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Post-COVID-19 Acute Disseminated in a 17-Month-Old

Loren A. McLendon, MD, Chethan K. Rao, DO, MS, Cintia Carla Da Hora, MD, Florinda Islamovic, MD, Fernando N. Galan, MD

DOI: 10.1542/peds.2020-049678 Journal: Pediatrics Article Type: Case Report

Citation: McLendon LA, Rao CK, Da Hora CC, Islamovic F, Galan FN. Post-COVID-19 acute disseminated encephalomyelitis in a 17-month-old. Pediatrics. 2021; doi: 10.1542/peds.2020- 049678

This is a prepublication version of an article that has undergone peer review and been accepted for publication but is not the final version of record. This paper may be cited using the DOI and date of access. This paper may contain information that has errors in facts, figures, and statements, and will be corrected in the final published version. The journal is providing an early version of this article to expedite access to this information. The American Academy of Pediatrics, the editors, and authors are not responsible for inaccurate information and data described in this version.

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Post-COVID-19 Acute Disseminated Encephalomyelitis in a 17-month-old

a,b Loren A. McLendon, MD, a,b Chethan K. Rao, DO, MS, c Cintia Carla Da Hora, MD, c Florinda Islamovic, MD, b Fernando N. Galan, MD

Affiliations: a Mayo Clinic College of Medical Science Florida, Division of Child and Adolescent , Jacksonville, Florida b Nemours Children Specialty Clinic, Division of Neurology, Jacksonville, Florida c University of Florida College of Medicine Jacksonville, Division of Pediatrics, Jacksonville, Florida

Corresponding Author: Fernando N. Galan, MD Division of Child Neurology 807 Children’s Way Jacksonville, Florida 32207 [email protected]

Conflict of Interest Disclosures: The authors have indicated they have no conflicts of interest relevant to this article to disclose.

Key Words: ADEM, COVID-19, , pediatrics, SARS-CoV2

Abbreviations: Acute disseminated encephalomyelitis (ADEM), antinuclear (ANA), Aquaporin 4 (NMO Ab), Central (CNS), Cerebral spinal fluid (CSF), (EEG), erythrocyte sedimentation rate (ESR), intravenous immunoglobin (IVIG), lactate dehydrogenase (LDH), magnetic resonance imaging (MRI), myelin oligodendrocyte glycoprotein antibodies (MOG Ab), pediatric intensive care unit (PICU), polymerase chain reaction (PCR), thyroid peroxidase antibodies (TPO)

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Funding/Support: No funding was secured for this study.

Table of Contents Summary: Case description of acute demyelinating encephalomyelitis (ADEM) in a toddler following SARS-CoV-2 and response to standard immunotherapy.

Contributors’ Statements:

Dr. McLendon performed data acquisition, drafted the initial manuscript, revising the figure, and critically reviewed the manuscript.

Dr. Rao performed data acquisition, contributed to drafting of the initial manuscript and drafting of Figure 1, and critically reviewed the manuscript.

Drs. Da Hora and Islamovic performed data acquisition and contributed to drafting of the initial manuscript.

Dr. Galan conceptualized the study, supervised data collection, and critically reviewed the manuscript.

All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

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Abstract:

Neurological manifestations of SARS-CoV-2 infection in pediatric patients have been reported

in the acute and post-infectious stages of COVID-19 . Acute disseminated encephalomyelitis (ADEM) typically presents in children following a viral illness at a mean age of three to seven years. Sixty to ninety percent of literature-reported pediatric patients with

