Case Reports require that reports that are 'First in Man' studies should be registered prospectively and failing that retrospectively. There are many places to register your First in Man case report:J o u r n a l P r e -p r o o f 3. Hyperlink to your specific registration (must be publicly accessible and will be checked):

The Guarantor is the one or more people who accept full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish Sara Esmaeili J o u r n a l P r e -p r o o f

The following information is required for submission. Please note that failure to respond to these questions/statements will mean your submission will be returned. If you have nothing to declare in any of these categories then this should be stated.

All authors must disclose any financial and personal relationships with other people or organisations that could inappropriately influence (bias) their work. Examples of potential conflicts of interest include employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding.The authors deny any conflict of interest in any terms or by any means during the study.

All sources of funding should be declared as an acknowledgement at the end of the text. Authors should declare the role of study sponsors, if any, in the collection, analysis and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication. If the study sponsors had no such involvement, the authors should so state.

Research studies involving patients require ethical approval. Please state whether approval has been given, name the relevant ethics committee and the state the reference number for their judgement.All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Studies on patients or volunteers require ethics committee approval and fully informed written consent which should be documented in the paper.Authors must obtain written and signed consent to publish a case report from the patient (or, where applicable, the patient's guardian or next of kin) prior to submission. We ask Authors to confirm as part of the submission process that such consent has been obtained, and the manuscript must include a statement to this effect in a consent section at the end of the manuscript, as follows: "Written informed J o u r n a l P r e -p r o o f consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request".Patients have a right to privacy. Patients' and volunteers' names, initials, or hospital numbers should not be used. Images of patients or volunteers should not be used unless the information is essential for scientific purposes and explicit permission has been given as part of the consent. If such consent is made subject to any conditions, the Editor in Chief must be made aware of all such conditions.Even where consent has been given, identifying details should be omitted if they are not essential. If identifying characteristics are altered to protect anonymity, such as in genetic pedigrees, authors should provide assurance that alterations do not distort scientific meaning and editors should so note.

Please specify the contribution of each author to the paper, eg study concept or design, data collection, data analysis or interpretation, writing the paper, others, who have contributed in othe ways should be listed as contributors.Dr. Sara Esmaeili and Dr. Mahin Jamshidi Makiani and DrHossein Nazarian.: conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript.Dr. Mohammad Hossein Abbasi and Dr. Maziar Emamikhah: Designed the data collection instruments, collected data, carried out the initial analyses, and reviewed and revised the manuscript.Dr. Mohammad Taghi Joghataei and Dr. Zahra Mirzaasgari: Coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content.

In accordance with the Declaration of Helsinki 2013, all research involving human participants has to be registered in a publicly accessible database. Please enter the name of the registry and the unique identifying number (UIN) of your study.