ADEM have minimal to no neurologic deficits at long-term follow-up. We present a 17-month-

old developmentally-typical female with parental complaints of irritability, upper extremity

weakness, and gait disturbance. She presented to the hospital afebrile and irritable with subtle

right-sided nasolabial fold flattening, significant neck stiffness, left upper extremity rigidity,

right upper extremity paresis, bilateral lower extremity hyperreflexia, and truncal . During

her hospital course, she became somnolent with autonomic instability and was transferred to

intensive care. Contrasted magnetic resonance imaging (MRI) revealed diffuse patchy T2

hyperintensities without evidence of contrast enhancement. Nasopharyngeal swab SARS-CoV-2

polymerase chain reaction (PCR) and serum antibody testing were both positive. Cerebral spinal

fluid (CSF) analysis was unremarkable. Respiratory viral panel, autoimmune encephalitis and

demyelinating disorders panel were negative. She was started on high dose methylprednisolone

and intravenous immunoglobulin (IVIG) with improvement in mental status, focal deficits, and

ambulation. Following hospital discharge, she received inpatient rehabilitation for two weeks

and at two month follow-up had full neurologic recovery. We report the youngest case of post-

infectious ADEM due to SARS-CoV-2 in a toddler. Early recognition of autoimmune and

inflammatory complications of SARS-CoV-2 is vital for early aggressive immunomodulatory

treatment and consequently improved morbidity in these patients.

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Introduction:

COVID-19 caused by the novel SARS-CoV-2 disproportionately spares pediatric populations, representing less than two percent of reported cases in multinational studies.1 Up to

35% of infected children are asymptomatic, and the remainder often have mild symptoms such as , cough, and . However, severe complications related to COVID-19 in children have been reported including , multisystem inflammatory , and a variety of neurological sequelae.2 Individual cases of , cerebrovascular infarction, encephalitis, and in children with active or recent COVID-19 infection have been reported.2,3

Acute disseminated encephalomyelitis (ADEM), or post-infectious encephalomyelitis, is an immune-mediated process marked by demyelination and multifocal neurological manifestations.4-6 ADEM is typically preceded by symptoms of fever, malaise, vomiting, and/or . Neurological symptoms are multifocal and correlate with radiologic lesions in the brain and/or ; clinically presenting as ataxia, , hemiplegia, hemiparesthesias, visual changes, , or cranial nerve palsies.4,5,7,8 This neurological decline occurs rapidly within days to weeks after the prodromal illness; symptoms in the majority of patients do not progress beyond three months.9 We present a case of ADEM secondary to COVID-19 in a 17-month-old girl who fared well with early and aggressive immunomodulating therapy which included high-dose and IVIG treatments.

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Case:

A 17-month-old African-American, non-Hispanic, previously-healthy, and developmentally- typical female presented to the emergency department with fatigue, progressively worsening weakness, and unsteady gait. She had five days of fever, approximately 13 days prior to presentation with a maximum temperature of 38.9 degrees Celsius without associated upper respiratory or gastrointestinal symptoms. After fever resolution, her parents noticed progressive fatigue, decreased communication, difficulty feeding herself, walking, and sitting without support. She presented to the hospital with parental complaints symptoms of irritability, weakness of upper extremities, and gait disturbance. She was found to be afebrile but irritable with subtle right-sided nasolabial fold flattening, significant neck stiffness with positive

Brudzinski’s sign, left upper extremity rigidity, right upper extremity paresis, bilateral lower extremity hyperreflexia, and truncal ataxia.

Initial evaluation included an electrocardiogram with normal sinus rhythm, possible right atrium enlargement, and left ventricular hypertrophy. Transthoracic echocardiogram performed in the

Pediatric Intensive Care Unit (PICU) was normal. Laboratory evaluation noted elevated inflammatory markers including an erythrocyte sedimentation rate (ESR) of 25 mm/hr which increased to 40 mm/hr within two days and lactate dehydrogenase (LDH) of 406 IU/L. Normal serum studies included , comprehensive metabolic panels, PT/INR, PTT, ferritin, D-dimer, BNP, troponins, levels, and creatine kinase. MRI of the brain with and without gadolinium contrast showed multifocal hyperintense T2 FLAIR signals in bilateral subcortical and periventricular white matter without contrast enhancement (Figure 1).

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MRI of the whole spine without contrast was unremarkable. CSF and serum studies were

performed prior to the initiation of high-dose methylprednisolone. CSF analysis revealed mild

pleocytosis with lymphocytic predominance; 5/mcl white blood cells (81% , 19%

monocytes), 1/mcl red blood cell, glucose of 58 mg/dl, and of 17 mg/dl. CSF had zero

oligoclonal bands with normal IgG index and IgG synthesis rate. CSF PCR for was

negative. Other infectious studies were not obtained given limited CSF sample. Serum studies

for antinuclear antibody (ANA), Aquaporin 4 antibodies (NMO Ab), myelin oligodendrocyte

glycoprotein antibodies (MOG Ab), and thyroid peroxidase antibodies (TPO) were negative.

CSF and serum bacterial cultures were negative. Upper respiratory viral PCR panel via

nasopharyngeal swab and stool PCR for enterovirus and antigen were negative. SARS-

CoV-2 PCR via nasopharyngeal swab and serum SARS-CoV IgG antibody testing were both

positive. Infection was evaluated utilizing Hologic Aptima SARS-CoV-2 assay (sensitivity

>90%) and serum SARS-CoV IgG antibody (sensitivity 84%, specificity 100%) testing

performed by Abbott Laboratories.10,11 The patient’s parents were healthcare workers. Her father tested positive for SARS-CoV-2 three months prior to the patient’s presentation.

On day two of hospitalization, she was transferred to the PICU due to increased lethargy, autonomic instability, and concern for seizures. Electroencephalography (EEG) showed diffuse slowing consistent with encephalopathy but no seizures or epileptiform activity. Due to clinical deterioration, IVIG 2g/kg divided over four days was initiated in addition to completion of a five day course of high-dose IV methylprednisolone (30 mg/kg/day).

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On day five of hospitalization, she was transferred to the general pediatric floor. Her exam continued to improve. She was alert, attentive to the examiner, able to sit unsupported, and able to walk with support. She was discharged to inpatient rehabilitation for two weeks with a six- week oral prednisone taper. Neurologic examination at two month post-discharge neurology follow-up had completely normalized.

Discussion:

There is a growing body of evidence of neurological sequelae secondary to COVID-19 disease.

Common neurological symptoms during active infection include headache, anosmia, and myalgias. Severe active COVID-19 disease has been associated with viral , hypoxic ischemic encephalopathy, acute cerebrovascular insults, and acute necrotizing hemorrhagic encephalopathy.12,13 Additional post-infectious sequelae have included Guillain-

Barre syndrome and acute disseminated encephalomyelitis. Neurological manifestations in pediatric populations mimic those seen in adult populations but also include febrile seizures, acute flaccid myelitis, and a single pediatric report of ADEM in an adolescent.2,3

ADEM is an autoimmune disorder of the with suspected pathogenesis from activation of the immune system by environmental triggers such as infection in genetically susceptible individuals.14,15 Myelin autoantigens such as myelin basic protein, proteolipid protein, and myelin oligodendrocyte glycoproteins are implicated in the pathogenesis.15 These share antigenic properties with those of an infectious ; this molecular mimicry triggers an autoimmune response leading to demyelination of the central nervous system

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(CNS).14 Antiviral antibodies or a cell-mediated response to these can cross-react with the myelin antigens leading to ADEM.14-16

In North America, the estimated incidence of ADEM is 0.2-0.4 per 100,000 per year in pediatric patients.5,17 ADEM is primarily seen in children, between three to seven years old, and young adults.6,18,19 There is a male to female predominance of 1 to 0.8.7 It is frequently associated with and recent immunization. In 64% to 93% of ADEM cases, a preceding infection was identified.4,5,7,8,20 In adults, COVID-19-associated encephalopathy has been reported in up to

37% of some infected cohorts, but the etiology has varied among toxic-metabolic, seizures, , and potentially direct infection.21

The proposed mechanisms of neuroinvasion include transsynaptic retrograde from peripheral nerve terminals to CNS tissues as in other . SARS-CoV-2 spreads across the blood-brain barrier via ACE2 receptors required for viral cell entry into brain endothelium.22 COVID-19 cases have been exceedingly low in pediatric populations, but cases of serious neurological manifestations have been reported in isolated cases.2,3,23,24 Kim et. al recently proposed that pediatric populations may be less susceptible to neurological complications of SARS-CoV-2 as ACE2 is expressed lowest in younger children.25

Many other causes of encephalopathy can mimic ADEM and a complete evaluation is indicated.26 Encephalopathy has a broad differential diagnosis and commonly results from an infectious agent such as a , , or -borne microorganism.6,26 If the CSF shows nonspecific abnormalities and there is evidence of white matter lesions on MRI, other

Downloaded from©202 www.aappublications.org/news1 American Academy by of guest Pediatrics on September 26, 2021 Prepublication Release inflammatory demyelinating disorders should be considered.17,27 Common demyelinating disorders in children include: (MS), myelin oligodendrocyte glycoprotein

(MOG) antibody-associated disease, neuromyelitis optica spectrum disorder (NMOSD), and clinically isolated (optic neuritis, , brainstem encephalitis).17,27

In pediatric patients, demyelinating disease etiologies can be difficult to stratify as many of the initial presentations overlap amongst disease and syndromes. Among patients initially diagnosed with ADEM, approximately 50% were found to have MOG antibodies; whereas, Aquaporin-4 antibodies traditionally associated with NMOSD are rarer in children.28 MOG antibody-positive spectrum disease is typically monophasic, however, persistent presence of antibodies has been associated with relapsing disease.29,30

Children appropriately diagnosed with ADEM infrequently progress to meet criteria for multiple sclerosis.28,31 At the time of presentation, our patient did not meet revised 2017 McDonald criteria for multiple sclerosis.32 Moreover, the incidence of multiple sclerosis is rare in children younger than 12 years of age.33 At two month follow-up, our patient had returned to baseline with a non-focal neurological exam. We do recognize that her follow-up interval was limited in duration but followed the typical clinical course for ADEM. Additionally, given our patient’s resolution of focal deficits reimaging was deferred to limit exposure to sedation.

Further consideration in the differential diagnosis of ADEM includes other infectious and autoimmune causes. Acute was considered in our patient but thought to be less

Downloaded from©202 www.aappublications.org/news1 American Academy by of guest Pediatrics on September 26, 2021 Prepublication Release likely as she was afebrile on admission. Screening respiratory viral panel and CSF culture was negative. The patient was unlikely to have had active SARS-CoV-2 infection at presentation given the timeline of parental exposure and preceding febrile illness which had resolved.

Furthermore, our patient’s timeframe of exposure, febrile illness with resolution, and hospital presentation are more clinically suggestive of post-infectious ADEM. Other etiologies such as small vessel childhood primary angiitis of the central nervous system, , and hemophagocytic lymphohistiocytosis were considered, but thought less likely given presentation.

Early intervention is crucial for early recovery in patients with ADEM.19,34 First-line therapy for

ADEM is high-dose glucocorticoids for a five day course which can be given concomitantly with and antivirals until infection is ruled out. Other immune therapies include IVIG and plasma exchange should be considered in fulminant disease, steroid-unresponsive cases, or in relapses as second-line therapy. Clinical improvement occurs within days of immunodulating therapy initiation. Many children diagnosed with ADEM have a full recovery. 27,34

Conclusions:

ADEM with typical findings of scattered T2 hyperintensities primarily affecting the deep white matter can potentially occur following COVID-19 infection in toddlers.

Immunomodulatory treatment with high-dose IV methylprednisolone and IVIG was effective in this case with full neurologic recovery noted at 12 weeks, although follow-up duration was limited. Healthcare providers should consider ADEM when evaluating a child with encephalopathy and neurologic deficits after recovering from COVID-19.

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Acknowledgments:

Thank you to the parents who provided consent to include their child in the medical literature.

Additionally, thanks to Dr. Harry Abram for his help with diagnosis and management of this patient.

References:

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13 Katal, S., Balakrishnan, S. & Gholamrezanezhad, A. Neuroimaging and neurologic findings in COVID-19 and other coronavirus infections: A systematic review in 116 patients. J Neuroradiol, doi:10.1016/j.neurad.2020.06.007 (2020). 14 Wingerchuk, D. M. & Lucchinetti, C. F. Comparative immunopathogenesis of acute disseminated encephalomyelitis, neuromyelitis optica, and multiple sclerosis. Curr Opin Neurol 20, 343-350, doi:10.1097/WCO.0b013e3280be58d8 (2007). 15 Wucherpfennig, K. W. & Strominger, J. L. Molecular mimicry in T cell-mediated autoimmunity: viral activate human T cell clones specific for myelin basic protein. Cell 80, 695-705, doi:10.1016/0092-8674(95)90348-8 (1995). 16 Stonehouse, M., Gupte, G., Wassmer, E. & Whitehouse, W. P. Acute disseminated encephalomyelitis: recognition in the hands of general paediatricians. Arch Dis Child 88, 122-124, doi:10.1136/adc.88.2.122 (2003). 17 Banwell, B. et al. Incidence of acquired demyelination of the CNS in Canadian children. Neurology 72, 232-239, doi:10.1212/01.wnl.0000339482.84392.bd (2009). 18 Alper, G. Acute Disseminated Encephalomyelitis. Journal of Child Neurology 27, 1408- 1425, doi:10.1177/0883073812455104 (2012). 19 Anlar, B. et al. Acute disseminated encephalomyelitis in children: outcome and prognosis. Neuropediatrics 34, 194-199, doi:10.1055/s-2003-42208 (2003). 20 Erol, I., Ozkale, Y., Alkan, O. & Alehan, F. Acute disseminated encephalomyelitis in children and adolescents: a single center experience. Pediatric neurology 49, 266-273, doi:10.1016/j.pediatrneurol.2013.03.021 (2013). 21 Mao, L. et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA neurology 77, 683-690 (2020). 22 Zubair, A. S. et al. Neuropathogenesis and Neurologic Manifestations of the Coronaviruses in the Age of Coronavirus Disease 2019: A Review. JAMA Neurology (2020). 23 Abdi, S., Ghorbani, A. & Fatehi, F. The association of SARS-CoV-2 infection and acute disseminated encephalomyelitis without prominent clinical pulmonary symptoms. J Neurol Sci 416, 117001, doi:10.1016/j.jns.2020.117001 (2020). 24 Correia, A. O. et al. Neurological manifestations of COVID-19 and other coronaviruses: A systematic review. Neurol Psychiatry Brain Res 37, 27-32, doi:10.1016/j.npbr.2020.05.008 (2020). 25 Kim, Y. et al. A Comprehensive Review of Neurologic Manifestations of COVID-19 and Management of Pre-existing Neurologic Disorders in Children. Journal of Child Neurology, 0883073820968995 (2020). 26 O'Mahony, J. et al. Masquerades of acquired demyelination in children: experiences of a national demyelinating disease program. J Child Neurol 28, 184-197, doi:10.1177/0883073812443006 (2013). 27 Krupp, L. B. et al. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions. Mult Scler 19, 1261-1267, doi:10.1177/1352458513484547 (2013). 28 Hacohen, Y. et al. Myelin oligodendrocyte glycoprotein antibodies are associated with a non-MS course in children. Neurol Neuroimmunol Neuroinflamm 2, e81-e81, doi:10.1212/NXI.0000000000000081 (2015).

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Figure 1: A) MRI Brain T2 FLAIR axial image demonstrating diffuse hyperintensities in the subcortical white matter. B). MRI Brain T2 axial image demonstrating diffuse patchy T2 hyperintensities. C) MRI Brain T2 Flair coronal image demonstrating hyperintensities in the cortical and subcortical white matter.

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